Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls

Joan C Han; Daniela P Reyes-Capo; Chia-Ying Liu; James C Reynolds; Evrim Turkbey; Ismail Baris Turkbey; Joy Bryant; Jan D Marshall; Jürgen K Naggert; William A Gahl; Jack A Yanovski; Meral Gunay-Aygun

doi:10.1210/jc.2018-00496

Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls

Han, Joan C;Reyes-Capo, Daniela P;Liu, Chia-Ying;Reynolds, James C;Turkbey, Evrim;Turkbey, Ismail Baris;Bryant, Joy;Marshall, Jan D;Naggert, Jürgen K;Gahl, William A;Yanovski, Jack A;Gunay-Aygun, Meral 2018-04-27 00:00:00 Abstract Background Alström syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body–associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements. Objective We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI)–matched controls. Methods We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed. Results Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two-thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps ≤ 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001). Conclusion Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development. Alström syndrome (AS) (Online Mendelian Inheritance in Man # 203800) is a monogenic form of obesity characterized by progressive retinal dystrophy, sensory hearing loss, cardiomyopathy, obesity, childhood-onset type 2 diabetes mellitus (T2DM), hypertriglyceridemia, and progressive hepatic and renal dysfunction in late childhood and adulthood (1). The estimated prevalence of AS is 1 to 10 in 1,000,000 persons (2). It is caused by recessive mutations in ALMS1 (Chr 2q13) (3, 4). Although its function is not completely understood, evidence to date suggests that ALMS1 plays roles in ciliary function, cell cycle regulation, endosomal trafficking, cell migration, and extracellular matrix production (5–7). Approximately 700 cases of AS have been reported worldwide (8) since the disorder was first described in 1959 (9). Chart reviews and family-completed questionnaire-based descriptions of AS have been reported (10–12), yet few encompass systematic single-center phenotyping and none use comparison with a body mass index (BMI)–matched control cohort. To characterize further the endocrine and metabolic complications of AS and to elucidate the pathogenesis of obesity and metabolic dysregulation, we conducted a detailed evaluation of 38 patients with AS and 76 controls to compare body composition, fat distribution [including findings from magnetic resonance spectroscopy (MRS]) of liver and muscle], and endocrine-metabolic parameters. Methods Subjects From February 2013 to June 2014, 38 patients who fulfilled the clinical diagnostic criteria for AS and had ALMS1 mutations from 32 families (Table 1) were evaluated at the National Institutes of Health (NIH) Clinical Center, with a protocol approved by the National Human Genome Research Institute Institutional Review Board (www.clinicaltrials.gov, NCT00068224). Patients were recruited through Alström Syndrome International, a support group for families and health care providers of patients with AS. For metabolic analyses, patients with AS were matched 1:2 with 76 volunteer control subjects by age, sex, race, and BMI. Control subjects with no known genetic disorder were participants of various clinical studies (1997 to 2014; NCT00001195, NCT00001522, NCT00001723, NCT00005669, NCT00006073, NCT00030238, NCT00320177, NCT00758108, NCT01517048) in the Section on Growth and Obesity at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. All metabolic studies for the control subjects were approved by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Institutional Review Board. Written informed consent was obtained from adults and parents or guardians of children and assent from children before participation. Table 1. Genetic Testing Results of Patients With AS Patient # Family # Age, y Sex ALMS1 Mutation 1 c.DNA ALMS1 Mutation 1 Protein ALMS1 Mutation 2 c.DNA ALMS1 Mutation 2 Protein 1 1 2 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 2 1 5 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 3 1 9 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 4 2 3 F c.10483C>T p.Gln3495* c.10483C>T p.Gln3495* 5 3 4 F c.10535G>A p.Trp3512* c.11291G>A p.Ser 3764* 6 4 4 F c.11316_11319delAGAG p.Glu3773Trpfs*18 c.7771_7772insT p.Thr2592Asnfs*3 7 5 5 F c.4156dupA p.Thr1386Asnfs*15 8 6 5 M c.10775delC p.Thr3592Lysfs*6 c.2234C>G p.Ser 745* 9 7 6 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 10 7 13 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 11 8 8 F c.10775delC p.Thr3592Lysfs*6 c.10775delC p.Thr3592Lysfs*6 12 9 9 M c.4156dupA p.Thr1386Asnfs*15 c.4156dupA p.Thr1386Asnfs*15 13 10 10 F c.5145T>G p.Tyr1715* c.3754C>T p.Gln1252* 14 11 11 M c.8352_8355delAGAA p.Glu2785* c.6436C>T p.Arg2146* 15 12 11 F c.9328C>T p.Gln3110* c.10549C>T p.Gln3517* 16 13 12 F c.10539_10557ins(n)19 p.Lys3545Asnfs*18 c.10539_10557ins(n)19 p.Lys3545Asnfs*18 17 14 12 F c.6436C>T p.Arg2146* c.6436C>T p.Arg2146* 18 15 12 F c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 19 15 12 M c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 20 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 21 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 22 17 14 F c.11651_11652insGTTA p.Asn3885Leufs*9 c.9900dupC p.Ser3301Leufs*7 23 18 16 F c.10539_10557ins(n)19 p.His3512fs c.11416C>T p.Arg3806* 24 19 17 F c.6305C>A p.Ser2102* c.10775delC p.Thr3592Lysfs*6 25 20 18 M c.10849G>T p.Glu3617* c.10483C>T p.Gln3495* 26 21 19 M c.10775delC p.Thr3592Lysfs*6 c.3716_3719del p.Ser1240Thrfs*23 27 22 19 F c.4180C>T p.Gln1394* c.4180C>T p.Gln1394* 28 23 21 F c.11314dupA p.Arg3772Trpfs*10 c.10885C>T p.Arg3629* 29 24 21 M c.5311C>T p.Gln1769* c.5311C>T p.Gln1769* 30 25 24 F c.11651_11652insGTTA p.Asn3885LeufsX9 c.4817delA p.Lys1608ArgfsX9 31 26 24 F c.11313_11316delTAGA p.Asp3771Glufs*20 c.2329C>T p.Gln777* 32 27 27 F c.8394_8395insA p.Leu2799Ilefs*4 c.9194T>G p.Leu3065* 33 28 33 M c.1903C>T p.Gln635* c.3579C>G p.Tyr1193* 34 29 34 M c.10849G>T p.Glu3617* c.3019dupA p.Arg1007Lysfs*15 35 30 35 F c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 36 31 36 F c.4039C>T p.Gln1347* c.5145T>G p.Tyr1715* 37 30 37 M c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 38 32 38 M c.7374_7375delAG p.Asp2459* c.7374_7375delAG p.Asp2459* Patient # Family # Age, y Sex ALMS1 Mutation 1 c.DNA ALMS1 Mutation 1 Protein ALMS1 Mutation 2 c.DNA ALMS1 Mutation 2 Protein 1 1 2 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 2 1 5 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 3 1 9 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 4 2 3 F c.10483C>T p.Gln3495* c.10483C>T p.Gln3495* 5 3 4 F c.10535G>A p.Trp3512* c.11291G>A p.Ser 3764* 6 4 4 F c.11316_11319delAGAG p.Glu3773Trpfs*18 c.7771_7772insT p.Thr2592Asnfs*3 7 5 5 F c.4156dupA p.Thr1386Asnfs*15 8 6 5 M c.10775delC p.Thr3592Lysfs*6 c.2234C>G p.Ser 745* 9 7 6 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 10 7 13 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 11 8 8 F c.10775delC p.Thr3592Lysfs*6 c.10775delC p.Thr3592Lysfs*6 12 9 9 M c.4156dupA p.Thr1386Asnfs*15 c.4156dupA p.Thr1386Asnfs*15 13 10 10 F c.5145T>G p.Tyr1715* c.3754C>T p.Gln1252* 14 11 11 M c.8352_8355delAGAA p.Glu2785* c.6436C>T p.Arg2146* 15 12 11 F c.9328C>T p.Gln3110* c.10549C>T p.Gln3517* 16 13 12 F c.10539_10557ins(n)19 p.Lys3545Asnfs*18 c.10539_10557ins(n)19 p.Lys3545Asnfs*18 17 14 12 F c.6436C>T p.Arg2146* c.6436C>T p.Arg2146* 18 15 12 F c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 19 15 12 M c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 20 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 21 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 22 17 14 F c.11651_11652insGTTA p.Asn3885Leufs*9 c.9900dupC p.Ser3301Leufs*7 23 18 16 F c.10539_10557ins(n)19 p.His3512fs c.11416C>T p.Arg3806* 24 19 17 F c.6305C>A p.Ser2102* c.10775delC p.Thr3592Lysfs*6 25 20 18 M c.10849G>T p.Glu3617* c.10483C>T p.Gln3495* 26 21 19 M c.10775delC p.Thr3592Lysfs*6 c.3716_3719del p.Ser1240Thrfs*23 27 22 19 F c.4180C>T p.Gln1394* c.4180C>T p.Gln1394* 28 23 21 F c.11314dupA p.Arg3772Trpfs*10 c.10885C>T p.Arg3629* 29 24 21 M c.5311C>T p.Gln1769* c.5311C>T p.Gln1769* 30 25 24 F c.11651_11652insGTTA p.Asn3885LeufsX9 c.4817delA p.Lys1608ArgfsX9 31 26 24 F c.11313_11316delTAGA p.Asp3771Glufs*20 c.2329C>T p.Gln777* 32 27 27 F c.8394_8395insA p.Leu2799Ilefs*4 c.9194T>G p.Leu3065* 33 28 33 M c.1903C>T p.Gln635* c.3579C>G p.Tyr1193* 34 29 34 M c.10849G>T p.Glu3617* c.3019dupA p.Arg1007Lysfs*15 35 30 35 F c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 36 31 36 F c.4039C>T p.Gln1347* c.5145T>G p.Tyr1715* 37 30 37 M c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 38 32 38 M c.7374_7375delAG p.Asp2459* c.7374_7375delAG p.Asp2459* Abbreviations: F, female; M, male. View Large Table 1. Genetic Testing Results of Patients With AS Patient # Family # Age, y Sex ALMS1 Mutation 1 c.DNA ALMS1 Mutation 1 Protein ALMS1 Mutation 2 c.DNA ALMS1 Mutation 2 Protein 1 1 2 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 2 1 5 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 3 1 9 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 4 2 3 F c.10483C>T p.Gln3495* c.10483C>T p.Gln3495* 5 3 4 F c.10535G>A p.Trp3512* c.11291G>A p.Ser 3764* 6 4 4 F c.11316_11319delAGAG p.Glu3773Trpfs*18 c.7771_7772insT p.Thr2592Asnfs*3 7 5 5 F c.4156dupA p.Thr1386Asnfs*15 8 6 5 M c.10775delC p.Thr3592Lysfs*6 c.2234C>G p.Ser 745* 9 7 6 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 10 7 13 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 11 8 8 F c.10775delC p.Thr3592Lysfs*6 c.10775delC p.Thr3592Lysfs*6 12 9 9 M c.4156dupA p.Thr1386Asnfs*15 c.4156dupA p.Thr1386Asnfs*15 13 10 10 F c.5145T>G p.Tyr1715* c.3754C>T p.Gln1252* 14 11 11 M c.8352_8355delAGAA p.Glu2785* c.6436C>T p.Arg2146* 15 12 11 F c.9328C>T p.Gln3110* c.10549C>T p.Gln3517* 16 13 12 F c.10539_10557ins(n)19 p.Lys3545Asnfs*18 c.10539_10557ins(n)19 p.Lys3545Asnfs*18 17 14 12 F c.6436C>T p.Arg2146* c.6436C>T p.Arg2146* 18 15 12 F c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 19 15 12 M c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 20 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 21 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 22 17 14 F c.11651_11652insGTTA p.Asn3885Leufs*9 c.9900dupC p.Ser3301Leufs*7 23 18 16 F c.10539_10557ins(n)19 p.His3512fs c.11416C>T p.Arg3806* 24 19 17 F c.6305C>A p.Ser2102* c.10775delC p.Thr3592Lysfs*6 25 20 18 M c.10849G>T p.Glu3617* c.10483C>T p.Gln3495* 26 21 19 M c.10775delC p.Thr3592Lysfs*6 c.3716_3719del p.Ser1240Thrfs*23 27 22 19 F c.4180C>T p.Gln1394* c.4180C>T p.Gln1394* 28 23 21 F c.11314dupA p.Arg3772Trpfs*10 c.10885C>T p.Arg3629* 29 24 21 M c.5311C>T p.Gln1769* c.5311C>T p.Gln1769* 30 25 24 F c.11651_11652insGTTA p.Asn3885LeufsX9 c.4817delA p.Lys1608ArgfsX9 31 26 24 F c.11313_11316delTAGA p.Asp3771Glufs*20 c.2329C>T p.Gln777* 32 27 27 F c.8394_8395insA p.Leu2799Ilefs*4 c.9194T>G p.Leu3065* 33 28 33 M c.1903C>T p.Gln635* c.3579C>G p.Tyr1193* 34 29 34 M c.10849G>T p.Glu3617* c.3019dupA p.Arg1007Lysfs*15 35 30 35 F c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 36 31 36 F c.4039C>T p.Gln1347* c.5145T>G p.Tyr1715* 37 30 37 M c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 38 32 38 M c.7374_7375delAG p.Asp2459* c.7374_7375delAG p.Asp2459* Patient # Family # Age, y Sex ALMS1 Mutation 1 c.DNA ALMS1 Mutation 1 Protein ALMS1 Mutation 2 c.DNA ALMS1 Mutation 2 Protein 1 1 2 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 2 1 5 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 3 1 9 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 4 2 3 F c.10483C>T p.Gln3495* c.10483C>T p.Gln3495* 5 3 4 F c.10535G>A p.Trp3512* c.11291G>A p.Ser 3764* 6 4 4 F c.11316_11319delAGAG p.Glu3773Trpfs*18 c.7771_7772insT p.Thr2592Asnfs*3 7 5 5 F c.4156dupA p.Thr1386Asnfs*15 8 6 5 M c.10775delC p.Thr3592Lysfs*6 c.2234C>G p.Ser 745* 9 7 6 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 10 7 13 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 11 8 8 F c.10775delC p.Thr3592Lysfs*6 c.10775delC p.Thr3592Lysfs*6 12 9 9 M c.4156dupA p.Thr1386Asnfs*15 c.4156dupA p.Thr1386Asnfs*15 13 10 10 F c.5145T>G p.Tyr1715* c.3754C>T p.Gln1252* 14 11 11 M c.8352_8355delAGAA p.Glu2785* c.6436C>T p.Arg2146* 15 12 11 F c.9328C>T p.Gln3110* c.10549C>T p.Gln3517* 16 13 12 F c.10539_10557ins(n)19 p.Lys3545Asnfs*18 c.10539_10557ins(n)19 p.Lys3545Asnfs*18 17 14 12 F c.6436C>T p.Arg2146* c.6436C>T p.Arg2146* 18 15 12 F c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 19 15 12 M c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 20 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 21 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 22 17 14 F c.11651_11652insGTTA p.Asn3885Leufs*9 c.9900dupC p.Ser3301Leufs*7 23 18 16 F c.10539_10557ins(n)19 p.His3512fs c.11416C>T p.Arg3806* 24 19 17 F c.6305C>A p.Ser2102* c.10775delC p.Thr3592Lysfs*6 25 20 18 M c.10849G>T p.Glu3617* c.10483C>T p.Gln3495* 26 21 19 M c.10775delC p.Thr3592Lysfs*6 c.3716_3719del p.Ser1240Thrfs*23 27 22 19 F c.4180C>T p.Gln1394* c.4180C>T p.Gln1394* 28 23 21 F c.11314dupA p.Arg3772Trpfs*10 c.10885C>T p.Arg3629* 29 24 21 M c.5311C>T p.Gln1769* c.5311C>T p.Gln1769* 30 25 24 F c.11651_11652insGTTA p.Asn3885LeufsX9 c.4817delA p.Lys1608ArgfsX9 31 26 24 F c.11313_11316delTAGA p.Asp3771Glufs*20 c.2329C>T p.Gln777* 32 27 27 F c.8394_8395insA p.Leu2799Ilefs*4 c.9194T>G p.Leu3065* 33 28 33 M c.1903C>T p.Gln635* c.3579C>G p.Tyr1193* 34 29 34 M c.10849G>T p.Glu3617* c.3019dupA p.Arg1007Lysfs*15 35 30 35 F c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 36 31 36 F c.4039C>T p.Gln1347* c.5145T>G p.Tyr1715* 37 30 37 M c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 38 32 38 M c.7374_7375delAG p.Asp2459* c.7374_7375delAG p.Asp2459* Abbreviations: F, female; M, male. View Large Genetic testing All patients with AS had prior genetic testing via Sanger sequencing, microarray-based arrayed primer extension, or targeted gene sequencing and custom analysis test as previously described (13). Clinical and laboratory assessments Physical examination and fasting venous blood sample All AS and control subjects were evaluated at the NIH Clinical Research Center. Participants underwent physical examination (by J.C.H. or M.G.