A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation

A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous... Abstract Background Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson–Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality. Mutations in lamin A/C (LMNA) gene can cause several disorders, including familial partial lipodystrophy, muscular dystrophies, cardiomyopathies, neuropathy, and progeroid syndromes (1, 2). The progeroid syndromes associated with LMNA mutations include the autosomal-dominant Hutchinson–Gilford progeria syndrome (HGPS) (3–5) and atypical progeroid syndrome (APS) (6–14), as well as autosomal recessive, mandibuloacral dysplasia (15, 16). Most patients with HGPS have a characteristic phenotype and a recurrent de novo heterozygous LMNA c.1824C>T; p.G608= mutation that activates a cryptic splice site resulting in the deletion of 50 amino acids near its carboxyl terminus (3). Patients with APS have variable progeroid features such as short stature, beaked nose, premature graying, partial loss of hair, high-pitched voice, skin atrophy over the hands and feet, generalized lipodystrophy, skin pigmentation, and mandibular hypoplasia (7). Interestingly, 5 of 31 patients with APS reported so far also had a recurrent de novo heterozygous LMNA c.29C>T; p.T10I mutation (7, 12–14), suggesting that this subset of patients could have another distinct progeroid disorder. All five patients had childhood onset of generalized lipodystrophy with variable metabolic, cardiac, cutaneous, and other similar clinical manifestations. In this study, we report nine new patients and follow-up of two previously reported patients with heterozygous LMNA p.T10I mutation, comparing clinical features and disease burden of all these patients to those with other APS patients to define unique characteristics of this novel progeroid syndrome. Case Reports Patients 1.1 to 4.1 were evaluated at the University of Texas Southwestern Medical Center; patients 5.1 to 7.1 at the National Institutes of Health; patient 8.1 at the University of Michigan; patient 9.1 at Moscow, Russia; and patient 10.1 at Rio de Janeiro, Brazil. Patients 6.1 and 6.2 were also evaluated at the University of Pennsylvania. The research protocol was approved by the respective Institutional Review Boards, and all participants provided written informed consent. Anthropometric and metabolic data of these patients are presented in Tables 1 and 2, respectively. Their pedigrees are shown in Supplemental Fig. 1. Unique clinical features of each patient are briefly summarized below. Table 1. Clinical Features of Patients With GLPS as a Result of Heterozygous LMNA p.T10I Mutation Variables  Patient No.  1.1  2.1  3.1  4.1  5.1  6.1  6.2  7.1  8.1  9.1  10.1  Age at report,a y  10  16  8.5  15  8  33  55  13  16  10  12  Age of onset of lipodystrophy, y  5  10  5.5  5  0.5  14  35  10  7  4  6  Sex  F  M  M  M  M  F  M  M  F  F  F  Ethnicity  White  White  White  White  White  White  White  Black  Black  White  Mixed  Nationality  American  American  American  Kazakhstan  Spain  American  American  American  American  Russian  Brazilian  Height, m  1.44  1.41  1.26  1.62  1.40  1.50  1.69  1.55  1.48  1.36  1.50  Height, z score  0.86  −1.11  −0.33  −1.02  2.10  −2.01  NA  0.78  −2.25  −0.31  −0.16  Weight, kg  24.9  33.5  20.9  39.6  27.5  34.4  71.6  38.8  32.3  21.1  32.2  BMI, kg/m2  11.8  16.8  13.5  15.2  14  15.2  25.1  14.8  14.8  11.4  14.3  DM (age of onset, y)  Y (9)  Y (13)  N  Y (12)  Y (7)  Y (13)  Y (47)  Y (11)  Y (7)  N  Y (12)  Acanthosis nigricans  N  Y  N  N  Y  N  N  NR  Y  N  Y  HTN (age of onset, y)  Y (10)  Y (NR)  N  NR  NR  N  Y  Y  N  N  N  Joint contractures  Y  Y  Y  Y  NR  Y  N  Y  Y  Y  N  Cardiomyopathy  N  N  N  Y  Y  Y  Y  Y  Y  Y  N  Valvular disease  Y  Y  N  Y  Y  Y  Y  N  Y  Y  N  Micrognathia  Y  Y  Y  Y  NR  Y  N  NR  Y  NR  Y  Mottled skin  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Atrophic skin  NR  Y  Y  Y  NR  Y  Y  Y  Y  Y  Y  Beaked nose  Y  NR  Y  NR  NR  Y  