-A.) and venous blood draw after 12-hour fast. Glucose, insulin, C-peptide, free fatty acids (FFAs), glucagon, triglycerides, high-density lipoprotein (HDL) cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase, IGF-1 (measured by chemiluminescence immunoassay), TSH, free T4, T3, prolactin, cortisol, ACTH (measured by chemiluminescence immunoassay), calcium, phosphorus, 25-hydroxyvitamin D (25OHD), 1,25-hydroxyvitamin D, LH, FSH, HbA1c (measured by HPLC), and creatinine concentrations were measured by the NIH Department of Laboratory Medicine. Testosterone and estradiol were measured by HPLC tandem mass spectrometry at Mayo Medical Laboratories (Rochester, MN). Mixed meal test A mixed meal test (MMT) was performed in 25 participants with AS and 26 control participants, who ingested a standard breakfast shake consisting of Boost® High Protein (Nestlé HealthCare Nutrition, Inc., Highland Park, MI; 55% carbohydrate, 24% protein, and 21% fat), 7 mL/kg (maximum 400 mL) over 5 minutes (14). Blood samples were drawn from an intravenous catheter at −10, 0, 15, 30, 60, 90, 120, 150, and 180 minutes after consumption of the shake for measurement of glucose, insulin, C-peptide, FFA, and glucagon concentrations. Body composition Height was measured in triplicate to the nearest 0.1 cm with a stadiometer. Weight was measured with an electronic digital scale to the nearest 0.1 kg. Waist circumference measurements at the iliac crest were obtained in triplicate by a registered dietitian. Total percentage body fat was measured by dual-energy X-ray absorptiometry with the Hologic QDR-4500A or Hologic Discovery A (Hologic, Waltham, MA). Visceral and subcutaneous fat volumes at L2–3 and L4–5 were measured by abdominal MRI, and fat contents of liver and right lateral midthigh quadriceps muscle were assessed by MRS with the Philips Achieva 3.0T TX (Amsterdam, Netherlands). The percentage abdominal visceral fat was calculated as the total volume of visceral fat divided by the total volume of subcutaneous and visceral fat combined for the L2–3 and L4–5 slices. Energy intake and expenditure A hyperphagia questionnaire (15) was administered to the parents and caregivers of subjects age ≤18 years regarding their observations of the subjects in their usual home environment. Resting energy expenditure (REE) was assessed by indirect calorimetry (TrueOne® 2400 Canopy System; Parvo Medics, Sandy, UT or VmaxTM Encore Metabolic Cart; Viasys, Conshohocken, PA). Predicted REE was calculated with the Mifflin-St. Jeor equation (16). Calculations and definitions BMI z scores were calculated according to the age- and sex-specific Centers for Disease Control and Prevention 2000 standards for age ≥2 years (17) and World Health Organization 2006 standards for age <2 years (18). Obesity was defined as a BMI ≥30 kg/m2 in adults or ≥95th percentile for age and sex in children. For the metabolic analyses, metabolic syndrome (MS) was defined as having three or more of the following (19): abdominal obesity [waist circumference >102 cm in men or >88 cm in women, or >90th percentile for age and sex (20)], hypertriglyceridemia [triglycerides >150 mg/dL or >90th percentile for age and sex (21)], low HDL-cholesterol [HDL-cholesterol <40 mg/dL for men, <50 mg/dL for women, or <10th percentile for age and sex (21)], elevated blood pressure [BP; systolic or diastolic BP >120/80 or >90th percentile adjusted for height, age, and sex (22)], impaired glucose tolerance (HbA1c ≥5.7%, fasting glucose ≥100 mg/dL, or 2-hour mixed meal glucose ≥140 mg/dL). Estimated glomerular filtration rate (eGFR) was calculated with the bedside Schwartz equation in children (23) and the Chronic Kidney Disease Epidemiology Collaboration equation in adults (24). Homeostatic model assessment of insulin resistance was calculated by the following equation: [Fasting insulin (μIU/mL) × fasting glucose (mg/dL)/405] (25). Insulin sensitivity during the MMT was assessed through the whole-body insulin sensitivity index (WBISI) with the following equation: 10,000/√[fasting glucose (mg/dL) × fasting insulin (μIU/mL) × mean glucose (mg/dL) × mean insulin (μIU/mL)] (26). Statistical analyses SPSS 22 (IBM Corp., Armonk, NY) was used for statistical analyses. Normality was assessed by skewness, kurtosis, and Kolmogorov-Smirnov test. Fisher’s exact (for binary) and χ2 (for three or more categories) tests compared categorical variables between groups. Independent-samples t tests and Pearson correlations were performed for continuous variables of normal distribution and skewed data that were normalized after log or arcsine square root transformation. Nonparametric data were analyzed by Mann-Whitney U tests. Analyses of covariance (ANCOVAs) compared variables between groups, adjusting for age, sex, race, and body composition. A P value <0.001 (0.05/50) was considered significant after Bonferroni correction for multiple comparisons. Nominal P values are shown. Results Genetic testing results for patients with AS The cohort included 32 families, with 5 families having multiple siblings with AS. Mutations in both alleles of ALMS1 were identified in 31 families, and in 1 family, only one (heterozygous) mutation was identified (Table 1). All mutations are predicted to result in premature protein truncation. Endocrine function in AS The 38 patients with AS (age 2 to 38 years), who had a high rate of obesity (76.3%), were compared with a group of 76 control subjects (age 2 to 48 years), whose selection was purposely enriched for obesity to match the high prevalence of obesity in patients with AS. Controls had comparable age, sex, race, and BMI z scores (Table 2). Despite their similar mean BMI z score, the AS group had 14 (36.8%) patients with T2DM compared with none in the control group (P < 0.0000001). Six of the 14 patients with AS with T2DM were obese, 7 were overweight, and 1 was normal weight. Representative photographs of an overweight but nonobese patient with AS who had severe acanthosis nigricans, extreme insulin resistance, and T2DM necessitating 7 units/kg/d of insulin are shown in Supplemental Fig. 1. Table 2. Characteristics of Patients With AS and Control Subjects n Alström n Control P Age, y 38 16.0 ± 10.5 76 16.2 ± 9.8 0.96 Sex, % female 38 52.6 76 52.6 1.00 Race, % African American 38 7.9 76 21.1 0.11 BMI, kg/m2 38 29.9 ± 10.6 76 29.6 ± 7.6 0.88 BMI z score 38 2.07 ± 0.93 76 1.91 ± 0.94 0.41 Height z score 38 −0.51 ± 1.20 76 0.52 ± 1.21 0.00004 Arm span/height ratio 21 1.00 ± 0.03 26 0.99 ± 0.13 0.85 Sitting/standing ratio 17 0.57 ± 0.09 16 0.55 ± 0.07 0.38 IGF-1, ng/mL 37 143 (96–309) 54 318 (203–463) 0.001 TSH, μU/mL 38 2.52 ± 1.52 66 2.07 ± 1.05 0.11 Free T4, ng/dL 38 1.0 ± 0.2 64 1.1 ± 0.2 0.002 T3, ng/dL 35 137 ± 33 36 148 ± 37 0.20 Morning cortisol, μg/dL 35 10.9 ± 5.2 40 10.0 ± 5.0 0.49 Morning ACTH, pg/mL 35 17.7 (14.6–27.9) 18 16.2 (9.1–24.5) 0.13 25OHD, ng/mL 35 33.2 ± 14.3 45 24.7 ± 9.2 0.004 1,25OHD, pg/mL 37 45.8 ± 19.3 19 47.7 ± 8.6 0.61 PTH, pg/mL 36 31.1 ± 14.6 23 42.1 ± 18.9 0.01 Calcium, mg/dL 38 9.5 ± 0.4 65 9.3 ± 0.4 0.04 Phosphorus, mg/dL 38 4.7 ± 0.8 52 4.3 ± 0.7 0.01 Prolactin, μg/L 33 6.9 (4.3–11.1) 39 6.5 (5.0–11.1) 0.58 Total body fat, % 30 34.8 ± 7.8 61 35.4 ± 9.1 0.89 Lean mass, kg 30 40.8 ± 14.0 61 49.7 ± 15.5 0.009 Bone mineral content, kg 30 1.8 ± 0.6 61 2.1 ± 0.6 0.02 Abdominal visceral fat, % 26 18.8 ± 8.1 34 21.5 ± 9.7 0.26 Waist circumference z score 31 1.05 ± 1.06 31 0.78 ± 1.00 0.30 REE, kcal/day 35 1389 ± 372 21 1638 ± 374 0.02 REE, % predicted 35 98.9 ± 17.7 21 98.1 ± 14.8 0.87 RQ 35 0.92 ± 0.09 21 0.84 ± 0.05 0.0006 Hyperphagia score 23 27 ± 13 27 17 ± 7 0.003 Systolic BP z score 36 1.08 ± 1.11 71 0.70 ± 1.22 0.12 Diastolic BP z score 36 0.29 ± 0.87 71 0.14 ± 0.67 0.33 Fasting triglycerides, mg/dL 38 123 (82–202) 74 79 (57–129) 0.000001 LDL-cholesterol, mg/dL 30 81 (66–100) 75 100 (83–115) 0.007 HDL-cholesterol, mg/dL 37 34 (29–43) 74 42 (36–53) 0.000002 ALT, U/L 38 51 ± 33 72 29 ± 14 0.00001 AST, U/L 38 37 ± 23 72 24 ± 9 0.0006 Liver fat, % 25 14.6 ± 10.7 27 4.9 ± 3.7 0.0002 Muscle fat, % 23 5.8 ± 3.5 11 3.6 ± 1.6 0.04 Fasting glucose, mg/dL 38 87 (82–110) 76 89 (84–92) 0.94 Fasting C-peptide, ng/mL 37 5.4 (2.5–9.8) 43 2.0 (1.5–3.3) 0.000003 Fasting insulin, mIU/L 38 42.3 (11.7–78.5) 72 10.5 (6.0–18.9) 0.000002 Fasting FFA, mEq/L 35 0.54 (0.43–0.76) 60 0.61 (0.47–0.98) 0.30 Fasting glucagon, pg/mL 33 31.0 (24.6–57.8) 26 27.3 (20.5–32.3) 0.048 HOMA-IR 38 9.88 (2.34–18.1) 71 2.34 (1.16–4.28) 0.000002 WBISI 25 1.07 ± 1.41 26 6.95 ± 4.94 0.000003 Mixed meal glucose AUC 25 29.7 ± 14.3 × 103 26 17.9 ± 1.5 × 103 0.0004 Mixed meal C-peptide AUC 25 3.7 ± 1.8 × 103 26 1.1 ± 0.4 × 103 0.0000002 Mixed meal insulin AUC 23 59.4 ± 38.3 × 103 26 9.8 ± 4.6 × 103 0.000003 Mixed meal FFA AUC 22 72.6 ± 30.4 24 55.6 ± 23.9 0.04 Mixed meal glucagon AUC 20 13.8 ± 11.3× 103 24 6.9 ± 3.4 × 103 0.016 HbA1c, % 36 5.4 (5.1–6.1) 60 5.2 (5.0–5.6) 0.005 Serum creatinine, mg/dL 38 0.63 (0.48–0.77) 73 0.62 (0.40–0.95) 0.24 eGFR, mL/min/1.73 m2 38 104 ± 37 73 112 ± 21 0.66 n Alström n Control P Age, y 38 16.0 ± 10.5 76 16.2 ± 9.8 0.96 Sex, % female 38 52.6 76 52.6 1.00 Race, % African American 38 7.9 76 21.1 0.11 BMI, kg/m2 38 29.9 ± 10.6 76 29.6 ± 7.6 0.88 BMI z score 38 2.07 ± 0.93 76 1.91 ± 0.94 0.41 Height z score 38 −0.51 ± 1.20 76 0.52 ± 1.21 0.00004 Arm span/height ratio 21 1.00 ± 0.03 26 0.99 ± 0.13 0.85 Sitting/standing ratio 17 0.57 ± 0.09 16 0.55 ± 0.07 0.38 IGF-1, ng/mL 37 143 (96–309) 54 318 (203–463) 0.001 TSH, μU/mL 38 2.52 ± 1.52 66 2.07 ± 1.05 0.11 Free T4, ng/dL 38 1.0 ± 0.2 64 1.1 ± 0.2 0.002 T3, ng/dL 35 137 ± 33 36 148 ± 37 0.20 Morning cortisol, μg/dL 35 10.9 ± 5.2 40 10.0 ± 5.0 0.49 Morning ACTH, pg/mL 35 17.7 (14.6–27.9) 18 16.2 (9.1–24.5) 0.13 25OHD, ng/mL 35 33.2 ± 14.3 45 24.7 ± 9.2 0.004 1,25OHD, pg/mL 37 45.8 ± 19.3 19 47.7 ± 8.6 0.61 PTH, pg/mL 36 31.1 ± 14.6 23 42.1 ± 18.9 0.01 Calcium, mg/dL 38 9.5 ± 0.4 65 9.3 ± 0.4 0.04 Phosphorus, mg/dL 38 4.7 ± 0.8 52 4.3 ± 0.7 0.01 Prolactin, μg/L 33 6.9 (4.3–11.1) 39 6.5 (5.0–11.1) 0.58 Total body fat, % 30 34.8 ± 7.8 61 35.4 ± 9.1 0.89 Lean mass, kg 30 40.8 ± 14.0 61 49.7 ± 15.5 0.009 Bone mineral content, kg 30 1.8 ± 0.6 61 2.1 ± 0.6 0.02 Abdominal visceral fat, % 26 18.8 ± 8.1 34 21.5 ± 9.7 0.26 Waist circumference z score 31 1.05 ± 1.06 31 0.78 ± 1.00 0.30 REE, kcal/day 35 1389 ± 372 21 1638 ± 374 0.02 REE, % predicted 35 98.9 ± 17.7 21 98.1 ± 14.8 0.87 RQ 35 0.92 ± 0.09 21 0.84 ± 0.05 0.0006 Hyperphagia score 23 27 ± 13 27 17 ± 7 0.003 Systolic BP z score 36 1.08 ± 1.11 71 0.70 ± 1.22 0.12 Diastolic BP z score 36 0.29 ± 0.87 71 0.14 ± 0.67 0.33 Fasting triglycerides, mg/dL 38 123 (82–202) 74 79 (57–129) 0.000001 LDL-cholesterol, mg/dL 30 81 (66–100) 75 100 (83–115) 0.007 HDL-cholesterol, mg/dL 37 34 (29–43) 74 42 (36–53) 0.000002 ALT, U/L 38 51 ± 33 72 29 ± 14 0.00001 AST, U/L 38 37 ± 23 72 24 ± 9 0.0006 Liver fat, % 25 14.6 ± 10.7 27 4.9 ± 3.7 0.0002 Muscle fat, % 23 5.8 ± 3.5 11 3.6 ± 1.6 0.04 Fasting glucose, mg/dL 38 87 (82–110) 76 89 (84–92) 0.94 Fasting C-peptide, ng/mL 37 5.4 (2.5–9.8) 43 2.0 (1.5–3.3) 0.000003 Fasting insulin, mIU/L 38 42.3 (11.7–78.5) 72 10.5 (6.0–18.9) 0.000002 Fasting FFA, mEq/L 35 0.54 (0.43–0.76) 60 0.61 (0.47–0.98) 0.30 Fasting glucagon, pg/mL 33 31.0 (24.6–57.8) 26 27.3 (20.5–32.3) 0.048 HOMA-IR 38 9.88 (2.34–18.1) 71 2.34 (1.16–4.28) 0.000002 WBISI 25 1.07 ± 1.41 26 6.95 ± 4.94 0.000003 Mixed meal glucose AUC 25 29.7 ± 14.3 × 103 26 17.9 ± 1.5 × 103 0.0004 Mixed meal C-peptide AUC 25 3.7 ± 1.8 × 103 26 1.1 ± 0.4 × 103 0.0000002 Mixed meal insulin AUC 23 59.4 ± 38.3 × 103 26 9.8 ± 4.6 × 103 0.000003 Mixed meal FFA AUC 22 72.6 ± 30.4 24 55.6 ± 23.9 0.04 Mixed meal glucagon AUC 20 13.8 ± 11.3× 103 24 6.9 ± 3.4 × 103 0.016 HbA1c, % 36 5.4 (5.1–6.1) 60 5.2 (5.0–5.6) 0.005 Serum creatinine, mg/dL 38 0.63 (0.48–0.77) 73 0.62 (0.40–0.95) 0.24 eGFR, mL/min/1.73 m2 38 104 ± 37 73 112 ± 21 0.66 Data are shown as mean ± SD for normally distributed values, median (interquartile range) for non–normally distributed values, or percentage. P values in bold indicate significance after correction for multiple comparisons. Abbreviations: 1,25OHD, 1,25-hydroxyvitamin D; AST, aspartate aminotransferase; HOMA-IR, homeostatic model assessment of insulin resistance; RQ, respiratory quotient. View Large Table 2. Characteristics of Patients With AS and Control Subjects n Alström n Control P Age, y 38 16.0 ± 10.5 76 16.2 ± 9.8 0.96 Sex, % female 38 52.6 76 52.6 1.00 Race, % African American 38 7.9 76 21.1 0.11 BMI, kg/m2 38 29.9 ± 10.6 76 29.6 ± 7.6 0.88 BMI z score 38 2.07 ± 0.93 76 1.91 ± 0.94 0.41 Height z score 38 −0.51 ± 1.20 76 0.52 ± 1.21 0.00004 Arm span/height ratio 21 1.00 ± 0.03 26 0.99 ± 0.13 0.85 Sitting/standing ratio 17 0.57 ± 0.09 16 0.55 ± 0.07 0.38 IGF-1, ng/mL 37 143 (96–309) 54 318 (203–463) 0.001 TSH, μU/mL 38 2.52 ± 1.52 66 2.07 ± 1.05 0.11 Free T4, ng/dL 38 1.0 ± 0.2 64 1.1 ± 0.2 0.002 T3, ng/dL 35 137 ± 33 36 148 ± 37 0.20 Morning cortisol, μg/dL 35 10.9 ± 5.2 40 10.0 ± 5.0 0.49 Morning ACTH, pg/mL 35 17.7 (14.6–27.9) 18 16.2 (9.1–24.5) 0.13 25OHD, ng/mL 35 33.2 ± 14.3 45 24.7 ± 9.2 0.004 1,25OHD, pg/mL 37 45.8 ± 19.3 19 47.7 ± 8.6 0.61 PTH, pg/mL 36 31.1 ± 14.6 23 42.1 ± 18.9 0.01 Calcium, mg/dL 38 9.5 ± 0.4 65 9.3 ± 0.4 0.04 Phosphorus, mg/dL 38 4.7 ± 0.8 52 4.3 ± 0.7 0.01 Prolactin, μg/L 33 6.9 (4.3–11.1) 39 6.5 (5.0–11.1) 0.58 Total body fat, % 30 34.8 ± 7.8 61 35.4 ± 9.1 0.89 Lean mass, kg 30 40.8 ± 14.0 61 49.7 ± 15.5 0.009 Bone mineral content, kg 30 1.8 ± 0.6 61 2.1 ± 0.6 0.02 Abdominal visceral fat, % 26 18.8 ± 8.1 34 21.5 ± 9.7 0.26 Waist circumference z score 31 1.05 ± 1.06 31 0.78 ± 1.00 0.30 REE, kcal/day 35 1389 ± 372 21 1638 ± 374 0.02 REE, % predicted 35 98.9 ± 17.7 21 98.1 ± 14.8 0.87 RQ 35 0.92 ± 0.09 21 0.84 ± 0.05 0.0006 Hyperphagia score 23 27 ± 13 27 17 ± 7 0.003 Systolic BP z score 36 1.08 ± 1.11 71 0.70 ± 1.22 0.12 Diastolic BP z score 36 0.29 ± 0.87 71 0.14 ± 0.67 0.33 Fasting triglycerides, mg/dL 38 123 (82–202) 74 79 (57–129) 0.000001 LDL-cholesterol, mg/dL 30 81 (66–100) 75 100 (83–115) 0.007 HDL-cholesterol, mg/dL 37 34 (29–43) 74 42 (36–53) 0.000002 ALT, U/L 38 51 ± 33 72 29 ± 14 0.00001 AST, U/L 38 37 ± 23 72 24 ± 9 0.0006 Liver fat, % 25 14.6 ± 10.7 27 4.9 ± 3.7 0.0002 Muscle fat, % 23 5.8 ± 3.5 11 3.6 ± 1.6 0.04 Fasting glucose, mg/dL 38 87 (82–110) 76 89 (84–92) 0.94 Fasting C-peptide, ng/mL 37 5.4 (2.5–9.8) 43 2.0 (1.5–3.3) 0.000003 Fasting insulin, mIU/L 38 42.3 (11.7–78.5) 72 10.5 (6.0–18.9) 0.000002 Fasting FFA, mEq/L 35 0.54 (0.43–0.76) 60 0.61 (0.47–0.98) 0.30 Fasting glucagon, pg/mL 33 31.0 (24.6–57.8) 26 27.3 (20.5–32.3) 0.048 HOMA-IR 38 9.88 (2.34–18.1) 71 2.34 (1.16–4.28) 0.000002 WBISI 25 1.07 ± 1.41 26 6.95 ± 4.94 0.000003 Mixed meal glucose AUC 25 29.7 ± 14.3 × 103 26 17.9 ± 1.5 × 103 0.0004 Mixed meal C-peptide AUC 25 3.7 ± 1.8 × 103 26 1.1 ± 0.4 × 103 0.0000002 Mixed meal insulin AUC 23 59.4 ± 38.3 × 103 26 9.8 ± 4.6 × 103 0.000003 Mixed meal FFA AUC 22 72.6 ± 30.4 24 55.6 ± 23.9 0.04 Mixed meal glucagon AUC 20 13.8 ± 11.3× 103 24 6.9 ± 3.4 × 103 0.016 HbA1c, % 36 5.4 (5.1–6.1) 60 5.2 (5.0–5.6) 0.005 Serum creatinine, mg/dL 38 0.63 (0.48–0.77) 73 0.62 (0.40–0.95) 0.24 eGFR, mL/min/1.73 m2 38 104 ± 37 73 112 ± 21 0.66 n Alström n Control P Age, y 38 16.0 ± 10.5 76 16.2 ± 9.8 0.96 Sex, % female 38 52.6 76 52.6 1.00 Race, % African American 38 7.9 76 21.1 0.11 BMI, kg/m2 38 29.9 ± 10.6 76 29.6 ± 7.6 0.88 BMI z score 38 2.07 ± 0.93 76 1.91 ± 0.94 0.41 Height z score 38 −0.51 ± 1.20 76 0.52 ± 1.21 0.00004 Arm span/height ratio 21 1.00 ± 0.03 26 0.99 ± 0.13 0.85 Sitting/standing ratio 17 0.57 ± 0.09 16 0.55 ± 0.07 0.38 IGF-1, ng/mL 37 143 (96–309) 54 318 (203–463) 0.001 TSH, μU/mL 38 2.52 ± 1.52 66 2.07 ± 1.05 0.11 Free T4, ng/dL 38 1.0 ± 0.2 64 1.1 ± 0.2 0.002 T3, ng/dL 35 137 ± 33 36 148 ± 37 0.20 Morning cortisol, μg/dL 35 10.9 ± 5.2 40 10.0 ± 5.0 0.49 Morning ACTH, pg/mL 35 17.7 (14.6–27.9) 18 16.2 (9.1–24.5) 0.13 25OHD, ng/mL 35 33.2 ± 14.3 45 24.7 ± 9.2 0.004 1,25OHD, pg/mL 37 45.8 ± 19.3 19 47.7 ± 8.6 0.61 PTH, pg/mL 36 31.1 ± 14.6 23 42.1 ± 18.9 0.01 Calcium, mg/dL 38 9.5 ± 0.4 65 9.3 ± 0.4 0.04 Phosphorus, mg/dL 38 4.7 ± 0.8 52 4.3 ± 0.7 0.01 Prolactin, μg/L 33 6.9 (4.3–11.1) 39 6.5 (5.0–11.1) 0.58 Total body fat, % 30 34.8 ± 7.8 61 35.4 ± 9.1 0.89 Lean mass, kg 30 40.8 ± 14.0 61 49.7 ± 15.5 0.009 Bone mineral content, kg 30 1.8 ± 0.6 61 2.1 ± 0.6 0.02 Abdominal visceral fat, % 26 18.8 ± 8.1 34 21.5 ± 9.7 0.26 Waist circumference z score 31 1.05 ± 1.06 31 0.78 ± 1.00 0.30 REE, kcal/day 35 1389 ± 372 21 1638 ± 374 0.02 REE, % predicted 35 98.9 ± 17.7 21 98.1 ± 14.8 0.87 RQ 35 0.92 ± 0.09 21 0.84 ± 0.05 0.0006 Hyperphagia score 23 27 ± 13 27 17 ± 7 0.003 Systolic BP z score 36 1.08 ± 1.11 71 0.70 ± 1.22 0.12 Diastolic BP z score 36 0.29 ± 0.87 71 0.14 ± 0.67 0.33 Fasting triglycerides, mg/dL 38 123 (82–202) 74 79 (57–129) 0.000001 LDL-cholesterol, mg/dL 30 81 (66–100) 75 100 (83–115) 0.007 HDL-cholesterol, mg/dL 37 34 (29–43) 74 42 (36–53) 0.000002 ALT, U/L 38 51 ± 33 72 29 ± 14 0.00001 AST, U/L 38 37 ± 23 72 24 ± 9 0.0006 Liver fat, % 25 14.6 ± 10.7 27 4.9 ± 3.7 0.0002 Muscle fat, % 23 5.8 ± 3.5 11 3.6 ± 1.6 0.04 Fasting glucose, mg/dL 38 87 (82–110) 76 89 (84–92) 0.94 Fasting C-peptide, ng/mL 37 5.4 (2.5–9.8) 43 2.0 (1.5–3.3) 0.000003 Fasting insulin, mIU/L 38 42.3 (11.7–78.5) 72 10.5 (6.0–18.9) 0.000002 Fasting FFA, mEq/L 35 0.54 (0.43–0.76) 60 0.61 (0.47–0.98) 0.30 Fasting glucagon, pg/mL 33 31.0 (24.6–57.8) 26 27.3 (20.5–32.3) 0.048 HOMA-IR 38 9.88 (2.34–18.1) 71 2.34 (1.16–4.28) 0.000002 WBISI 25 1.07 ± 1.41 26 6.95 ± 4.94 0.000003 Mixed meal glucose AUC 25 29.7 ± 14.3 × 103 26 17.9 ± 1.5 × 103 0.0004 Mixed meal C-peptide AUC 25 3.7 ± 1.8 × 103 26 1.1 ± 0.4 × 103 0.0000002 Mixed meal insulin AUC 23 59.4 ± 38.3 × 103 26 9.8 ± 4.6 × 103 0.000003 Mixed meal FFA AUC 22 72.6 ± 30.4 24 55.6 ± 23.9 0.04 Mixed meal glucagon AUC 20 13.8 ± 11.3× 103 24 6.9 ± 3.4 × 103 0.016 HbA1c, % 36 5.4 (5.1–6.1) 60 5.2 (5.0–5.6) 0.005 Serum creatinine, mg/dL 38 0.63 (0.48–0.77) 73 0.62 (0.40–0.95) 0.24 eGFR, mL/min/1.73 m2 38 104 ± 37 73 112 ± 21 0.66 Data are shown as mean ± SD for normally distributed values, median (interquartile range) for non–normally distributed values, or percentage. P values in bold indicate significance after correction for multiple comparisons. Abbreviations: 1,25OHD, 1,25-hydroxyvitamin D; AST, aspartate aminotransferase; HOMA-IR, homeostatic model assessment of insulin resistance; RQ, respiratory quotient. View Large Height z score was significantly lower in patients with AS compared with controls (P = 0.00004, Table 2). Patients with AS and controls had similar arm span/height ratios (P = 0.85, Table 2) and sitting/standing height ratios (P = 0.38, Table 2). IGF-1 was nominally lower in patients with AS compared with controls (P = 0.001). Hypothyroidism was observed in 11 patients with AS, 28.9% of the cohort. Four patients were diagnosed with central hypothyroidism: two patients had midnormal free T4 but suppressed TSH while taking levothyroxine for a previous diagnosis of central hypothyroidism; two other patients had low free T4 and normal TSH (diurnal pattern abnormal for one and not tested for the other). Two patients with AS had evidence of autoimmune primary hypothyroidism (low free T4, elevated TSH, and positive antithyroid antibodies), and five patients with a previous diagnosis of hypothyroidism appeared to have antibody-negative primary hypothyroidism, with normal free T4, normal TSH, and negative antibodies while they were taking appropriate replacement doses of levothyroxine. In contrast, none of the control subjects had a previous diagnosis of hypothyroidism, and of the 66 control subjects who had thyroid function test results available, only 2 had elevated TSH values and none had low free T4. Mean TSH and T3 were similar between groups, but free T4 was nominally lower for AS (P = 0.002, Table 2). Morning cortisol (P = 0.49) and morning ACTH (P = 0.13) were similar between groups (Table 2). One patient with AS had a previous diagnosis of central adrenal insufficiency (2.6%, Table 3); no additional patients were diagnosed with adrenal insufficiency at evaluation. None (0%) of 29 patients with AS who had 24-hour urinary free cortisol measured had values above the reference range for age, compared with 3 (12%, P = 0.09) of 25 in the control group with urinary cortisol measured who had values above reference range for age, but none were greater than two times the upper limits of normal. Table 3. Endocrine Abnormalities in Patients With AS % (n) AS (n = 38) Obesity 76.3 (29) T2DM 36.8 (14) Hypothyroidism 28.9 (11) Short stature 10.5 (4) Adrenal insufficiency 2.6 (1) Hypogonadism in adulthood (n = 14) 57.1 (8) Male patients (n = 18) Microphallus 50.0 (9) Undescended testes 11.1 (2) Hypospadias 5.6 (1) Small testes in adulthood (n = 7) 100.0 (7) Low testosterone in adulthood (n = 7) 42.9 (3) Female patients (n = 20) Oligomenorrhea or amenorrhea in adulthood (n = 7) 71.4 (5) Alopecia 40.0 (8) High testosterone 25.0 (5) Hirsutism 15.0 (3) % (n) AS (n = 38) Obesity 76.3 (29) T2DM 36.8 (14) Hypothyroidism 28.9 (11) Short stature 10.5 (4) Adrenal insufficiency 2.6 (1) Hypogonadism in adulthood (n = 14) 57.1 (8) Male patients (n = 18) Microphallus 50.0 (9) Undescended testes 11.1 (2) Hypospadias 5.6 (1) Small testes in adulthood (n = 7) 100.0 (7) Low testosterone in adulthood (n = 7) 42.9 (3) Female patients (n = 20) Oligomenorrhea or amenorrhea in adulthood (n = 7) 71.4 (5) Alopecia 40.0 (8) High testosterone 25.0 (5) Hirsutism 15.0 (3) View Large Table 3. Endocrine Abnormalities in Patients With AS % (n) AS (n = 38) Obesity 76.3 (29) T2DM 36.8 (14) Hypothyroidism 28.9 (11) Short stature 10.5 (4) Adrenal insufficiency 2.6 (1) Hypogonadism in adulthood (n = 14) 57.1 (8) Male patients (n = 18) Microphallus 50.0 (9) Undescended testes 11.1 (2) Hypospadias 5.6 (1) Small testes in adulthood (n = 7) 100.0 (7) Low testosterone in adulthood (n = 7) 42.9 (3) Female patients (n = 20) Oligomenorrhea or amenorrhea in adulthood (n = 7) 71.4 (5) Alopecia 40.0 (8) High testosterone 25.0 (5) Hirsutism 15.0 (3) % (n) AS (n = 38) Obesity 76.3 (29) T2DM 36.8 (14) Hypothyroidism 28.9 (11) Short stature 10.5 (4) Adrenal insufficiency 2.6 (1) Hypogonadism in adulthood (n = 14) 57.1 (8) Male patients (n = 18) Microphallus 50.0 (9) Undescended testes 11.1 (2) Hypospadias 5.6 (1) Small testes in adulthood (n = 7) 100.0 (7) Low testosterone in adulthood (n = 7) 42.9 (3) Female patients (n = 20) Oligomenorrhea or amenorrhea in adulthood (n = 7) 71.4 (5) Alopecia 40.0 (8) High testosterone 25.0 (5) Hirsutism 15.0 (3) View Large Serum calcium (P = 0.04), phosphorus (P = 0.01), and 25OHD (P = 0.004) were nominally higher, whereas plasma PTH (P = 0.01) was nominally lower and 1,25-hydroxyvitamin D (P = 0.61) was similar in patients with AS compared with control subjects (Table 2). A higher percentage of patients with AS were prescribed vitamin D supplementation (55.3% in AS vs 15.8% in controls, P < 0.0001). After adjustment for age, sex, race, and BMI z score, 25OHD remained nominally higher in patients with AS (P = 0.009). In ANCOVAs adjusted for 25OHD, the difference in PTH was attenuated (P = 0.05). Prolactin was normal for all participants with AS and similar between groups (P = 0.58, Table 2). Hypogonadism was observed in 57.1% of adults with AS (35.7% primary gonadal insufficiency with elevated gonadotropins; 21.4% central gonadotropin insufficiency with nonelevated or suppressed LH and FSH) but only in 6.7% of control adults (P = 0.005). Sex steroid–associated abnormalities in male patients with AS included microphallus (50%), undescended testes (11.1%), hypospadias (5.6%), small testes in adulthood (100%), and low testosterone in adulthood (42.9%) (Table 3). Female patients with AS frequently had alopecia (40%, Supplemental Fig. 2), elevated testosterone (25%), hirsutism (15%, Supplemental Fig. 2), and oligomenorrhea or amenorrhea in adulthood (85.7%) (Table 3). Testosterone was nominally higher in female patients with AS compared with controls (51 ± 39 vs 26 ± 17 ng/dL, P = 0.002), and nominally lower in adult male patients with AS compared with controls (265 ± 107 vs 475 ± 169 ng/dL, P = 0.01). Comparison of metabolic parameters in patients with AS vs BMI-matched controls Total body composition and fat distribution Total percentage body fat measured by dual-energy X-ray absorptiometry was similar between patients with AS and controls in both unadjusted (P = 0.89, Table 2) and adjusted analyses [covariates: age, sex, and race; adjusted mean (95% CI): patients with AS vs controls: 33.9% (31.1% to 36.9%) vs 35.1% (33.0% to 37.1%); P = 0.54]. Unadjusted lean mass and bone mineral content were nominally lower in patients with AS (Table 2) but similar after adjustment for the shorter stature of patients with AS (lean body mass: P = 0.25, and bone mineral content: P = 0.18). Waist circumference z score (normed by age and sex) was similar in patients with AS compared with controls in both unadjusted analysis (P = 0.30, Table 2) and after adjustment for race (P = 0.47). Patients with AS and controls had similar percentages of abdominal visceral fat at L2–5 (P = 0.26, Table 2), which remained comparable after adjustment for age, sex, and race (P = 0.15). Liver and muscle fat content BMI z score was nominally positively correlated with liver fat percentage (r = 0.43, P = 0.002) and muscle fat percentage (r = 0.53, P = 0.001) with all subjects combined, and this relationship remained nominally significant when subjects were analyzed by separate diagnosis categories (all Ps < 0.05, Figs. 1A and 1B). Mean liver fat content was significantly higher in patients with AS compared with controls (P = 0.0002, Table 2) and remained significant after we adjusted for age, sex, race, and BMI z score (P = 0.0005 Fig. 1C), indicating that even after we controlled for severity of obesity, patients with AS had a higher percentage of liver fat. ALT and aspartate aminotransferase were significantly higher in AS in both unadjusted analyses (Ps < 0.001, Table 2) and after adjustment for age, sex, race, and BMI z score (Ps < 0.001, Figs. 1D and 1E). Muscle fat content was nominally higher in patients with AS compared with controls (P = 0.02, Table 2), but this difference was eliminated after adjustment for age, sex, race, and BMI z score [AS vs controls: 4.9% (95% CI, 4.0% to 5.9%) vs 4.3% (95% CI, 2.9% to 5.8%), P = 0.50]. Figure 1. View largeDownload slide Liver and muscle fat content in patients with AS compared with controls. (A) Positive correlations of liver fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of liver fat percentage measured by MRS. Significant difference in intercept of linear regressions indicate higher liver fat values for patients with AS compared with controls for any given BMI (P = 0.0001). (B) Positive correlations of right lateral midthigh quadriceps fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of muscle fat percentage measured by MRS. Possible trends in the difference in intercept of linear regressions indicate a tendency for higher muscle fat values for patients with AS compared with controls for any given BMI (P = 0.08). (C) Liver fat percentage adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver fat compared with controls. (D) Serum ALT and (E) aspartate aminotransferase adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver function tests compared with controls. Figure 1. View largeDownload slide Liver and muscle fat content in patients with AS compared with controls. (A) Positive correlations of liver fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of liver fat percentage measured by MRS. Significant difference in intercept of linear regressions indicate higher liver fat values for patients with AS compared with controls for any given BMI (P = 0.0001). (B) Positive correlations of right lateral midthigh quadriceps fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of muscle fat percentage measured by MRS. Possible trends in the difference in intercept of linear regressions indicate a tendency for higher muscle fat values for patients with AS compared with controls for any given BMI (P = 0.08). (C) Liver fat percentage adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver fat compared with controls. (D) Serum ALT and (E) aspartate aminotransferase adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver function tests compared with controls. Energy balance The parent- or caregiver-reported hyperphagia questionnaire total score was nominally higher in patients with AS vs controls (P = 0.003, Table 2) and remained nominally higher after we controlled for age and BMI z score (P = 0.03). REE was nominally lower in patients with AS vs controls (P = 0.02, Table 2) but no longer different after adjustment for age, sex, race, and lean body mass [1469 (95% CI, 1377 to 1561) vs 1510 (95% CI, 1398 to 1623) kcal/day, P = 0.59]. Patients with AS had a higher respiratory quotient in both unadjusted analysis (P = 0.0006, Table 2) and after adjustment for age, sex, race, and BMI z score (P = 0.0006, Fig. 2A), indicating relatively greater utilization of carbohydrate vs fat as the energy substrate. The Mifflin-St. Jeor equation predicted REE in both patients with AS and controls equally well (P = 0.87). Figure 2. View largeDownload slide Energy balance and glucose homeostasis in patients with AS compared with controls. (A) Adjusted respiratory quotient from indirect calorimetry. Higher respiratory quotient in AS indicates greater utilization of carbohydrate vs fat as the energy substrate. (B) Adjusted WBISI. Patients with AS had lower insulin sensitivity. (C) Unadjusted glucose values and (D) adjusted glucose AUC during the MMT. Patients with AS had higher glucose AUC compared with controls. (E) Unadjusted insulin values and (F) adjusted insulin AUC during the MMT. Patients with AS had higher insulin AUC compared with controls. For (A), (B), (D), and (F), the covariates for adjustment were age, sex, race, and BMI z score. Figure 2. View largeDownload slide Energy balance and glucose homeostasis in patients with AS compared with controls. (A) Adjusted respiratory quotient from indirect calorimetry. Higher respiratory quotient in AS indicates greater utilization of carbohydrate vs fat as the energy substrate. (B) Adjusted WBISI. Patients with AS had lower insulin sensitivity. (C) Unadjusted glucose values and (D) adjusted glucose AUC during the MMT. Patients with AS had higher glucose AUC compared with controls. (E) Unadjusted insulin values and (F) adjusted insulin AUC during the MMT. Patients with AS had higher insulin AUC compared with controls. For (A), (B), (D), and (F), the covariates for adjustment were age, sex, race, and BMI z score. Glucose homeostasis Compared with controls, patients with AS had similar fasting glucose (P = 0.84, Table 2) but higher fasting C-peptide and insulin, with consequently higher homeostatic model assessment of insulin resistance (Ps < 0.001, Table 2). Both unadjusted and adjusted WBISI derived from the MMT were significantly lower in patients with AS (Ps < 0.001, Table 2 and Fig. 2B). MMT glucose and insulin measurements and their adjusted area under the curve (AUC) values were higher in patients with AS (Ps < 0.001, Table 2 and Figs. 2C–2F). Fasting FFA was similar between groups, and MMT FFA AUC was nominally higher in patients with AS (Table 2), but after adjustment for age, sex, race, and BMI z score, both fasting FFA (P = 0.13) and MMT FFA AUC (P = 0.32) were similar for patients with AS and controls. Fasting glucagon and MMT glucagon AUC were nominally higher in patients with AS (Table 2), but neither was significant after we adjusted for age, sex, race, and BMI z score (fasting: P = 0.29; AUC: P = 0.06). HbA1c was nominally higher in patients with AS (Table 2) and significantly different after adjustment for age, sex, race, and BMI z score (P = 0.0002). After we excluded the subjects with diabetes (14 in patients with AS, none for controls), the outcomes were unchanged (data not shown). Thus, even nondiabetic patients with AS displayed higher glucose and greater insulin resistance compared with BMI z score matched controls. Blood pressure Patients with AS and controls had similar systolic and diastolic BP z scores (Table 2). Fifteen patients in the AS group had been taking antihypertensive medications prescribed by their home medical providers at baseline, whereas there was one taking antihypertensive medication in the control group (P < 0.0001). After we excluded those patients from the AS cohort, unadjusted systolic (P = 0.06) and diastolic (P = 0.23) BP z scores were not significantly different between patients with AS and controls, but after adjustment for age, sex, race, and BMI z score, nominally higher systolic BP z scores and no difference in diastolic BP z scores were observed in patients with AS (P = 0.03, Figs. 3A and 3B). Figure 3. View largeDownload slide BP, lipid profile, and MS in patients with AS compared with controls. (A) Systolic and (B) diastolic BP z scores adjusted for age, sex, race, and BMI z score. Subjects taking BP-lowering medications were excluded. (C) Triglycerides, (D) HDL-cholesterol, and (E) LDL-cholesterol adjusted for age, sex, race, and BMI z score. Subjects taking lipid-altering medications were excluded. (F) Percentage meeting MS criteria (three or more of the following: abdominal obesity, hypertriglyceridemia, low HDL-cholesterol, elevated BP, or impaired glucose tolerance). Figure 3. View largeDownload slide BP, lipid profile, and MS in patients with AS compared with controls. (A) Systolic and (B) diastolic BP z scores adjusted for age, sex, race, and BMI z score. Subjects taking BP-lowering medications were excluded. (C) Triglycerides, (D) HDL-cholesterol, and (E) LDL-cholesterol adjusted for age, sex, race, and BMI z score. Subjects taking lipid-altering medications were excluded. (F) Percentage meeting MS criteria (three or more of the following: abdominal obesity, hypertriglyceridemia, low HDL-cholesterol, elevated BP, or impaired glucose tolerance). Lipid profile Patients with AS had significantly higher triglycerides, significantly lower HDL-cholesterol, and nominally lower low-density lipoprotein (LDL) cholesterol in adjusted analyses (Table 2) and after adjustment for age, sex, race, and BMI z score (P values: 0.000003 for triglycerides, 0.00001 for HDL, and 0.002 for LDL). After we excluded subjects taking lipid-altering medications (eight in patients with AS, none for controls), outcomes were unchanged (Figs. 3C–3E). MS The percentage (95% CI) of patients with MS in AS was 52.6% (35.8% to 69.0%) vs 5.3% (1.5% to 12.9%) among controls [relative risk 9.9 (2.8 to 46.0), P < 0.0000001, Fig. 3F]. With all ages combined, the AS and control groups had similar serum creatinine and eGFR (Table 2), but in adults, patients with AS had nominally higher serum Cr (P = 0.04) and nominally lower eGFR (P = 0.009) than controls. For all MS components that were significantly greater in patients with AS compared with controls, this difference remained significant after we adjusted for eGFR (Ps < 0.001). Discussion In this study, we observed a high frequency of endocrine abnormalities in patients with AS and found the presence of MS to be 10 times higher in patients with AS compared with BMI-matched controls. The most commonly observed abnormalities in our AS cohort were obesity, T2DM, hypothyroidism (central and primary), hypogonadism (central and primary), hyperandrogenism in female patients, and short stature [with proportional body dimensions accompanied by low IGF-1, potentially corroborating previous reports of GH secretion insufficiency in AS (27)]. Although unstimulated cortisol values were similar between AS and control groups, central adrenal insufficiency had been diagnosed in one patient with AS, indicating that, though less common than other endocrinopathies, cortisol deficit is a potential risk in AS. Together these findings point to the diverse role of cilia in the function of the hypothalamic-pituitary axis and peripheral endocrine organs. The pathogenesis of obesity in AS is unclear, but rodent models suggest dual dysfunctions in central nervous system regulation of appetite (28) and adipocyte differentiation (29). Alms1 is expressed in the hypothalamus, a key brain region for energy balance (28). Foz/foz mice with a truncating mutation of Alms1 have normal ciliary formation, but cilia are not maintained postnatally, resulting in a reduction in the number of hypothalamic neuronal cilia (28). Recently, a key receptor in the energy homeostasis regulating leptin-melanocortin pathway, melanocortin-4 receptor, was found to be localized to the primary cilia of hypothalamic neurons (30). Peripherally, ALMS1 is expressed in preadipocytes (31), and disruption of Alms1 induces alterations of adipocyte morphology and gene expression profiles (29). Our group previously reported higher serum leptin concentrations in AS and another hyperphagia- and obesity-associated ciliopathy, Bardet-Biedl syndrome, compared with BMI-matched controls (32–34), an observation consistent with murine data showing that cilia are needed for leptin receptor trafficking (35). Our current study expands the clinical phenotyping of human AS and examines energy balance by using a validated hyperphagia questionnaire and indirect calorimetry in patients with AS and BMI-matched controls. We observed that REE adjusted for lean body mass was comparable in patients with AS and controls but that the hyperphagia score trended higher, suggesting that higher intake rather than the lower metabolic rate is probably the primary driver for obesity in AS. Reduced activity thermogenesis caused by lower mobility due to visual and auditory impairments may also be a contributing factor that we did not directly assess in the current study. Previous studies that have examined metabolic complications in patients with AS lacked an equally obese control group for comparison. By eliminating the confounding contribution of obesity by matching each subject with AS with two controls (of similar age, sex, race, and BMI z score), we were able to ascertain the scope of metabolic disease caused by AS independent of BMI. We also performed ANCOVAs adjusting for age, sex, race, and BMI z score and observed that all differences meeting the threshold for significance after multiple-comparison correction remained significant (P < 0.001), verifying that patients with AS and controls were well matched. The most striking feature of AS that we observed was the severity of insulin resistance, which was more than five times that of equally obese control subjects. The mechanism by which loss of ALMS1 function leads to insulin resistance has not been fully elucidated. In Alms1GT/GT mice, insulin-stimulated translocation of GLUT4 to the plasma membrane is reduced (29). Reduced expression of alms1 in zebrafish resulted in significantly decreased β-cell mass (36, 37). Together, these animal data point to a combination of insulin resistance and relative insulin insufficiency in AS. Based on our observations in this human study, we hypothesize that fat deposition in the liver and potentially skeletal muscle could play a key role in the insulin resistance of AS. Fat content of liver and muscle as measured by MRS was positively correlated with BMI for all subjects, but the curve for this relationship was shifted upward in AS, such that at any given BMI, patients with AS had more fat in the liver and quadriceps muscle compared with controls. Glucose uptake and utilization within the liver and muscle are critical for glycemic control (38). Fat deposition could create an inflammatory milieu (as evidenced by elevated transaminases in our subjects with AS) that underlies the pathophysiology for the severe insulin resistance and accompanying hyperglycemia, dyslipidemia, and other MS components observed in AS. Interestingly, elevated LDL-cholesterol (which is not typically included in the criteria for MS but is a common complication of obesity) was not seen in our AS cohort, and in fact LDL-cholesterol was nominally lower in patients with AS compared with BMI-matched controls. The clinical significance is unclear but may be protective for patients with AS. Other investigators have also observed hepatic steatosis and fibrosis in AS (12), but our study demonstrates that the severity of liver disease is significantly higher than in obese controls, suggesting a direct role of ALMS1 dysfunction, independent of obesity, in the pathogenesis of liver disease in AS. In a study of patients with AS in the United Kingdom, higher baseline aortic pulse wave velocity was positively associated with the duration of diabetes and predicted occurrence of cardiovascular events during 5 years of follow-up (39). Along the same line, longitudinal studies are needed to elucidate the temporal relationship between liver pathology and insulin resistance. Conclusion Endocrine problems are common in AS, with severe insulin resistance and T2DM causing significant morbidity, even in those who are not obese. Although aerobic exercise and restriction of simple carbohydrate intake are important foundations for the management of AS in the context of multidisciplinary team-based care (40), identification of therapies that target the hypothalamic defects causing hyperphagia and the peripheral metabolic derangements causing deposition of fat in the liver and muscle are needed. Abbreviations: Abbreviations: 25OHD 25-hydroxyvitamin D ALT alanine aminotransferase ANCOVA analysis of covariance AS Alström syndrome AUC area under the curve BMI body mass index BP blood pressure eGFR estimated glomerular filtration rate FFA free fatty acid HDL high-density lipoprotein LDL low-density lipoprotein MMT mixed meal test MRS magnetic resonance spectroscopy MS metabolic syndrome NIH National Institutes of Health REE resting energy expenditure T2DM type 2 diabetes mellitus WBISI whole-body insulin sensitivity index Acknowledgments We thank Gayle B. Collin for assistance with manuscript preparation and the families of Alström Syndrome International for their participation and support. This article is dedicated to the memory of our colleague Jan Davis Marshall, who worked tirelessly to improve the lives of patients with Alström syndrome and made numerous important scientific contributions during her 46-year career at The Jackson Laboratory. Financial Support: This study was funded by the Intramural Research Program of National Human Genome Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIAHD00641 to J.A.Y. and ZIAHD008898 to J.C.H.), and an NIH Bench-to-Bedside Award to J.C.H. Clinical Trial Information: ClinicalTrials.gov nos. NCT00068224 (registered 10 September 2003), NCT00001195 (registered 4 November 1999), NCT00001522 (registered 4 November 1999), NCT00001723 (registered 4 November 1999), NCT00005669 (registered 22 May 2000), NCT00006073 (registered 14 July 2003), NCT00030238 (registered 12 February 2002), NCT00320177 (registered 3 May 2006), NCT00758108 (registered 23 September 2008), NCT01517048 (registered 25 January 2012). Author Contributions: J.C.H. and M.G.-A. conceived and designed the study, performed patient examinations, supervised research testing, interpreted results, performed statistical analyses, and wrote the manuscript. D.P.R.-C. recruited control subjects, administered questionnaires, performed indirect calorimetry, performed statistical analyses, and contributed in writing the manuscript. C.-Y.L. and J.C.R. interpreted MRS results. E.T. and I.B.T. interpreted MRI results. J.B. coordinated all testing. J.D.M. and J.K.N. recruited patients and performed ALMS1 sequencing. M.G.-A. is the principal investigator of the NIH protocol “Clinical and Molecular Investigations Into Ciliopathies.” W.A.G. is the financially accountable investigator of the NIH protocol “Clinical and Molecular Investigations Into Ciliopathies.” J.A.Y. is the principal investigator of the NIH protocols that provided the control subjects. All co-authors contributed to data interpretation and revised the manuscript. Current Affiliation: C.-Y. Liu’s current affiliation is the Department of Radiology, Johns Hopkins University, Baltimore, Maryland. Disclosure Summary: J.C.H. has received an unrestricted research grant from Rhythm Pharmaceuticals. J.A.Y. reports receiving research grant support from Rhythm Pharmaceuticals for a study of pharmacotherapy to treat the obesity observed in rare disorders, including Alström syndrome. The remaining authors have nothing to disclose. References 1. Marshall JD , Maffei P , Collin GB , Naggert JK . Alström syndrome: genetics and clinical overview . Curr Genomics . 2011 ; 12 ( 3 ): 225 – 235 . 2. Marshall JD , Paisey RB , Carey C , Macdermott S . Alstrom syndrome. In: Pagon RA , Adam MP , Ardinger HH , Wallace SE , Amemiya A , Bean LJH , Bird TD , Ledbetter N , Mefford HC , Smith RJH , Stephens K , eds. GeneReviews(R) . Seattle, WA : University of Washington ; 1993–2018 . Available at: www.ncbi.nlm.nih.gov/books/NBK1267/. Accessed 15 January 2018. 3. 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A truncating mutation of Alms1 reduces the number of hypothalamic neuronal cilia in obese mice . Dev Neurobiol . 2013 ; 73 ( 1 ): 1 – 13 . 29. Favaretto F , Milan G , Collin GB , Marshall JD , Stasi F , Maffei P , Vettor R , Naggert JK . GLUT4 defects in adipose tissue are early signs of metabolic alterations in Alms1GT/GT, a mouse model for obesity and insulin resistance . PLoS One . 2014 ; 9 ( 10 ): e109540 . 30. Siljee JE , Wang Y , Bernard AA , Ersoy BA , Zhang S , Marley A , Von Zastrow M , Reiter JF , Vaisse C . Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity . Nat Genet . 2018 ; 50 ( 2 ): 180 – 185 . 31. Romano S , Milan G , Veronese C , Collin GB , Marshall JD , Centobene C , Favaretto F , Dal Pra C , Scarda A , Leandri S , Naggert JK , Maffei P , Vettor R . Regulation of Alström syndrome gene expression during adipogenesis and its relationship with fat cell insulin sensitivity . Int J Mol Med . 2008 ; 21 ( 6 ): 731 – 736 . 32. Hicks MD , Marshall JD , Maffei P , Hanish AE , Hunter LA , Brady SM , Sedaka NM , Sherafat Kazemzadeh R , Tsao JW , Milan G , Naggert J , Yanovski JA , Han JC . Hyperphagia, leptin, and brain-derived neurotrophic factor in subjects with Alström syndrome and BMI-Z matched controls (poster 2702T). Abstract presented at the Annual Scientific Meeting of the American Society for Human Genetics; 8 November 2012; San Francisco, CA. Available at: www.ashg.org/2012meeting/abstracts/fulltext/f120122612.htm. Accessed 15 January 2018. 33. Feuillan PP , Ng D , Han JC , Sapp JC , Wetsch K , Spaulding E , Zheng YC , Caruso RC , Brooks BP , Johnston JJ , Yanovski JA , Biesecker LG . Patients with Bardet-Biedl syndrome have hyperleptinemia suggestive of leptin resistance . J Clin Endocrinol Metab . 2011 ; 96 ( 3 ): E528 – E535 . 34. Sherafat-Kazemzadeh R , Ivey L , Kahn SR , Sapp JC , Hicks MD , Kim RC , Krause AJ , Shomaker LB , Biesecker LG , Han JC , Yanovski JA . Hyperphagia among patients with Bardet-Biedl syndrome . Pediatr Obes . 2013 ; 8 ( 5 ): e64 – e67 . 35. Seo S , Guo DF , Bugge K , Morgan DA , Rahmouni K , Sheffield VC . Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling . Hum Mol Genet . 2009 ; 18 ( 7 ): 1323 – 1331 . 36. Lodh S , Hostelley TL , Leitch CC , O’Hare EA , Zaghloul NA . Differential effects on β-cell mass by disruption of Bardet-Biedl syndrome or Alstrom syndrome genes . Hum Mol Genet . 2016 ; 25 ( 1 ): 57 – 68 . 37. Leitch CC , Lodh S , Prieto-Echagüe V , Badano JL , Zaghloul NA . Basal body proteins regulate Notch signaling through endosomal trafficking . J Cell Sci . 2014 ; 127 ( Pt 11 ): 2407 – 2419 . 38. Meex RCR , Watt MJ . Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance . Nat Rev Endocrinol . 2017 ; 13 ( 9 ): 509 – 520 . 39. Paisey RB , Smith J , Carey C , Barrett T , Campbell F , Maffei P , Marshall JD , Paisey C , Steeds RP , Edwards NC , Bunce S , Geberhiwot T . Duration of diabetes predicts aortic pulse wave velocity and vascular events in Alström syndrome . J Clin Endocrinol Metab . 2015 ; 100 ( 8 ): E1116 – E1124 . 40. Paisey RB , Leeson-Beevers K . Current management of Alström syndrome and recent advances in treatment . Expert Opin Orphan Drugs . 2016 ; 4 ( 7 ): 747 – 759 . http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press http://www.deepdyve.com/lp/oxford-university-press/comprehensive-endocrine-metabolic-evaluation-of-patients-with-alstr-m-xphaB7oFjQ