N  NR  N  NR  Y  Thin lips  Y  NR  NR  NR  NR  Y  Y  NR  NR  Y  Y  Receding hairline  NR  Y  NR  NR  NR  Y  N  NR  Y  NR  Y  Loss of hair  Y  N  N  NR  N  NR  Y  NR  Y  NR  Y  Hepatomegaly  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Splenomegaly  N  Y  N  Y  Y  N  N  N  Y  Y  Y  Underdeveloped breasts  Y  NA  NA  NA  NA  Y  NA  NA  Y  NA  Y  Spinal deformities  Y  N  N  NR  NR  N  N  Y  N  Y  Y  Variables  Patient No.  1.1  2.1  3.1  4.1  5.1  6.1  6.2  7.1  8.1  9.1  10.1  Age at report,a y  10  16  8.5  15  8  33  55  13  16  10  12  Age of onset of lipodystrophy, y  5  10  5.5  5  0.5  14  35  10  7  4  6  Sex  F  M  M  M  M  F  M  M  F  F  F  Ethnicity  White  White  White  White  White  White  White  Black  Black  White  Mixed  Nationality  American  American  American  Kazakhstan  Spain  American  American  American  American  Russian  Brazilian  Height, m  1.44  1.41  1.26  1.62  1.40  1.50  1.69  1.55  1.48  1.36  1.50  Height, z score  0.86  −1.11  −0.33  −1.02  2.10  −2.01  NA  0.78  −2.25  −0.31  −0.16  Weight, kg  24.9  33.5  20.9  39.6  27.5  34.4  71.6  38.8  32.3  21.1  32.2  BMI, kg/m2  11.8  16.8  13.5  15.2  14  15.2  25.1  14.8  14.8  11.4  14.3  DM (age of onset, y)  Y (9)  Y (13)  N  Y (12)  Y (7)  Y (13)  Y (47)  Y (11)  Y (7)  N  Y (12)  Acanthosis nigricans  N  Y  N  N  Y  N  N  NR  Y  N  Y  HTN (age of onset, y)  Y (10)  Y (NR)  N  NR  NR  N  Y  Y  N  N  N  Joint contractures  Y  Y  Y  Y  NR  Y  N  Y  Y  Y  N  Cardiomyopathy  N  N  N  Y  Y  Y  Y  Y  Y  Y  N  Valvular disease  Y  Y  N  Y  Y  Y  Y  N  Y  Y  N  Micrognathia  Y  Y  Y  Y  NR  Y  N  NR  Y  NR  Y  Mottled skin  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Atrophic skin  NR  Y  Y  Y  NR  Y  Y  Y  Y  Y  Y  Beaked nose  Y  NR  Y  NR  NR  Y  N  NR  N  NR  Y  Thin lips  Y  NR  NR  NR  NR  Y  Y  NR  NR  Y  Y  Receding hairline  NR  Y  NR  NR  NR  Y  N  NR  Y  NR  Y  Loss of hair  Y  N  N  NR  N  NR  Y  NR  Y  NR  Y  Hepatomegaly  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Splenomegaly  N  Y  N  Y  Y  N  N  N  Y  Y  Y  Underdeveloped breasts  Y  NA  NA  NA  NA  Y  NA  NA  Y  NA  Y  Spinal deformities  Y  N  N  NR  NR  N  N  Y  N  Y  Y  Abbreviations: BMI, body mass index; DM, diabetes mellitus; F, female; HTN, hypertension; M, male; N, no; NA, not applicable; NR, not reported; Y, yes. a Age at which patient was last seen by investigators. View Large Table 2. Metabolic Parameters of Patients With GLPS as a Result of Heterozygous LMNA p.T10I Mutation Variables  Patient No.  1.1  2.1  3.1  4.1  5.1  6.1  6.2  7.1  8.1  9.1  10.1  Triglycerides, mg/dL  580  571  293  445  335  7420  238  2238  10,623  1134  2056  Cholesterol, mg/dL  145  145  125  164  165  740  172  173  NR  225  145  HDL cholesterol, mg/dL  22  23  21  42  32  18  31  NR  23  19  28  HbA1C, %  6.4  5.4  5.3  10.7  6.3  8  5.2  10.4  9.3  5.5  11.5  Glucose, mg/dL  125  87  74  176  111  283  87  218  277  83  102  Insulin, µU/mL  55.7  208  8.7  15.6  55.9  26.8  46.4  55.2  NR  218.9  47.1  Leptin, ng/mL  NR  1  0.6  0.1  0.4  1.48  4  1.62  0  0.5  1  ALT, IU/L  70  92  11  31  216  97  56  119  27  103  146  AST, IU/L  35  50  22  31  120  70  31  66  20  66  71  Proteinuria, g/d  0.926  0.099  NR  0.271  0.518  10.099  0.110  2.12  0.30  NA  0.420  Body fat,a %  13.6  14.4  13.6  6.6  NR  3.1  25  8.3  4.3  4.0  4.5  Variables  Patient No.  1.1  2.1  3.1  4.1  5.1  6.1  6.2  7.1  8.1  9.1  10.1  Triglycerides, mg/dL  580  571  293  445  335  7420  238  2238  10,623  1134  2056  Cholesterol, mg/dL  145  145  125  164  165  740  172  173  NR  225  145  HDL cholesterol, mg/dL  22  23  21  42  32  18  31  NR  23  19  28  HbA1C, %  6.4  5.4  5.3  10.7  6.3  8  5.2  10.4  9.3  5.5  11.5  Glucose, mg/dL  125  87  74  176  111  283  87  218  277  83  102  Insulin, µU/mL  55.7  208  8.7  15.6  55.9  26.8  46.4  55.2  NR  218.9  47.1  Leptin, ng/mL  NR  1  0.6  0.1  0.4  1.48  4  1.62  0  0.5  1  ALT, IU/L  70  92  11  31  216  97  56  119  27  103  146  AST, IU/L  35  50  22  31  120  70  31  66  20  66  71  Proteinuria, g/d  0.926  0.099  NR  0.271  0.518  10.099  0.110  2.12  0.30  NA  0.420  Body fat,a %  13.6  14.4  13.6  6.6  NR  3.1  25  8.3  4.3  4.0  4.5  For patients who were treated with metreleptin, the data reported are before the initiation of therapy. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; HbA1c, hemoglobin A1c; NR, not reported. a Body fat from dual-energy x-ray absorptiometry. View Large Patient 1.1 This 11-year-old white female presented with failure to thrive since birth and remained at the 10th percentile for weight during childhood (Fig. 1A). At age 9, generalized absence of subcutaneous fat and mottled skin hyperpigmentation around the neck, axillae, and groin were noted. She had birdlike facies with dental crowding, a receding hairline, and anteverted ears. She had mild scoliosis and joint contractures, especially at the knees. Hypertriglyceridemia, mild diabetes mellitus, hypertension, and proteinuria were also noted. An echocardiogram showed normal cardiac function with mild mitral and aortic regurgitation. At age 10, she started metreleptin therapy resulting in marked lowering of fasting serum triglycerides from 1026 mg/dL to 118 mg/dL after 4 months. Figure 1. View largeDownload slide Phenotypic and anthropometric features of patients with GLPS with heterozygous LMNA p.T10I mutation. All patients have generalized lipodystrophy with notable micrognathia and prominent scapulae. (A) Lateral and (B) posterior views of patient 1.1, a 9-year-old white girl with generalized loss of subcutaneous fat, extremely thin arms and legs, and mildly protuberant abdomen. She has a progeroid appearance with sharp features along with curly hair. (C) Lateral and (D) posterior views of patient 3.1, an 8-year-old white boy with generalized fat loss and muscular extremities. He also has a receding chin and protuberant abdomen. (E) Anterior view of the neck of patient 7.1, a 13-year-old African-American male with mottled skin pigmentation. (F) Anterior view of the abdomen and (G) left axilla of patient 9.1, a 10-year-old white girl showing mottled pigmentation and abdominal protuberance. (H) Anterior view of left thigh of patient 10.1 showing marked loss of subcutaneous fat and eruptive xanthomas. (I) Right axilla of patient 10.1 with eruptive xanthomas, mottled skin, acanthosis nigricans, and marked fat loss. (J) Skinfold thickness of three female patients (1.1, 6.1, and 9.1) marked by filled diamonds, squares, and inverted triangles, respectively, as measured with standard calipers. The gray bars show 10th to 90th percentile values of normal age-matched girls with the median value marked by a horizontal line. (K) Skinfold thickness of two male GLPS patients (2.1 and 3.1) marked by filled circles and triangles, respectively. The gray bars show the 10th and 90th percentile values of normal age-matched boys with the median value marked by a horizontal line. All patients have markedly decreased skinfold thickness at all anatomic sites indicating generalized loss of subcutaneous fat. This appears to be even more pronounced in the upper and lower extremities. Figure 1. View largeDownload slide Phenotypic and anthropometric features of patients with GLPS with heterozygous LMNA p.T10I mutation. All patients have generalized lipodystrophy with notable micrognathia and prominent scapulae. (A) Lateral and (B) posterior views of patient 1.1, a 9-year-old white girl with generalized loss of subcutaneous fat, extremely thin arms and legs, and mildly protuberant abdomen. She has a progeroid appearance with sharp features along with curly hair. (C) Lateral and (D) posterior views of patient 3.1, an 8-year-old white boy with generalized fat loss and muscular extremities. He also has a receding chin and protuberant abdomen. (E) Anterior view of the neck of patient 7.1, a 13-year-old African-American male with mottled skin pigmentation. (F) Anterior view of the abdomen and (G) left axilla of patient 9.1, a 10-year-old white girl showing mottled pigmentation and abdominal protuberance. (H) Anterior view of left thigh of patient 10.1 showing marked loss of subcutaneous fat and eruptive xanthomas. (I) Right axilla of patient 10.1 with eruptive xanthomas, mottled skin, acanthosis nigricans, and marked fat loss. (J) Skinfold thickness of three female patients (1.1, 6.1, and 9.1) marked by filled diamonds, squares, and inverted triangles, respectively, as measured with standard calipers. The gray bars show 10th to 90th percentile values of normal age-matched girls with the median value marked by a horizontal line. (K) Skinfold thickness of two male GLPS patients (2.1 and 3.1) marked by filled circles and triangles, respectively. The gray bars show the 10th and 90th percentile values of normal age-matched boys with the median value marked by a horizontal line. All patients have markedly decreased skinfold thickness at all anatomic sites indicating generalized loss of subcutaneous fat. This appears to be even more pronounced in the upper and lower extremities. Patient 2.1 This 16-year-old white male presented at age 11.3 years with remarkable loss of adiposity, especially from the face and the extremities. He had micrognathia and curly hair that was reportedly straight at birth. His skin was atrophic with mottled hyperpigmentation and mild acanthosis nigricans. He had joint contractures of the phalangeal joints, wrists, and ankles, as well as hammer toes. Abdominal ultrasound showed hepatosplenomegaly with severe hepatic steatosis. Oral glucose tolerance test revealed mild diabetes and his fasting serum triglycerides were 571 mg/dL. Echocardiogram showed trivial pulmonary and tricuspid regurgitation. Mild motor neuropathy was reported on a nerve conduction study. Metreleptin therapy was started at age 11.6 years; however, he was noncompliant. At age 14, he developed worsening of diabetes (hemoglobin A1c, 9.2%) and extreme hypertriglyceridemia (serum triglycerides, 6640 mg/dL) with eruptive xanthomas, and insulin therapy was initiated. At age 16 years, with improved compliance to metreleptin, gemfibrozil, and insulin therapy, his fasting serum triglycerides were 1287 mg/dL and hemoglobin A1c was 8.3%. Patient 3.1 This 8.5-year-old white male presented with failure to thrive despite having voracious appetite and generalized absence of subcutaneous fat (Fig. 1C and 1D). He had significant dental crowding due to micrognathia. Superficial veins and mottled hyperpigmentation on the trunk were prominent features. He had contractures of the phalangeal joints and knees and hepatomegaly. Echocardiographic evaluation was normal. Patient 4.1 This patient from Kazakhstan (previously reported as APS 800.3) (7, 17) had generalized loss of fat at age 5 and joint contractures of ankles, knees, and hips. He received metreleptin therapy for only 10 months at age 15 years, which improved diabetes and hypertriglyceridemia (18). Echocardiogram revealed severe concentric left ventricular hypertrophy and aortic stenosis with heavily calcified aortic and mitral valves. Subsequently, he had worsening of hyperglycemia and hypertriglyceridemia due to noncompliance with insulin. He developed a foot infection leading to sepsis and death at age 17 years. Patient 5.1 This 15-year-old male from Spain (previously reported as APS 1700.4) (7) initially presented with acanthosis nigricans at the age of 6 months and was treated with metreleptin since age 8 years with marked improvement in diabetes and hyperlipidemia. He had cardiac transplantation at age 13 years for progressively worsening dilated cardiomyopathy and valvular disease (19). The explanted heart showed extensive areas of myocardial sclerosis in both ventricles with normal coronary arteries (19). Patient 6.1 This 33-year-old white female (previously reported as NIH-1) developed extreme hypertriglyceridemia (>19,000 mg/dL) with painful, eruptive xanthomas on the face, trunk, and extremities at age 12 years, requiring plasmapheresis for ∼24 months (20). She also had severe diabetes with insulin resistance and primary amenorrhea and was diagnosed with “acquired” generalized