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Publisher: Oxford University Press
ISSN: 0021-972X
eISSN: 1945-7197
DOI: 10.1210/jc.2018-00496
Publisher site: See Article on Publisher Site

Abstract

Abstract Background Alström syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body–associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements. Objective We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI)–matched controls. Methods We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed. Results Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two-thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps ≤ 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001). Conclusion Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development. Alström syndrome (AS) (Online Mendelian Inheritance in Man # 203800) is a monogenic form of obesity characterized by progressive retinal dystrophy, sensory hearing loss, cardiomyopathy, obesity, childhood-onset type 2 diabetes mellitus (T2DM), hypertriglyceridemia, and progressive hepatic and renal dysfunction in late childhood and adulthood (1). The estimated prevalence of AS is 1 to 10 in 1,000,000 persons (2). It is caused by recessive mutations in ALMS1 (Chr 2q13) (3, 4). Although its function is not completely understood, evidence to date suggests that ALMS1 plays roles in ciliary function, cell cycle regulation, endosomal trafficking, cell migration, and extracellular matrix production (5–7). Approximately 700 cases of AS have been reported worldwide (8) since the disorder was first described in 1959 (9). Chart reviews and family-completed questionnaire-based descriptions of AS have been reported (10–12), yet few encompass systematic single-center phenotyping and none use comparison with a body mass index (BMI)–matched control cohort. To characterize further the endocrine and metabolic complications of AS and to elucidate the pathogenesis of obesity and metabolic dysregulation, we conducted a detailed evaluation of 38 patients with AS and 76 controls to compare body composition, fat distribution [including findings from magnetic resonance spectroscopy (MRS]) of liver and muscle], and endocrine-metabolic parameters. Methods Subjects From February 2013 to June 2014, 38 patients who fulfilled the clinical diagnostic criteria for AS and had ALMS1 mutations from 32 families (Table 1) were evaluated at the National Institutes of Health (NIH) Clinical Center, with a protocol approved by the National Human Genome Research Institute Institutional Review Board (www.clinicaltrials.gov, NCT00068224). Patients were recruited through Alström Syndrome International, a support group for families and health care providers of patients with AS. For metabolic analyses, patients with AS were matched 1:2 with 76 volunteer control subjects by age, sex, race, and BMI. Control subjects with no known genetic disorder were participants of various clinical studies (1997 to 2014; NCT00001195, NCT00001522, NCT00001723, NCT00005669, NCT00006073, NCT00030238, NCT00320177, NCT00758108, NCT01517048) in the Section on Growth and Obesity at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. All metabolic studies for the control subjects were approved by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Institutional Review Board. Written informed consent was obtained from adults and parents or guardians of children and assent from children before participation. Table 1. Genetic Testing Results of Patients With AS Patient # Family # Age, y Sex ALMS1 Mutation 1 c.DNA ALMS1 Mutation 1 Protein ALMS1 Mutation 2 c.DNA ALMS1 Mutation 2 Protein 1 1 2 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 2 1 5 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 3 1 9 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 4 2 3 F c.10483C>T p.Gln3495* c.10483C>T p.Gln3495* 5 3 4 F c.10535G>A p.Trp3512* c.11291G>A p.Ser 3764* 6 4 4 F c.11316_11319delAGAG p.Glu3773Trpfs*18 c.7771_7772insT p.Thr2592Asnfs*3 7 5 5 F c.4156dupA p.Thr1386Asnfs*15 8 6 5 M c.10775delC p.Thr3592Lysfs*6 c.2234C>G p.Ser 745* 9 7 6 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 10 7 13 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 11 8 8 F c.10775delC p.Thr3592Lysfs*6 c.10775delC p.Thr3592Lysfs*6 12 9 9 M c.4156dupA p.Thr1386Asnfs*15 c.4156dupA p.Thr1386Asnfs*15 13 10 10 F c.5145T>G p.Tyr1715* c.3754C>T p.Gln1252* 14 11 11 M c.8352_8355delAGAA p.Glu2785* c.6436C>T p.Arg2146* 15 12 11 F c.9328C>T p.Gln3110* c.10549C>T p.Gln3517* 16 13 12 F c.10539_10557ins(n)19 p.Lys3545Asnfs*18 c.10539_10557ins(n)19 p.Lys3545Asnfs*18 17 14 12 F c.6436C>T p.Arg2146* c.6436C>T p.Arg2146* 18 15 12 F c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 19 15 12 M c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 20 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 21 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 22 17 14 F c.11651_11652insGTTA p.Asn3885Leufs*9 c.9900dupC p.Ser3301Leufs*7 23 18 16 F c.10539_10557ins(n)19 p.His3512fs c.11416C>T p.Arg3806* 24 19 17 F c.6305C>A p.Ser2102* c.10775delC p.Thr3592Lysfs*6 25 20 18 M c.10849G>T p.Glu3617* c.10483C>T p.Gln3495* 26 21 19 M c.10775delC p.Thr3592Lysfs*6 c.3716_3719del p.Ser1240Thrfs*23 27 22 19 F c.4180C>T p.Gln1394* c.4180C>T p.Gln1394* 28 23 21 F c.11314dupA p.Arg3772Trpfs*10 c.10885C>T p.Arg3629* 29 24 21 M c.5311C>T p.Gln1769* c.5311C>T p.Gln1769* 30 25 24 F c.11651_11652insGTTA p.Asn3885LeufsX9 c.4817delA p.Lys1608ArgfsX9 31 26 24 F c.11313_11316delTAGA p.Asp3771Glufs*20 c.2329C>T p.Gln777* 32 27 27 F c.8394_8395insA p.Leu2799Ilefs*4 c.9194T>G p.Leu3065* 33 28 33 M c.1903C>T p.Gln635* c.3579C>G p.Tyr1193* 34 29 34 M c.10849G>T p.Glu3617* c.3019dupA p.Arg1007Lysfs*15 35 30 35 F c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 36 31 36 F c.4039C>T p.Gln1347* c.5145T>G p.Tyr1715* 37 30 37 M c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 38 32 38 M c.7374_7375delAG p.Asp2459* c.7374_7375delAG p.Asp2459* Patient # Family # Age, y Sex ALMS1 Mutation 1 c.DNA ALMS1 Mutation 1 Protein ALMS1 Mutation 2 c.DNA ALMS1 Mutation 2 Protein 1 1 2 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 2 1 5 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 3 1 9 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 4 2 3 F c.10483C>T p.Gln3495* c.10483C>T p.Gln3495* 5 3 4 F c.10535G>A p.Trp3512* c.11291G>A p.Ser 3764* 6 4 4 F c.11316_11319delAGAG p.Glu3773Trpfs*18 c.7771_7772insT p.Thr2592Asnfs*3 7 5 5 F c.4156dupA p.Thr1386Asnfs*15 8 6 5 M c.10775delC p.Thr3592Lysfs*6 c.2234C>G p.Ser 745* 9 7 6 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 10 7 13 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 11 8 8 F c.10775delC p.Thr3592Lysfs*6 c.10775delC p.Thr3592Lysfs*6 12 9 9 M c.4156dupA p.Thr1386Asnfs*15 c.4156dupA p.Thr1386Asnfs*15 13 10 10 F c.5145T>G p.Tyr1715* c.3754C>T p.Gln1252* 14 11 11 M c.8352_8355delAGAA p.Glu2785* c.6436C>T p.Arg2146* 15 12 11 F c.9328C>T p.Gln3110* c.10549C>T p.Gln3517* 16 13 12 F c.10539_10557ins(n)19 p.Lys3545Asnfs*18 c.10539_10557ins(n)19 p.Lys3545Asnfs*18 17 14 12 F c.6436C>T p.Arg2146* c.6436C>T p.Arg2146* 18 15 12 F c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 19 15 12 M c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 20 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 21 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 22 17 14 F c.11651_11652insGTTA p.Asn3885Leufs*9 c.9900dupC p.Ser3301Leufs*7 23 18 16 F c.10539_10557ins(n)19 p.His3512fs c.11416C>T p.Arg3806* 24 19 17 F c.6305C>A p.Ser2102* c.10775delC p.Thr3592Lysfs*6 25 20 18 M c.10849G>T p.Glu3617* c.10483C>T p.Gln3495* 26 21 19 M c.10775delC p.Thr3592Lysfs*6 c.3716_3719del p.Ser1240Thrfs*23 27 22 19 F c.4180C>T p.Gln1394* c.4180C>T p.Gln1394* 28 23 21 F c.11314dupA p.Arg3772Trpfs*10 c.10885C>T p.Arg3629* 29 24 21 M c.5311C>T p.Gln1769* c.5311C>T p.Gln1769* 30 25 24 F c.11651_11652insGTTA p.Asn3885LeufsX9 c.4817delA p.Lys1608ArgfsX9 31 26 24 F c.11313_11316delTAGA p.Asp3771Glufs*20 c.2329C>T p.Gln777* 32 27 27 F c.8394_8395insA p.Leu2799Ilefs*4 c.9194T>G p.Leu3065* 33 28 33 M c.1903C>T p.Gln635* c.3579C>G p.Tyr1193* 34 29 34 M c.10849G>T p.Glu3617* c.3019dupA p.Arg1007Lysfs*15 35 30 35 F c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 36 31 36 F c.4039C>T p.Gln1347* c.5145T>G p.Tyr1715* 37 30 37 M c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 38 32 38 M c.7374_7375delAG p.Asp2459* c.7374_7375delAG p.Asp2459* Abbreviations: F, female; M, male. View Large Table 1. Genetic Testing Results of Patients With AS Patient # Family # Age, y Sex ALMS1 Mutation 1 c.DNA ALMS1 Mutation 1 Protein ALMS1 Mutation 2 c.DNA ALMS1 Mutation 2 Protein 1 1 2 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 2 1 5 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 3 1 9 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 4 2 3 F c.10483C>T p.Gln3495* c.10483C>T p.Gln3495* 5 3 4 F c.10535G>A p.Trp3512* c.11291G>A p.Ser 3764* 6 4 4 F c.11316_11319delAGAG p.Glu3773Trpfs*18 c.7771_7772insT p.Thr2592Asnfs*3 7 5 5 F c.4156dupA p.Thr1386Asnfs*15 8 6 5 M c.10775delC p.Thr3592Lysfs*6 c.2234C>G p.Ser 745* 9 7 6 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 10 7 13 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 11 8 8 F c.10775delC p.Thr3592Lysfs*6 c.10775delC p.Thr3592Lysfs*6 12 9 9 M c.4156dupA p.Thr1386Asnfs*15 c.4156dupA p.Thr1386Asnfs*15 13 10 10 F c.5145T>G p.Tyr1715* c.3754C>T p.Gln1252* 14 11 11 M c.8352_8355delAGAA p.Glu2785* c.6436C>T p.Arg2146* 15 12 11 F c.9328C>T p.Gln3110* c.10549C>T p.Gln3517* 16 13 12 F c.10539_10557ins(n)19 p.Lys3545Asnfs*18 c.10539_10557ins(n)19 p.Lys3545Asnfs*18 17 14 12 F c.6436C>T p.Arg2146* c.6436C>T p.Arg2146* 18 15 12 F c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 19 15 12 M c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 20 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 21 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 22 17 14 F c.11651_11652insGTTA p.Asn3885Leufs*9 c.9900dupC p.Ser3301Leufs*7 23 18 16 F c.10539_10557ins(n)19 p.His3512fs c.11416C>T p.Arg3806* 24 19 17 F c.6305C>A p.Ser2102* c.10775delC p.Thr3592Lysfs*6 25 20 18 M c.10849G>T p.Glu3617* c.10483C>T p.Gln3495* 26 21 19 M c.10775delC p.Thr3592Lysfs*6 c.3716_3719del p.Ser1240Thrfs*23 27 22 19 F c.4180C>T p.Gln1394* c.4180C>T p.Gln1394* 28 23 21 F c.11314dupA p.Arg3772Trpfs*10 c.10885C>T p.Arg3629* 29 24 21 M c.5311C>T p.Gln1769* c.5311C>T p.Gln1769* 30 25 24 F c.11651_11652insGTTA p.Asn3885LeufsX9 c.4817delA p.Lys1608ArgfsX9 31 26 24 F c.11313_11316delTAGA p.Asp3771Glufs*20 c.2329C>T p.Gln777* 32 27 27 F c.8394_8395insA p.Leu2799Ilefs*4 c.9194T>G p.Leu3065* 33 28 33 M c.1903C>T p.Gln635* c.3579C>G p.Tyr1193* 34 29 34 M c.10849G>T p.Glu3617* c.3019dupA p.Arg1007Lysfs*15 35 30 35 F c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 36 31 36 F c.4039C>T p.Gln1347* c.5145T>G p.Tyr1715* 37 30 37 M c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 38 32 38 M c.7374_7375delAG p.Asp2459* c.7374_7375delAG p.Asp2459* Patient # Family # Age, y Sex ALMS1 Mutation 1 c.DNA ALMS1 Mutation 1 Protein ALMS1 Mutation 2 c.DNA ALMS1 Mutation 2 Protein 1 1 2 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 2 1 5 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 3 1 9 M c.11316_11319delAGAG p.Glu3773Trpfs*18 c.11416C>T p.Arg3806* 4 2 3 F c.10483C>T p.Gln3495* c.10483C>T p.Gln3495* 5 3 4 F c.10535G>A p.Trp3512* c.11291G>A p.Ser 3764* 6 4 4 F c.11316_11319delAGAG p.Glu3773Trpfs*18 c.7771_7772insT p.Thr2592Asnfs*3 7 5 5 F c.4156dupA p.Thr1386Asnfs*15 8 6 5 M c.10775delC p.Thr3592Lysfs*6 c.2234C>G p.Ser 745* 9 7 6 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 10 7 13 M c.10265delC p.Pro3422Glnfs*2 c.2930_2933dupGAGA p.Ser979fs 11 8 8 F c.10775delC p.Thr3592Lysfs*6 c.10775delC p.Thr3592Lysfs*6 12 9 9 M c.4156dupA p.Thr1386Asnfs*15 c.4156dupA p.Thr1386Asnfs*15 13 10 10 F c.5145T>G p.Tyr1715* c.3754C>T p.Gln1252* 14 11 11 M c.8352_8355delAGAA p.Glu2785* c.6436C>T p.Arg2146* 15 12 11 F c.9328C>T p.Gln3110* c.10549C>T p.Gln3517* 16 13 12 F c.10539_10557ins(n)19 p.Lys3545Asnfs*18 c.10539_10557ins(n)19 p.Lys3545Asnfs*18 17 14 12 F c.6436C>T p.Arg2146* c.6436C>T p.Arg2146* 18 15 12 F c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 19 15 12 M c.4885C>T p.Gln1629* c. 5923 C>T p.Gln 1975* 20 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 21 16 12 M c.592C>T p.Gln198* c.1610_1611delTC p.Leu538Glnfs22 22 17 14 F c.11651_11652insGTTA p.Asn3885Leufs*9 c.9900dupC p.Ser3301Leufs*7 23 18 16 F c.10539_10557ins(n)19 p.His3512fs c.11416C>T p.Arg3806* 24 19 17 F c.6305C>A p.Ser2102* c.10775delC p.Thr3592Lysfs*6 25 20 18 M c.10849G>T p.Glu3617* c.10483C>T p.Gln3495* 26 21 19 M c.10775delC p.Thr3592Lysfs*6 c.3716_3719del p.Ser1240Thrfs*23 27 22 19 F c.4180C>T p.Gln1394* c.4180C>T p.Gln1394* 28 23 21 F c.11314dupA p.Arg3772Trpfs*10 c.10885C>T p.Arg3629* 29 24 21 M c.5311C>T p.Gln1769* c.5311C>T p.Gln1769* 30 25 24 F c.11651_11652insGTTA p.Asn3885LeufsX9 c.4817delA p.Lys1608ArgfsX9 31 26 24 F c.11313_11316delTAGA p.Asp3771Glufs*20 c.2329C>T p.Gln777* 32 27 27 F c.8394_8395insA p.Leu2799Ilefs*4 c.9194T>G p.Leu3065* 33 28 33 M c.1903C>T p.Gln635* c.3579C>G p.Tyr1193* 34 29 34 M c.10849G>T p.Glu3617* c.3019dupA p.Arg1007Lysfs*15 35 30 35 F c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 36 31 36 F c.4039C>T p.Gln1347* c.5145T>G p.Tyr1715* 37 30 37 M c.5283delA p.His1762Ifs*24 c.10483C>T p.Gln3495* 38 32 38 M c.7374_7375delAG p.Asp2459* c.7374_7375delAG p.Asp2459* Abbreviations: F, female; M, male. View Large Genetic testing All patients with AS had prior genetic testing via Sanger sequencing, microarray-based arrayed primer extension, or targeted gene sequencing and custom analysis test as previously described (13). Clinical and laboratory assessments Physical examination and fasting venous blood sample All AS and control subjects were evaluated at the NIH Clinical Research Center. Participants underwent physical examination (by J.C.H. or M.G.