lipodystrophy at age 14 years. She had pinched facies with sunken cheeks. The skin was mottled in appearance with patchy areas of hyperpigmentation and hypopigmentation on the neck and trunk. Liver biopsy showed severe steatohepatitis with mild inflammation, as well as fibrosis. Kidney biopsy performed for proteinuria (>2 g daily) revealed focal segmental glomerulosclerosis. At age 17 years, metreleptin therapy was initiated with a remarkable metabolic response and onset of menarche at age 17 (21, 22). However, by age 30 years, she developed mild to moderate regurgitation of the aortic, mitral, and tricuspid valves and moderate-to-severe calcification of the aortic and mitral valves. She also required a cardiac resynchronization therapy device for wide left bundle branch block. At age 32 years, the left ventricular ejection fraction declined to 15%, and she received cardiac transplantation at age 33. Pathology of the explanted heart revealed heavily calcified mitral and aortic valves, left ventricular myocyte hypertrophy with interstitial fibrosis, and mild calcific coronary atherosclerosis with minimal luminal occlusion (Fig. 2). Despite metreleptin, posttransplantation steroid therapy worsened hyperglycemia and hypertriglyceridemia, resulting in acute pancreatitis 2 months afterward. With strict dietary intervention, she was able to stabilize serum triglyceride levels. Figure 2. View largeDownload slide Photomicrographs showing histopathology of the explanted heart of patient 6.1. Magnifications are given in the right-hand upper corner. (A) Hematoxylin and eosin staining showing expanding subendocardial fibrotic changes (shown by blue arrow). (B) Trichrome staining of section of left ventricle showing fibrotic changes (blue) of the cardiac myocytes. (C) Hematoxylin and eosin staining showing mild myocyte hypertrophy (examples of enlarged, hyperchromatic, slightly bizarre nuclei circled) and fibrosis (shown by arrows) of the left ventricle. (D) Hematoxylin and eosin staining highlighting an atherosclerotic plaque with foam cells (blue arrow), calcifications (green arrows), and inflammatory cells (black arrow) in the left circumflex coronary artery. Figure 2. View largeDownload slide Photomicrographs showing histopathology of the explanted heart of patient 6.1. Magnifications are given in the right-hand upper corner. (A) Hematoxylin and eosin staining showing expanding subendocardial fibrotic changes (shown by blue arrow). (B) Trichrome staining of section of left ventricle showing fibrotic changes (blue) of the cardiac myocytes. (C) Hematoxylin and eosin staining showing mild myocyte hypertrophy (examples of enlarged, hyperchromatic, slightly bizarre nuclei circled) and fibrosis (shown by arrows) of the left ventricle. (D) Hematoxylin and eosin staining highlighting an atherosclerotic plaque with foam cells (blue arrow), calcifications (green arrows), and inflammatory cells (black arrow) in the left circumflex coronary artery. Patient 6.2 This 55-year-old white male is the father of patient 6.1 (Supplemental Fig. 1). He was an unusually thin child who had mottled skin pigmentation on his abdomen, which resolved around age 13 years. At age 35 years, he was noted to have sunken cheeks and muscular arms and legs. Abdominal ultrasound showed fatty liver and increased intra-abdominal fat. At age 38, he had a myocardial infarction and required coronary stents. At age 47 years, he required cardiac transplantation for deteriorating “cardiomyopathy.” Pathology of the explanted heart revealed myocardium with patchy interstitial fibrosis and myocyte hypertrophy, myxoid degeneration of mitral and tricuspid valves, and moderate-to-severe calcific coronary atherosclerosis. After transplantation, he developed mild steroid-induced diabetes mellitus with the highest fasting serum triglycerides of 493 mg/dL. Patient 7.1 This 13-year-old African American male had gradual generalized loss of subcutaneous fat between ages 10 and 12 years. He had micrognathia and sunken cheeks. His skin was mottled