-A.) and venous blood draw after 12-hour fast. Glucose, insulin, C-peptide, free fatty acids (FFAs), glucagon, triglycerides, high-density lipoprotein (HDL) cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase, IGF-1 (measured by chemiluminescence immunoassay), TSH, free T4, T3, prolactin, cortisol, ACTH (measured by chemiluminescence immunoassay), calcium, phosphorus, 25-hydroxyvitamin D (25OHD), 1,25-hydroxyvitamin D, LH, FSH, HbA1c (measured by HPLC), and creatinine concentrations were measured by the NIH Department of Laboratory Medicine. Testosterone and estradiol were measured by HPLC tandem mass spectrometry at Mayo Medical Laboratories (Rochester, MN). Mixed meal test A mixed meal test (MMT) was performed in 25 participants with AS and 26 control participants, who ingested a standard breakfast shake consisting of Boost® High Protein (Nestlé HealthCare Nutrition, Inc., Highland Park, MI; 55% carbohydrate, 24% protein, and 21% fat), 7 mL/kg (maximum 400 mL) over 5 minutes (14). Blood samples were drawn from an intravenous catheter at −10, 0, 15, 30, 60, 90, 120, 150, and 180 minutes after consumption of the shake for measurement of glucose, insulin, C-peptide, FFA, and glucagon concentrations. Body composition Height was measured in triplicate to the nearest 0.1 cm with a stadiometer. Weight was measured with an electronic digital scale to the nearest 0.1 kg. Waist circumference measurements at the iliac crest were obtained in triplicate by a registered dietitian. Total percentage body fat was measured by dual-energy X-ray absorptiometry with the Hologic QDR-4500A or Hologic Discovery A (Hologic, Waltham, MA). Visceral and subcutaneous fat volumes at L2–3 and L4–5 were measured by abdominal MRI, and fat contents of liver and right lateral midthigh quadriceps muscle were assessed by MRS with the Philips Achieva 3.0T TX (Amsterdam, Netherlands). The percentage abdominal visceral fat was calculated as the total volume of visceral fat divided by the total volume of subcutaneous and visceral fat combined for the L2–3 and L4–5 slices. Energy intake and expenditure A hyperphagia questionnaire (15) was administered to the parents and caregivers of subjects age ≤18 years regarding their observations of the subjects in their usual home environment. Resting energy expenditure (REE) was assessed by indirect calorimetry (TrueOne® 2400 Canopy System; Parvo Medics, Sandy, UT or VmaxTM Encore Metabolic Cart; Viasys, Conshohocken, PA). Predicted REE was calculated with the Mifflin-St. Jeor equation (16). Calculations and definitions BMI z scores were calculated according to the age- and sex-specific Centers for Disease Control and Prevention 2000 standards for age ≥2 years (17) and World Health Organization 2006 standards for age <2 years (18). Obesity was defined as a BMI ≥30 kg/m2 in adults or ≥95th percentile for age and sex in children. For the metabolic analyses, metabolic syndrome (MS) was defined as having three or more of the following (19): abdominal obesity [waist circumference >102 cm in men or >88 cm in women, or >90th percentile for age and sex (20)], hypertriglyceridemia [triglycerides >150 mg/dL or >90th percentile for age and sex (21)], low HDL-cholesterol [HDL-cholesterol <40 mg/dL for men, <50 mg/dL for women, or <10th percentile for age and sex (21)], elevated blood pressure [BP; systolic or diastolic BP >120/80 or >90th percentile adjusted for height, age, and sex (22)], impaired glucose tolerance (HbA1c ≥5.7%, fasting glucose ≥100 mg/dL, or 2-hour mixed meal glucose ≥140 mg/dL). Estimated glomerular filtration rate (eGFR) was calculated with the bedside Schwartz equation in children (23) and the Chronic Kidney Disease Epidemiology Collaboration equation in adults (24). Homeostatic model assessment of insulin resistance was calculated by the following equation: [Fasting insulin (μIU/mL) × fasting glucose (mg/dL)/405] (25). Insulin sensitivity during the MMT was assessed through the whole-body insulin sensitivity index (WBISI) with the following equation: 10,000/√[fasting glucose (mg/dL) × fasting insulin (μIU/mL) × mean glucose (mg/dL) × mean insulin (μIU/mL)] (26). Statistical analyses SPSS 22 (IBM Corp., Armonk, NY) was used for statistical analyses. Normality was assessed by skewness, kurtosis, and Kolmogorov-Smirnov test. Fisher’s exact (for binary) and χ2 (for three or more categories) tests compared categorical variables between groups. Independent-samples t tests and Pearson correlations were performed for continuous variables of normal distribution and skewed data that were normalized after log or arcsine square root transformation. Nonparametric data were analyzed by Mann-Whitney U tests. Analyses of covariance (ANCOVAs) compared variables between groups, adjusting for age, sex, race, and body composition. A P value <0.001 (0.05/50) was considered significant after Bonferroni correction for multiple comparisons. Nominal P values are shown. Results Genetic testing results for patients with AS The cohort included 32 families, with 5 families having multiple siblings with AS. Mutations in both alleles of ALMS1 were identified in 31 families, and in 1 family, only one (heterozygous) mutation was identified (Table 1). All mutations are predicted to result in premature protein truncation. Endocrine function in AS The 38 patients with AS (age 2 to 38 years), who had a high rate of obesity (76.3%), were compared with a group of 76 control subjects (age 2 to 48 years), whose selection was purposely enriched for obesity to match the high prevalence of obesity in patients with AS. Controls had comparable age, sex, race, and BMI z scores (Table 2). Despite their similar mean BMI z score, the AS group had 14 (36.8%) patients with T2DM compared with none in the control group (P < 0.0000001). Six of the 14 patients with AS with T2DM were obese, 7 were overweight, and 1 was normal weight. Representative photographs of an overweight but nonobese patient with AS who had severe acanthosis nigricans, extreme insulin resistance, and T2DM necessitating 7 units/kg/d of insulin are shown in Supplemental Fig. 1. Table 2. Characteristics of Patients With AS and Control Subjects n Alström n Control P Age, y 38 16.0 ± 10.5 76 16.2 ± 9.8 0.96 Sex, % female 38 52.6 76 52.6 1.00 Race, % African American 38 7.9 76 21.1 0.11 BMI, kg/m2 38 29.9 ± 10.6 76 29.6 ± 7.6 0.88 BMI z score 38 2.07 ± 0.93 76 1.91 ± 0.94 0.41 Height z score 38 −0.51 ± 1.20 76 0.52 ± 1.21 0.00004 Arm span/height ratio 21 1.00 ± 0.03 26 0.99 ± 0.13 0.85 Sitting/standing ratio 17 0.57 ± 0.09 16 0.55 ± 0.07 0.38 IGF-1, ng/mL 37 143 (96–309) 54 318 (203–463) 0.001 TSH, μU/mL 38 2.52 ± 1.52 66 2.07 ± 1.05 0.11 Free T4, ng/dL 38 1.0 ± 0.2 64 1.1 ± 0.2 0.002 T3, ng/dL 35 137 ± 33 36 148 ± 37 0.20 Morning cortisol, μg/dL 35 10.9 ± 5.2 40 10.0 ± 5.0 0.49 Morning ACTH, pg/mL 35 17.7 (14.6–27.9) 18 16.2 (9.1–24.5) 0.13 25OHD, ng/mL 35 33.2 ± 14.3 45 24.7 ± 9.2 0.004 1,25OHD, pg/mL 37 45.8 ± 19.3 19 47.7 ± 8.6 0.61 PTH, pg/mL 36 31.1 ± 14.6 23 42.1 ± 18.9 0.01 Calcium, mg/dL 38 9.5 ± 0.4 65 9.3 ± 0.4 0.04 Phosphorus, mg/dL 38 4.7 ± 0.8 52 4.3 ± 0.7 0.01 Prolactin, μg/L 33 6.9 (4.3–11.1) 39 6.5 (5.0–11.1) 0.58 Total body fat, % 30 34.8 ± 7.8 61 35.4 ± 9.1 0.89 Lean mass, kg 30 40.8 ± 14.0 61 49.7 ± 15.5 0.009 Bone mineral content, kg 30 1.8 ± 0.6 61 2.1 ± 0.6 0.02 Abdominal visceral fat, % 26 18.8 ± 8.1 34 21.5 ± 9.7 0.26 Waist circumference z score 31 1.05 ± 1.06 31 0.78 ± 1.00 0.30 REE, kcal/day 35 1389 ± 372 21 1638 ± 374 0.02 REE, % predicted 35 98.9 ± 17.7 21 98.1 ± 14.8 0.87 RQ 35 0.92 ± 0.09 21 0.84 ± 0.05 0.0006 Hyperphagia score 23 27 ± 13 27 17 ± 7 0.003 Systolic BP z score 36 1.08 ± 1.11 71 0.70 ± 1.22 0.12 Diastolic BP z score 36 0.29 ± 0.87 71 0.14 ± 0.67 0.33 Fasting triglycerides, mg/dL 38 123 (82–202) 74 79 (57–129) 0.000001 LDL-cholesterol, mg/dL 30 81 (66–100) 75 100 (83–115) 0.007 HDL-cholesterol, mg/dL 37 34 (29–43) 74 42 (36–53) 0.000002 ALT, U/L 38 51 ± 33 72 29 ± 14 0.00001 AST, U/L 38 37 ± 23 72 24 ± 9 0.0006 Liver fat, % 25 14.6 ± 10.7 27 4.9 ± 3.7 0.0002 Muscle fat, % 23 5.8 ± 3.5 11 3.6 ± 1.6 0.04 Fasting glucose, mg/dL 38 87 (82–110) 76 89 (84–92) 0.94 Fasting C-peptide, ng/mL 37 5.4 (2.5–9.8) 43 2.0 (1.5–3.3) 0.000003 Fasting insulin, mIU/L 38 42.3 (11.7–78.5) 72 10.5 (6.0–18.9) 0.000002 Fasting FFA, mEq/L 35 0.54 (0.43–0.76) 60 0.61 (0.47–0.98) 0.30 Fasting glucagon, pg/mL 33 31.0 (24.6–57.8) 26 27.3 (20.5–32.3) 0.048 HOMA-IR 38 9.88 (2.34–18.1) 71 2.34 (1.16–4.28) 0.000002 WBISI 25 1.07 ± 1.41 26 6.95 ± 4.94 0.000003 Mixed meal glucose AUC 25 29.7 ± 14.3 × 103 26 17.9 ± 1.5 × 103 0.0004 Mixed meal C-peptide AUC 25 3.7 ± 1.8 × 103 26 1.1 ± 0.4 × 103 0.0000002 Mixed meal insulin AUC 23 59.4 ± 38.3 × 103 26 9.8 ± 4.6 × 103 0.000003 Mixed meal FFA AUC 22 72.6 ± 30.4 24 55.6 ± 23.9 0.04 Mixed meal glucagon AUC 20 13.8 ± 11.3× 103 24 6.9 ± 3.4 × 103 0.016 HbA1c, % 36 5.4 (5.1–6.1) 60 5.2 (5.0–5.6) 0.005 Serum creatinine, mg/dL 38 0.63 (0.48–0.77) 73 0.62 (0.40–0.95) 0.24 eGFR, mL/min/1.73 m2 38 104 ± 37 73 112 ± 21 0.66 n Alström n Control P Age, y 38 16.0 ± 10.5 76 16.2 ± 9.8 0.96 Sex, % female 38 52.6 76 52.6 1.00 Race, % African American 38 7.9 76 21.1 0.11 BMI, kg/m2 38 29.9 ± 10.6 76 29.6 ± 7.6 0.88 BMI z score 38 2.07 ± 0.93 76 1.91 ± 0.94 0.41 Height z score 38 −0.51 ± 1.20 76 0.52 ± 1.21 0.00004 Arm span/height ratio 21 1.00 ± 0.03 26 0.99 ± 0.13 0.85 Sitting/standing ratio 17 0.57 ± 0.09 16 0.55 ± 0.07 0.38 IGF-1, ng/mL 37 143 (96–309) 54 318 (203–463) 0.001 TSH, μU/mL 38 2.52 ± 1.52 66 2.07 ± 1.05 0.11 Free T4, ng/dL 38 1.0 ± 0.2 64 1.1 ± 0.2 0.002 T3, ng/dL 35 137 ± 33 36 148 ± 37 0.20 Morning cortisol, μg/dL 35 10.9 ± 5.2 40 10.0 ± 5.0 0.49 Morning ACTH, pg/mL 35 17.7 (14.6–27.9) 18 16.2 (9.1–24.5) 0.13 25OHD, ng/mL 35 33.2 ± 14.3 45 24.7 ± 9.2 0.004 1,25OHD, pg/mL 37 45.8 ± 19.3 19 47.7 ± 8.6 0.61 PTH, pg/mL 36 31.1 ± 14.6 23 42.1 ± 18.9 0.01 Calcium, mg/dL 38 9.5 ± 0.4 65 9.3 ± 0.4 0.04 Phosphorus, mg/dL 38 4.7 ± 0.8 52 4.3 ± 0.7 0.01 Prolactin, μg/L 33 6.9 (4.3–11.1) 39 6.5 (5.0–11.1) 0.58 Total body fat, % 30 34.8 ± 7.8 61 35.4 ± 9.1 0.89 Lean mass, kg 30 40.8 ± 14.0 61 49.7 ± 15.5 0.009 Bone mineral content, kg 30 1.8 ± 0.6 61 2.1 ± 0.6 0.02 Abdominal visceral fat, % 26 18.8 ± 8.1 34 21.5 ± 9.7 0.26 Waist circumference z score 31 1.05 ± 1.06 31 0.78 ± 1.00 0.30 REE, kcal/day 35 1389 ± 372 21 1638 ± 374 0.02 REE, % predicted 35 98.9 ± 17.7 21 98.1 ± 14.8 0.87 RQ 35 0.92 ± 0.09 21 0.84 ± 0.05 0.0006 Hyperphagia score 23 27 ± 13 27 17 ± 7 0.003 Systolic BP z score 36 1.08 ± 1.11 71 0.70 ± 1.22 0.12 Diastolic BP z score 36 0.29 ± 0.87 71 0.14 ± 0.67 0.33 Fasting triglycerides, mg/dL 38 123 (82–202) 74 79 (57–129) 0.000001 LDL-cholesterol, mg/dL 30 81 (66–100) 75 100 (83–115) 0.007 HDL-cholesterol, mg/dL 37 34 (29–43) 74 42 (36–53) 0.000002 ALT, U/L 38 51 ± 33 72 29 ± 14 0.00001 AST, U/L 38 37 ± 23 72 24 ± 9 0.0006 Liver fat, % 25 14.6 ± 10.7 27 4.9 ± 3.7 0.0002 Muscle fat, % 23 5.8 ± 3.5 11 3.6 ± 1.6 0.04 Fasting glucose, mg/dL 38 87 (82–110) 76 89 (84–92) 0.94 Fasting C-peptide, ng/mL 37 5.4 (2.5–9.8) 43 2.0 (1.5–3.3) 0.000003 Fasting insulin, mIU/L 38 42.3 (11.7–78.5) 72 10.5 (6.0–18.9) 0.000002 Fasting FFA, mEq/L 35 0.54 (0.43–0.76) 60 0.61 (0.47–0.98) 0.30 Fasting glucagon, pg/mL 33 31.0 (24.6–57.8) 26 27.3 (20.5–32.3) 0.048 HOMA-IR 38 9.88 (2.34–18.1) 71 2.34 (1.16–4.28) 0.000002 WBISI 25 1.07 ± 1.41 26 6.95 ± 4.94 0.000003 Mixed meal glucose AUC 25 29.7 ± 14.3 × 103 26 17.9 ± 1.5 × 103 0.0004 Mixed meal C-peptide AUC 25 3.7 ± 1.8 × 103 26 1.1 ± 0.4 × 103 0.0000002 Mixed meal insulin AUC 23 59.4 ± 38.3 × 103 26 9.8 ± 4.6 × 103 0.000003 Mixed meal FFA AUC 22 72.6 ± 30.4 24 55.6 ± 23.9 0.04 Mixed meal glucagon AUC 20 13.8 ± 11.3× 103 24 6.9 ± 3.4 × 103 0.016 HbA1c, % 36 5.4 (5.1–6.1) 60 5.2 (5.0–5.6) 0.005 Serum creatinine, mg/dL 38 0.63 (0.48–0.77) 73 0.62 (0.40–0.95) 0.24 eGFR, mL/min/1.73 m2 38 104 ± 37 73 112 ± 21 0.66 Data are shown as mean ± SD for normally distributed values, median (interquartile range) for non–normally distributed values, or percentage. P values in bold indicate significance after correction for multiple comparisons. Abbreviations: 1,25OHD, 1,25-hydroxyvitamin D; AST, aspartate aminotransferase; HOMA-IR, homeostatic model assessment of insulin resistance; RQ, respiratory quotient. View Large Table 2. Characteristics of Patients With AS and Control Subjects n Alström n Control P Age, y 38 16.0 ± 10.5 76 16.2 ± 9.8 0.96 Sex, % female 38 52.6 76 52.6 1.00 Race, % African American 38 7.9 76 21.1 0.11 BMI, kg/m2 38 29.9 ± 10.6 76 29.6 ± 7.6 0.88 BMI z score 38 2.07 ± 0.93 76 1.91 ± 0.94 0.41 Height z score 38 −0.51 ± 1.20 76 0.52 ± 1.21 0.00004 Arm span/height ratio 21 1.00 ± 0.03 26 0.99 ± 0.13 0.85 Sitting/standing ratio 17 0.57 ± 0.09 16 0.55 ± 0.07 0.38 IGF-1, ng/mL 37 143 (96–309) 54 318 (203–463) 0.001 TSH, μU/mL 38 2.52 ± 1.52 66 2.07 ± 1.05 0.11 Free T4, ng/dL 38 1.0 ± 0.2 64 1.1 ± 0.2 0.002 T3, ng/dL 35 137 ± 33 36 148 ± 37 0.20 Morning cortisol, μg/dL 35 10.9 ± 5.2 40 10.0 ± 5.0 0.49 Morning ACTH, pg/mL 35 17.7 (14.6–27.9) 18 16.2 (9.1–24.5) 0.13 25OHD, ng/mL 35 33.2 ± 14.3 45 24.7 ± 9.2 0.004 1,25OHD, pg/mL 37 45.8 ± 19.3 19 47.7 ± 8.6 0.61 PTH, pg/mL 36 31.1 ± 14.6 23 42.1 ± 18.9 0.01 Calcium, mg/dL 38 9.5 ± 0.4 65 9.3 ± 0.4 0.04 Phosphorus, mg/dL 38 4.7 ± 0.8 52 4.3 ± 0.7 0.01 Prolactin, μg/L 33 6.9 (4.3–11.1) 39 6.5 (5.0–11.1) 0.58 Total body fat, % 30 34.8 ± 7.8 61 35.4 ± 9.1 0.89 Lean mass, kg 30 40.8 ± 14.0 61 49.7 ± 15.5 0.009 Bone mineral content, kg 30 1.8 ± 0.6 61 2.1 ± 0.6 0.02 Abdominal visceral fat, % 26 18.8 ± 8.1 34 21.5 ± 9.7 0.26 Waist circumference z score 31 1.05 ± 1.06 31 0.78 ± 1.00 0.30 REE, kcal/day 35 1389 ± 372 21 1638 ± 374 0.02 REE, % predicted 35 98.9 ± 17.7 21 98.1 ± 14.8 0.87 RQ 35 0.92 ± 0.09 21 0.84 ± 0.05 0.0006 Hyperphagia score 23 27 ± 13 27 17 ± 7 0.003 Systolic BP z score 36 1.08 ± 1.11 71 0.70 ± 1.22 0.12 Diastolic BP z score 36 0.29 ± 0.87 71 0.14 ± 0.67 0.33 Fasting triglycerides, mg/dL 38 123 (82–202) 74 79 (57–129) 0.000001 LDL-cholesterol, mg/dL 30 81 (66–100) 75 100 (83–115) 0.007 HDL-cholesterol, mg/dL 37 34 (29–43) 74 42 (36–53) 0.000002 ALT, U/L 38 51 ± 33 72 29 ± 14 0.00001 AST, U/L 38 37 ± 23 72 24 ± 9 0.0006 Liver fat, % 25 14.6 ± 10.7 27 4.9 ± 3.7 0.0002 Muscle fat, % 23 5.8 ± 3.5 11 3.6 ± 1.6 0.04 Fasting glucose, mg/dL 38 87 (82–110) 76 89 (84–92) 0.94 Fasting C-peptide, ng/mL 37 5.4 (2.5–9.8) 43 2.0 (1.5–3.3) 0.000003 Fasting insulin, mIU/L 38 42.3 (11.7–78.5) 72 10.5 (6.0–18.9) 0.000002 Fasting FFA, mEq/L 35 0.54 (0.43–0.76) 60 0.61 (0.47–0.98) 0.30 Fasting glucagon, pg/mL 33 31.0 (24.6–57.8) 26 27.3 (20.5–32.3) 0.048 HOMA-IR 38 9.88 (2.34–18.1) 71 2.34 (1.16–4.28) 0.000002 WBISI 25 1.07 ± 1.41 26 6.95 ± 4.94 0.000003 Mixed meal glucose AUC 25 29.7 ± 14.3 × 103 26 17.9 ± 1.5 × 103 0.0004 Mixed meal C-peptide AUC 25 3.7 ± 1.8 × 103 26 1.1 ± 0.4 × 103 0.0000002 Mixed meal insulin AUC 23 59.4 ± 38.3 × 103 26 9.8 ± 4.6 × 103 0.000003 Mixed meal FFA AUC 22 72.6 ± 30.4 24 55.6 ± 23.9 0.04 Mixed meal glucagon AUC 20 13.8 ± 11.3× 103 24 6.9 ± 3.4 × 103 0.016 HbA1c, % 36 5.4 (5.1–6.1) 60 5.2 (5.0–5.6) 0.005 Serum creatinine, mg/dL 38 0.63 (0.48–0.77) 73 0.62 (0.40–0.95) 0.24 eGFR, mL/min/1.73 m2 38 104 ± 37 73 112 ± 21 0.66 n Alström n Control P Age, y 38 16.0 ± 10.5 76 16.2 ± 9.8 0.96 Sex, % female 38 52.6 76 52.6 1.00 Race, % African American 38 7.9 76 21.1 0.11 BMI, kg/m2 38 29.9 ± 10.6 76 29.6 ± 7.6 0.88 BMI z score 38 2.07 ± 0.93 76 1.91 ± 0.94 0.41 Height z score 38 −0.51 ± 1.20 76 0.52 ± 1.21 0.00004 Arm span/height ratio 21 1.00 ± 0.03 26 0.99 ± 0.13 0.85 Sitting/standing ratio 17 0.57 ± 0.09 16 0.55 ± 0.07 0.38 IGF-1, ng/mL 37 143 (96–309) 54 318 (203–463) 0.001 TSH, μU/mL 38 2.52 ± 1.52 66 2.07 ± 1.05 0.11 Free T4, ng/dL 38 1.0 ± 0.2 64 1.1 ± 0.2 0.002 T3, ng/dL 35 137 ± 33 36 148 ± 37 0.20 Morning cortisol, μg/dL 35 10.9 ± 5.2 40 10.0 ± 5.0 0.49 Morning ACTH, pg/mL 35 17.7 (14.6–27.9) 18 16.2 (9.1–24.5) 0.13 25OHD, ng/mL 35 33.2 ± 14.3 45 24.7 ± 9.2 0.004 1,25OHD, pg/mL 37 45.8 ± 19.3 19 47.7 ± 8.6 0.61 PTH, pg/mL 36 31.1 ± 14.6 23 42.1 ± 18.9 0.01 Calcium, mg/dL 38 9.5 ± 0.4 65 9.3 ± 0.4 0.04 Phosphorus, mg/dL 38 4.7 ± 0.8 52 4.3 ± 0.7 0.01 Prolactin, μg/L 33 6.9 (4.3–11.1) 39 6.5 (5.0–11.1) 0.58 Total body fat, % 30 34.8 ± 7.8 61 35.4 ± 9.1 0.89 Lean mass, kg 30 40.8 ± 14.0 61 49.7 ± 15.5 0.009 Bone mineral content, kg 30 1.8 ± 0.6 61 2.1 ± 0.6 0.02 Abdominal visceral fat, % 26 18.8 ± 8.1 34 21.5 ± 9.7 0.26 Waist circumference z score 31 1.05 ± 1.06 31 0.78 ± 1.00 0.30 REE, kcal/day 35 1389 ± 372 21 1638 ± 374 0.02 REE, % predicted 35 98.9 ± 17.7 21 98.1 ± 14.8 0.87 RQ 35 0.92 ± 0.09 21 0.84 ± 0.05 0.0006 Hyperphagia score 23 27 ± 13 27 17 ± 7 0.003 Systolic BP z score 36 1.08 ± 1.11 71 0.70 ± 1.22 0.12 Diastolic BP z score 36 0.29 ± 0.87 71 0.14 ± 0.67 0.33 Fasting triglycerides, mg/dL 38 123 (82–202) 74 79 (57–129) 0.000001 LDL-cholesterol, mg/dL 30 81 (66–100) 75 100 (83–115) 0.007 HDL-cholesterol, mg/dL 37 34 (29–43) 74 42 (36–53) 0.000002 ALT, U/L 38 51 ± 33 72 29 ± 14 0.00001 AST, U/L 38 37 ± 23 72 24 ± 9 0.0006 Liver fat, % 25 14.6 ± 10.7 27 4.9 ± 3.7 0.0002 Muscle fat, % 23 5.8 ± 3.5 11 3.6 ± 1.6 0.04 Fasting glucose, mg/dL 38 87 (82–110) 76 89 (84–92) 0.94 Fasting C-peptide, ng/mL 37 5.4 (2.5–9.8) 43 2.0 (1.5–3.3) 0.000003 Fasting insulin, mIU/L 38 42.3 (11.7–78.5) 72 10.5 (6.0–18.9) 0.000002 Fasting FFA, mEq/L 35 0.54 (0.43–0.76) 60 0.61 (0.47–0.98) 0.30 Fasting glucagon, pg/mL 33 31.0 (24.6–57.8) 26 27.3 (20.5–32.3) 0.048 HOMA-IR 38 9.88 (2.34–18.1) 71 2.34 (1.16–4.28) 0.000002 WBISI 25 1.07 ± 1.41 26 6.95 ± 4.94 0.000003 Mixed meal glucose AUC 25 29.7 ± 14.3 × 103 26 17.9 ± 1.5 × 103 0.0004 Mixed meal C-peptide AUC 25 3.7 ± 1.8 × 103 26 1.1 ± 0.4 × 103 0.0000002 Mixed meal insulin AUC 23 59.4 ± 38.3 × 103 26 9.8 ± 4.6 × 103 0.000003 Mixed meal FFA AUC 22 72.6 ± 30.4 24 55.6 ± 23.9 0.04 Mixed meal glucagon AUC 20 13.8 ± 11.3× 103 24 6.9 ± 3.4 × 103 0.016 HbA1c, % 36 5.4 (5.1–6.1) 60 5.2 (5.0–5.6) 0.005 Serum creatinine, mg/dL 38 0.63 (0.48–0.77) 73 0.62 (0.40–0.95) 0.24 eGFR, mL/min/1.73 m2 38 104 ± 37 73 112 ± 21 0.66 Data are shown as mean ± SD for normally distributed values, median (interquartile range) for non–normally distributed values, or percentage. P values in bold indicate significance after correction for multiple comparisons. Abbreviations: 1,25OHD, 1,25-hydroxyvitamin D; AST, aspartate aminotransferase; HOMA-IR, homeostatic model assessment of insulin resistance; RQ, respiratory quotient. View Large Height z score was significantly lower in patients with AS compared with controls (P = 0.00004, Table 2). Patients with AS and controls had similar arm span/height ratios (P = 0.85, Table 2) and sitting/standing height ratios (P = 0.38, Table 2). IGF-1 was nominally lower in patients with AS compared with controls (P = 0.001). Hypothyroidism was observed in 11 patients with AS, 28.9% of the cohort. Four patients were diagnosed with central hypothyroidism: two patients had midnormal free T4 but suppressed TSH while taking levothyroxine for a previous diagnosis of central hypothyroidism; two other patients had low free T4 and normal TSH (diurnal pattern abnormal for one and not tested for the other). Two patients with AS had evidence of autoimmune primary hypothyroidism (low free T4, elevated TSH, and positive antithyroid antibodies), and five patients with a previous diagnosis of hypothyroidism appeared to have antibody-negative primary hypothyroidism, with normal free T4, normal TSH, and negative antibodies while they were taking appropriate replacement doses of levothyroxine. In contrast, none of the control subjects had a previous diagnosis of hypothyroidism, and of the 66 control subjects who had thyroid function test results available, only 2 had elevated TSH values and none had low free T4. Mean TSH and T3 were similar between groups, but free T4 was nominally lower for AS (P = 0.002, Table 2). Morning cortisol (P = 0.49) and morning ACTH (P = 0.13) were similar between groups (Table 2). One patient with AS had a previous diagnosis of central adrenal insufficiency (2.6%, Table 3); no additional patients were diagnosed with adrenal insufficiency at evaluation. None (0%) of 29 patients with AS who had 24-hour urinary free cortisol measured had values above the reference range for age, compared with 3 (12%, P = 0.09) of 25 in the control group with urinary cortisol measured who had values above reference range for age, but none were greater than two times the upper limits of normal. Table 3. Endocrine Abnormalities in Patients With AS % (n) AS (n = 38) Obesity 76.3 (29) T2DM 36.8 (14) Hypothyroidism 28.9 (11) Short stature 10.5 (4) Adrenal insufficiency 2.6 (1) Hypogonadism in adulthood (n = 14) 57.1 (8) Male patients (n = 18) Microphallus 50.0 (9) Undescended testes 11.1 (2) Hypospadias 5.6 (1) Small testes in adulthood (n = 7) 100.0 (7) Low testosterone in adulthood (n = 7) 42.9 (3) Female patients (n = 20) Oligomenorrhea or amenorrhea in adulthood (n = 7) 71.4 (5) Alopecia 40.0 (8) High testosterone 25.0 (5) Hirsutism 15.0 (3) % (n) AS (n = 38) Obesity 76.3 (29) T2DM 36.8 (14) Hypothyroidism 28.9 (11) Short stature 10.5 (4) Adrenal insufficiency 2.6 (1) Hypogonadism in adulthood (n = 14) 57.1 (8) Male patients (n = 18) Microphallus 50.0 (9) Undescended testes 11.1 (2) Hypospadias 5.6 (1) Small testes in adulthood (n = 7) 100.0 (7) Low testosterone in adulthood (n = 7) 42.9 (3) Female patients (n = 20) Oligomenorrhea or amenorrhea in adulthood (n = 7) 71.4 (5) Alopecia 40.0 (8) High testosterone 25.0 (5) Hirsutism 15.0 (3) View Large Table 3. Endocrine Abnormalities in Patients With AS % (n) AS (n = 38) Obesity 76.3 (29) T2DM 36.8 (14) Hypothyroidism 28.9 (11) Short stature 10.5 (4) Adrenal insufficiency 2.6 (1) Hypogonadism in adulthood (n = 14) 57.1 (8) Male patients (n = 18) Microphallus 50.0 (9) Undescended testes 11.1 (2) Hypospadias 5.6 (1) Small testes in adulthood (n = 7) 100.0 (7) Low testosterone in adulthood (n = 7) 42.9 (3) Female patients (n = 20) Oligomenorrhea or amenorrhea in adulthood (n = 7) 71.4 (5) Alopecia 40.0 (8) High testosterone 25.0 (5) Hirsutism 15.0 (3) % (n) AS (n = 38) Obesity 76.3 (29) T2DM 36.8 (14) Hypothyroidism 28.9 (11) Short stature 10.5 (4) Adrenal insufficiency 2.6 (1) Hypogonadism in adulthood (n = 14) 57.1 (8) Male patients (n = 18) Microphallus 50.0 (9) Undescended testes 11.1 (2) Hypospadias 5.6 (1) Small testes in adulthood (n = 7) 100.0 (7) Low testosterone in adulthood (n = 7) 42.9 (3) Female patients (n = 20) Oligomenorrhea or amenorrhea in adulthood (n = 7) 71.4 (5) Alopecia 40.0 (8) High testosterone 25.0 (5) Hirsutism 15.0 (3) View Large Serum calcium (P = 0.04), phosphorus (P = 0.01), and 25OHD (P = 0.004) were nominally higher, whereas plasma PTH (P = 0.01) was nominally lower and 1,25-hydroxyvitamin D (P = 0.61) was similar in patients with AS compared with control subjects (Table 2). A higher percentage of patients with AS were prescribed vitamin D supplementation (55.3% in AS vs 15.8% in controls, P < 0.0001). After adjustment for age, sex, race, and BMI z score, 25OHD remained nominally higher in patients with AS (P = 0.009). In ANCOVAs adjusted for 25OHD, the difference in PTH was attenuated (P = 0.05). Prolactin was normal for all participants with AS and similar between groups (P = 0.58, Table 2). Hypogonadism was observed in 57.1% of adults with AS (35.7% primary gonadal insufficiency with elevated gonadotropins; 21.4% central gonadotropin insufficiency with nonelevated or suppressed LH and FSH) but only in 6.7% of control adults (P = 0.005). Sex steroid–associated abnormalities in male patients with AS included microphallus (50%), undescended testes (11.1%), hypospadias (5.6%), small testes in adulthood (100%), and low testosterone in adulthood (42.9%) (Table 3). Female patients with AS frequently had alopecia (40%, Supplemental Fig. 2), elevated testosterone (25%), hirsutism (15%, Supplemental Fig. 2), and oligomenorrhea or amenorrhea in adulthood (85.7%) (Table 3). Testosterone was nominally higher in female patients with AS compared with controls (51 ± 39 vs 26 ± 17 ng/dL, P = 0.002), and nominally lower in adult male patients with AS compared with controls (265 ± 107 vs 475 ± 169 ng/dL, P = 0.01). Comparison of metabolic parameters in patients with AS vs BMI-matched controls Total body composition and fat distribution Total percentage body fat measured by dual-energy X-ray absorptiometry was similar between patients with AS and controls in both unadjusted (P = 0.89, Table 2) and adjusted analyses [covariates: age, sex, and race; adjusted mean (95% CI): patients with AS vs controls: 33.9% (31.1% to 36.9%) vs 35.1% (33.0% to 37.1%); P = 0.54]. Unadjusted lean mass and bone mineral content were nominally lower in patients with AS (Table 2) but similar after adjustment for the shorter stature of patients with AS (lean body mass: P = 0.25, and bone mineral content: P = 0.18). Waist circumference z score (normed by age and sex) was similar in patients with AS compared with controls in both unadjusted analysis (P = 0.30, Table 2) and after adjustment for race (P = 0.47). Patients with AS and controls had similar percentages of abdominal visceral fat at L2–5 (P = 0.26, Table 2), which remained comparable after adjustment for age, sex, and race (P = 0.15). Liver and muscle fat content BMI z score was nominally positively correlated with liver fat percentage (r = 0.43, P = 0.002) and muscle fat percentage (r = 0.53, P = 0.001) with all subjects combined, and this relationship remained nominally significant when subjects were analyzed by separate diagnosis categories (all Ps < 0.05, Figs. 1A and 1B). Mean liver fat content was significantly higher in patients with AS compared with controls (P = 0.0002, Table 2) and remained significant after we adjusted for age, sex, race, and BMI z score (P = 0.0005 Fig. 1C), indicating that even after we controlled for severity of obesity, patients with AS had a higher percentage of liver fat. ALT and aspartate aminotransferase were significantly higher in AS in both unadjusted analyses (Ps < 0.001, Table 2) and after adjustment for age, sex, race, and BMI z score (Ps < 0.001, Figs. 1D and 1E). Muscle fat content was nominally higher in patients with AS compared with controls (P = 0.02, Table 2), but this difference was eliminated after adjustment for age, sex, race, and BMI z score [AS vs controls: 4.9% (95% CI, 4.0% to 5.9%) vs 4.3% (95% CI, 2.9% to 5.8%), P = 0.50]. Figure 1. View largeDownload slide Liver and muscle fat content in patients with AS compared with controls. (A) Positive correlations of liver fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of liver fat percentage measured by MRS. Significant difference in intercept of linear regressions indicate higher liver fat values for patients with AS compared with controls for any given BMI (P = 0.0001). (B) Positive correlations of right lateral midthigh quadriceps fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of muscle fat percentage measured by MRS. Possible trends in the difference in intercept of linear regressions indicate a tendency for higher muscle fat values for patients with AS compared with controls for any given BMI (P = 0.08). (C) Liver fat percentage adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver fat compared with controls. (D) Serum ALT and (E) aspartate aminotransferase adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver function tests compared with controls. Figure 1. View largeDownload slide Liver and muscle fat content in patients with AS compared with controls. (A) Positive correlations of liver fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of liver fat percentage measured by MRS. Significant difference in intercept of linear regressions indicate higher liver fat values for patients with AS compared with controls for any given BMI (P = 0.0001). (B) Positive correlations of right lateral midthigh quadriceps fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of muscle fat percentage measured by MRS. Possible trends in the difference in intercept of linear regressions indicate a tendency for higher muscle fat values for patients with AS compared with controls for any given BMI (P = 0.08). (C) Liver fat percentage adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver fat compared with controls. (D) Serum ALT and (E) aspartate aminotransferase adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver function tests compared with controls. Energy balance The parent- or caregiver-reported hyperphagia questionnaire total score was nominally higher in patients with AS vs controls (P = 0.003, Table 2) and remained nominally higher after we controlled for age and BMI z score (P = 0.03). REE was nominally lower in patients with AS vs controls (P = 0.02, Table 2) but no longer different after adjustment for age, sex, race, and lean body mass [1469 (95% CI, 1377 to 1561) vs 1510 (95% CI, 1398 to 1623) kcal/day, P = 0.59]. Patients with AS had a higher respiratory quotient in both unadjusted analysis (P = 0.0006, Table 2) and after adjustment for age, sex, race, and BMI z score (P = 0.0006, Fig. 2A), indicating relatively greater utilization of carbohydrate vs fat as the energy substrate. The Mifflin-St. Jeor equation predicted REE in both patients with AS and controls equally well (P = 0.87). Figure 2. View largeDownload slide Energy balance and glucose homeostasis in patients with AS compared with controls. (A) Adjusted respiratory quotient from indirect calorimetry. Higher respiratory quotient in AS indicates greater utilization of carbohydrate vs fat as the energy substrate. (B) Adjusted WBISI. Patients with AS had lower insulin sensitivity. (C) Unadjusted glucose values and (D) adjusted glucose AUC during the MMT. Patients with AS had higher glucose AUC compared with controls. (E) Unadjusted insulin values and (F) adjusted insulin AUC during the MMT. Patients with AS had higher insulin AUC compared with controls. For (A), (B), (D), and (F), the covariates for adjustment were age, sex, race, and BMI z score. Figure 2. View largeDownload slide Energy balance and glucose homeostasis in patients with AS compared with controls. (A) Adjusted respiratory