with patches of hypopigmentation and hyperpigmentation (Fig. 1E), noted since birth on the neck, torso, and the extremities. He had mild thoracic scoliosis and kyphosis, as well as mildly limited joint mobility. He developed hypertriglyceridemia, diabetes mellitus, and severe insulin resistance at age 11 years. An abdominal ultrasound revealed severe hepatic steatosis, and a biopsy confirmed steatohepatitis without fibrosis. An echocardiogram at age 13 years revealed possible noncompaction cardiomyopathy without valvular abnormalities. Metreleptin therapy for 1 year improved his hemoglobin A1c from 10.4% to 5.7% and he was able to discontinue insulin therapy; his serum triglycerides declined from 2238 mg/dL to 112 mg/dL. Patient 8.1 This 16-year-old female of African-American ethnicity developed decreased muscle strength at age 4, and at age 6 years she was diagnosed with juvenile dermatomyositis based on clinical features and elevated serum creatine kinase (477 U/L; normal range, 25 to 240 U/L) and was treated with methotrexate (23). Serum antinuclear, anti–double-stranded DNA, Rh factor, and anticardiolipin antibodies were negative. Subsequently, serum antinuclear antibody titer was 1:160 with speckled pattern. Later, she developed progressive contractures of the phalangeal joints, wrists, left elbow, and right shoulder with calcium deposits. Around age 7 years, she started losing subcutaneous fat, gradually resulting in generalized lipodystrophy and diabetes mellitus. She had a small midface, high-arched palate, and micrognathia with crowding of teeth. She had mottled skin and eruptive xanthomas. At age 9 years, she developed acute pancreatitis with serum triglycerides of 10,623 mg/dL and diabetic ketoacidosis. Metreleptin treatment was started at age 9 years (23). She had menarche at age 10 years but was diagnosed with polycystic ovarian syndrome associated with hirsutism and clitoromegaly. An echocardiogram showed a small secundum atrial septal defect. Abdominal imaging study revealed nephromegaly and bilateral kidney cysts. Patient 9.1 This 10-year-old white female from Russia had failure to thrive since 2 months of age. Around age 4 years, she had generalized loss of fat, mandibular hypoplasia, and low-set, deformed ears. She had mottled skin on the torso and extremities (Fig. 1F and 1G). Her lower extremities appeared hypertrophic. She had scoliosis and flexion contractures of all interphalangeal joints, elbows, and knees. At age 6 years, she complained of intermittent epigastric pain likely due to acute pancreatitis with extreme hypertriglyceridemia (serum triglycerides 1134 mg/dL). She had normal glucose tolerance, but with extreme hyperinsulinemia. An echocardiogram revealed pulmonary hypertension with pulmonary artery pressure of 36 mm Hg, along with nonsignificant pulmonary and tricuspid regurgitation. Patient 10.1 This 12-year-old female of mixed African-European origin from Brazil reported gradual loss of subcutaneous fat since age 6 despite increased appetite. She was noted to have hypertriglyceridemia at age 9 years. She had generalized loss of subcutaneous fat, including the palms and soles, and acanthosis nigricans in the axillae and neck. The liver was palpable at 6 cm below the right costal margin. The skin was atrophic with mottled hypopigmentation over the trunk and extremities. She had loss of the hair in frontal region, micrognathia, beaked nose with thin lips, and birdlike face. She had lumbar lordosis but no joint contractures. Abdominal ultrasonography showed hepatosplenomegaly and hepatic steatosis, and a liver biopsy revealed steatohepatitis stage 3 with grade 1a fibrosis. At age 12 years, she developed severe hyperglycemia (hemoglobin A1c 11.5%) and hypertriglyceridemia (serum triglycerides 2056 mg/dL) despite high doses of insulin (180 U/d), fibrate, and pioglitazone therapy and suffered from acute pancreatitis. She had eruptive xanthomas on the neck, trunk, and lower limbs and Tanner stage 3 pubic hair, but with no menarche or breast development. Materials