quotient from indirect calorimetry. Higher respiratory quotient in AS indicates greater utilization of carbohydrate vs fat as the energy substrate. (B) Adjusted WBISI. Patients with AS had lower insulin sensitivity. (C) Unadjusted glucose values and (D) adjusted glucose AUC during the MMT. Patients with AS had higher glucose AUC compared with controls. (E) Unadjusted insulin values and (F) adjusted insulin AUC during the MMT. Patients with AS had higher insulin AUC compared with controls. For (A), (B), (D), and (F), the covariates for adjustment were age, sex, race, and BMI z score. Glucose homeostasis Compared with controls, patients with AS had similar fasting glucose (P = 0.84, Table 2) but higher fasting C-peptide and insulin, with consequently higher homeostatic model assessment of insulin resistance (Ps < 0.001, Table 2). Both unadjusted and adjusted WBISI derived from the MMT were significantly lower in patients with AS (Ps < 0.001, Table 2 and Fig. 2B). MMT glucose and insulin measurements and their adjusted area under the curve (AUC) values were higher in patients with AS (Ps < 0.001, Table 2 and Figs. 2C–2F). Fasting FFA was similar between groups, and MMT FFA AUC was nominally higher in patients with AS (Table 2), but after adjustment for age, sex, race, and BMI z score, both fasting FFA (P = 0.13) and MMT FFA AUC (P = 0.32) were similar for patients with AS and controls. Fasting glucagon and MMT glucagon AUC were nominally higher in patients with AS (Table 2), but neither was significant after we adjusted for age, sex, race, and BMI z score (fasting: P = 0.29; AUC: P = 0.06). HbA1c was nominally higher in patients with AS (Table 2) and significantly different after adjustment for age, sex, race, and BMI z score (P = 0.0002). After we excluded the subjects with diabetes (14 in patients with AS, none for controls), the outcomes were unchanged (data not shown). Thus, even nondiabetic patients with AS displayed higher glucose and greater insulin resistance compared with BMI z score matched controls. Blood pressure Patients with AS and controls had similar systolic and diastolic BP z scores (Table 2). Fifteen patients in the AS group had been taking antihypertensive medications prescribed by their home medical providers at baseline, whereas there was one taking antihypertensive medication in the control group (P < 0.0001). After we excluded those patients from the AS cohort, unadjusted systolic (P = 0.06) and diastolic (P = 0.23) BP z scores were not significantly different between patients with AS and controls, but after adjustment for age, sex, race, and BMI z score, nominally higher systolic BP z scores and no difference in diastolic BP z scores were observed in patients with AS (P = 0.03, Figs. 3A and 3B). Figure 3. View largeDownload slide BP, lipid profile, and MS in patients with AS compared with controls. (A) Systolic and (B) diastolic BP z scores adjusted for age, sex, race, and BMI z score. Subjects taking BP-lowering medications were excluded. (C) Triglycerides, (D) HDL-cholesterol, and (E) LDL-cholesterol adjusted for age, sex, race, and BMI z score. Subjects taking lipid-altering medications were excluded. (F) Percentage meeting MS criteria (three or more of the following: abdominal obesity, hypertriglyceridemia, low HDL-cholesterol, elevated BP, or impaired glucose tolerance). Figure 3. View largeDownload slide BP, lipid profile, and MS in patients with AS compared with controls. (A) Systolic and (B) diastolic BP z scores adjusted for age, sex, race, and BMI z score. Subjects taking BP-lowering medications were excluded. (C) Triglycerides, (D) HDL-cholesterol, and (E) LDL-cholesterol adjusted for age, sex, race, and BMI z score. Subjects taking lipid-altering medications were excluded. (F) Percentage meeting MS criteria (three or more of the following: abdominal obesity, hypertriglyceridemia, low HDL-cholesterol, elevated BP, or impaired glucose tolerance). Lipid profile Patients with AS had significantly higher triglycerides, significantly lower HDL-cholesterol, and nominally lower low-density lipoprotein (LDL) cholesterol in adjusted analyses (Table 2) and after adjustment for age, sex, race, and BMI z score (P values: 0.000003 for triglycerides, 0.00001 for HDL, and 0.002 for LDL). After we excluded subjects taking lipid-altering medications (eight in patients with AS, none for controls), outcomes were unchanged (Figs. 3C–3E). MS The percentage (95% CI) of patients with MS in AS was 52.6% (35.8% to 69.0%) vs 5.3% (1.5% to 12.9%) among controls [relative risk 9.9 (2.8 to 46.0), P < 0.0000001, Fig. 3F]. With all ages combined, the AS and control groups had similar serum creatinine and eGFR (Table 2), but in adults, patients with AS had nominally higher serum Cr (P = 0.04) and nominally lower eGFR (P = 0.009) than controls. For all MS components that were significantly greater in patients with AS compared with controls, this difference remained significant after we adjusted for eGFR (Ps < 0.001). Discussion In this study, we observed a high frequency of endocrine abnormalities in patients with AS and found the presence of MS to be 10 times higher in patients with AS compared with BMI-matched controls. The most commonly observed abnormalities in our AS cohort were obesity, T2DM, hypothyroidism (central and primary), hypogonadism (central and primary), hyperandrogenism in female patients, and short stature [with proportional body dimensions accompanied by low IGF-1, potentially corroborating previous reports of GH secretion insufficiency in AS (27)]. Although unstimulated cortisol values were similar between AS and control groups, central adrenal insufficiency had been diagnosed in one patient with AS, indicating that, though less common than other endocrinopathies, cortisol deficit is a potential risk in AS. Together these findings point to the diverse role of cilia in the function of the hypothalamic-pituitary axis and peripheral endocrine organs. The pathogenesis of obesity in AS is unclear, but rodent models suggest dual dysfunctions in central nervous system regulation of appetite (28) and adipocyte differentiation (29). Alms1 is expressed in the hypothalamus, a key brain region for energy balance (28). Foz/foz mice with a truncating mutation of Alms1 have normal ciliary formation, but cilia are not maintained postnatally, resulting in a reduction in the number of hypothalamic neuronal cilia (28). Recently, a key receptor in the energy homeostasis regulating leptin-melanocortin pathway, melanocortin-4 receptor, was found to be localized to the primary cilia of hypothalamic neurons (30). Peripherally, ALMS1 is expressed in preadipocytes (31), and disruption of Alms1 induces alterations of adipocyte morphology and gene expression profiles (29). Our group previously reported higher serum leptin concentrations in AS and another hyperphagia- and obesity-associated ciliopathy, Bardet-Biedl syndrome, compared with BMI-matched controls (32–34), an observation consistent with murine data showing that cilia are needed for leptin receptor trafficking (35). Our current study expands the clinical phenotyping of human AS and examines energy balance by using a validated hyperphagia questionnaire and indirect calorimetry in patients with AS and BMI-matched controls. We observed that REE adjusted for lean body mass was comparable in patients with AS and controls but that the hyperphagia score trended higher, suggesting that higher intake rather than the lower metabolic rate is probably the primary driver for obesity in AS. Reduced activity thermogenesis caused by lower mobility due to visual and auditory impairments may also be a contributing factor that we did not directly assess in the current study. Previous studies that have examined metabolic complications in patients with AS lacked an equally obese control group for comparison. By eliminating the confounding contribution of obesity by matching each subject with AS with two controls (of similar age, sex, race, and BMI z score), we were able to ascertain the scope of metabolic disease caused by AS independent of BMI. We also performed ANCOVAs adjusting for age, sex, race, and BMI z score and observed that all differences meeting the threshold for significance after multiple-comparison correction remained significant (P < 0.001), verifying that patients with AS and controls were well matched. The most striking feature of AS that we observed was the severity of insulin resistance, which was more than five times that of equally obese control subjects. The mechanism by which loss of ALMS1 function leads to insulin resistance has not been fully elucidated. In Alms1GT/GT mice, insulin-stimulated translocation of GLUT4 to the plasma membrane is reduced (29). Reduced expression of alms1 in zebrafish resulted in significantly decreased β-cell mass (36, 37). Together, these animal data point to a combination of insulin resistance and relative insulin insufficiency in AS. Based on our observations in this human study, we hypothesize that fat deposition in the liver and potentially skeletal muscle could play a key role in the insulin resistance of AS. Fat content of liver and muscle as measured by MRS was positively correlated with BMI for all subjects, but the curve for this relationship was shifted upward in AS, such that at any given BMI, patients with AS had more fat in the liver and quadriceps muscle compared with controls. Glucose uptake and utilization within the liver and muscle are critical for glycemic control (38). Fat deposition could create an inflammatory milieu (as evidenced by elevated transaminases in our subjects with AS) that underlies the pathophysiology for the severe insulin resistance and accompanying hyperglycemia, dyslipidemia, and other MS components observed in AS. Interestingly, elevated LDL-cholesterol (which is not typically included in the criteria for MS but is a common complication of obesity) was not seen in our AS cohort, and in fact LDL-cholesterol was nominally lower in patients with AS compared with BMI-matched controls. The clinical significance is unclear but may be protective for patients with AS. Other investigators have also observed hepatic steatosis and fibrosis in AS (12), but our study demonstrates that the severity of liver disease is significantly higher than in obese controls, suggesting a direct role of ALMS1 dysfunction, independent of obesity, in the pathogenesis of liver disease in AS. In a study of patients with AS in the United Kingdom, higher baseline aortic pulse wave velocity was positively associated with the duration of diabetes and predicted occurrence of cardiovascular events during 5 years of follow-up (39). Along the same line, longitudinal studies are needed to elucidate the temporal relationship between liver pathology and insulin resistance. Conclusion Endocrine problems are common in AS, with severe insulin resistance and T2DM causing significant morbidity, even in those who are not obese. Although aerobic exercise and restriction of simple carbohydrate intake are important foundations for the management of AS in the context of multidisciplinary team-based care (40), identification of therapies that target the hypothalamic defects causing hyperphagia and the peripheral metabolic derangements causing deposition of fat in the liver and muscle are needed. Abbreviations: Abbreviations: 25OHD 25-hydroxyvitamin D ALT alanine aminotransferase ANCOVA analysis of covariance AS Alström syndrome AUC area under the curve BMI body mass index BP blood pressure eGFR estimated glomerular filtration rate FFA free fatty acid HDL high-density lipoprotein LDL low-density lipoprotein MMT mixed meal test MRS magnetic resonance spectroscopy MS metabolic syndrome NIH National Institutes of Health REE resting energy expenditure T2DM type 2 diabetes mellitus WBISI whole-body insulin sensitivity index Acknowledgments We thank Gayle B. Collin for assistance with manuscript preparation and the families of Alström Syndrome International for their participation and support. This article is dedicated to the memory of our colleague Jan Davis Marshall, who worked tirelessly to improve the lives of patients with Alström syndrome and made numerous important scientific contributions during her 46-year career at The Jackson Laboratory. Financial Support: This study was funded by the Intramural Research Program of National Human Genome Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIAHD00641 to J.A.Y. and ZIAHD008898 to J.C.H.), and an NIH Bench-to-Bedside Award to J.C.H. Clinical Trial Information: ClinicalTrials.gov nos. NCT00068224 (registered 10 September 2003), NCT00001195 (registered 4 November 1999), NCT00001522 (registered 4 November 1999), NCT00001723 (registered 4 November 1999), NCT00005669 (registered 22 May 2000), NCT00006073 (registered 14 July 2003), NCT00030238 (registered 12 February 2002), NCT00320177 (registered 3 May 2006), NCT00758108 (registered 23 September 2008), NCT01517048 (registered 25 January 2012). Author Contributions: J.C.H. and M.G.-A. conceived and designed the study, performed patient examinations, supervised research testing, interpreted results, performed statistical analyses, and wrote the manuscript. D.P.R.-C. recruited control subjects, administered questionnaires, performed indirect calorimetry, performed statistical analyses, and contributed in writing the manuscript. C.-Y.L. and J.C.R. interpreted MRS results. E.T. and I.B.T. interpreted MRI results. J.B. coordinated all testing. J.D.M. and J.K.N. recruited patients and performed ALMS1 sequencing. M.G.-A. is the principal investigator of the NIH protocol “Clinical and Molecular Investigations Into Ciliopathies.” W.A.G. is the financially accountable investigator of the NIH protocol “Clinical and Molecular Investigations Into Ciliopathies.” J.A.Y. is the principal investigator of the NIH protocols that provided the control subjects. All co-authors contributed to data interpretation and revised the manuscript. Current Affiliation: C.-Y. Liu’s current affiliation is the Department of Radiology, Johns Hopkins University, Baltimore, Maryland. Disclosure Summary: J.C.H. has received an unrestricted research grant from Rhythm Pharmaceuticals. J.A.Y. reports receiving research grant support from Rhythm Pharmaceuticals for a study of pharmacotherapy to treat the obesity observed in rare disorders, including Alström syndrome. The remaining authors have nothing to disclose. References 1. Marshall JD , Maffei P , Collin GB , Naggert JK . Alström syndrome: genetics and clinical overview . Curr Genomics . 2011 ; 12 ( 3 ): 225 – 235 . 2. Marshall JD , Paisey RB , Carey C , Macdermott S . Alstrom syndrome. In: Pagon RA , Adam MP , Ardinger HH , Wallace SE , Amemiya A , Bean LJH , Bird TD , Ledbetter N , Mefford HC , Smith RJH , Stephens K , eds. GeneReviews(R) . Seattle, WA : University of Washington ; 1993–2018 . Available at: www.ncbi.nlm.nih.gov/books/NBK1267/. Accessed 15 January 2018. 3. 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Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls

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Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls

Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls

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