and Methods Anthropometry Anthropometric measurements Height, body weight, and skinfold thickness were measured by standard procedures as reported previously (7). Dual-energy x-ray absorptiometry Whole-body fat and regional fat in the head, trunk, and upper and lower extremities were determined using a Hologic QDR-2000 densitometer (Hologic, Waltham, MA) or GE Lunar Prodigy (General Electric, Madison, WI). Magnetic resonance imaging Magnetic resonance imaging studies were performed using a 1.5-Tesla imaging device (Philips Medical Systems, Best, Netherlands) and version 5.2-2 viewing software as reported previously (7). Metabolic assessments and genetic analysis Biochemical analyses Plasma glucose was measured by the glucose oxidase method with a glucose analyzer. Serum insulin and leptin levels were determined by immunoassays using commercial laboratories or kits (EMD Millipore, Billerica, MA). Serum cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and chemistry as well as blood hemoglobin A1C were analyzed as part of a systematic multichannel analysis. Mutational analyses The exons and exon–intron boundaries of the LMNA gene were sequenced according to Chen et al. (24). For patients 6.1 and 6.2, DNA was extracted from the whole blood on the QIAsymphony SP system with the use of a QIAsymphony DSP DNA kit as specified by the manufacture (Qiagen, Germantown, MD). LipidSeq, a custom targeted lipid gene panel focusing on known lipodystrophy genes (25), was used for analysis using Illumina MiSeq platform with subsequent confirmation by Sanger sequencing. A targeted next generation sequencing panel was used to genotype patient 10.1. Results The same heterozygous pathogenic LMNA mutation c.29C>T (g.156084738C>T; GRCh37/hg19), which translates to p.Thr10Ile in lamin A/C (NM_170707.3), was identified in all 11 patients, occurring de novo except in patient 6.1, who inherited it from her father, patient 6.2. We then compared clinical features and laboratory data of all these and 3 other previously reported patients with heterozygous LMNA p.T10I mutation to 26 other previously reported patients with APS with many different heterozygous LMNA variants. All patients with heterozygous LMNA p.T10I mutation had generalized lipodystrophy except for patient 6.2, who was assessed to have partial lipodystrophy, and patient 8.1, where the degree of lipodystrophy was not specified. Compared with other patients with APS, the patients with the heterozygous LMNA p.T10I mutation had significantly increased prevalence of generalized lipodystrophy, diabetes mellitus, hypertriglyceridemia, hepatomegaly, and acanthosis nigricans despite being significantly younger (Table 3). Generalized lack of body fat was also noticed on skinfold thickness measurements in five patients with p.T10I mutation (Fig. 1H and 1I) and in a previously reported patient (7), and on whole-body magnetic resonance imaging (Supplemental Fig. 2). Dual-energy x-ray absorptiometry scans further confirmed significantly reduced total and regional body fat in patients with heterozygous LMNA p.T10I mutation (Table 3). Patients with heterozygous LMNA p.T10I mutation also had markedly lower levels of serum leptin and HDL cholesterol and had higher levels of triglycerides and insulin compared with other patients with APS (Table 3). The prevalence of other features such as mottled skin pigmentation, joint contractures, and cardiomyopathy, however, were not significantly different in the two groups. Age was not found to be a significant covariate. Table 3. Comparison of Clinical Features and Metabolic Parameters of Patients With GLPS With Heterozygous LMNA p.T10I Mutation and Others With APS   GLPS  Total n  APSb  Total n  95% CI of the Differences  P Value  Females, %  50  14  63  27  −41, 17  0.50  Age reported, y  14 (8–55)  14  23.0 (7–53)  26  −14, −2  0.01  BMI, kg/m2  14.6 (11.4–25.1)  12  15.4 (10.1–19.6)  20  −3.3, 1.1  0.39  Fasting TG, mg/dL  776 (238–10,623)  13  121 (34–3000)  14  214, 2022  0.0007  HbA1c, %  8.0 (5.2–10.7)  13  5.3 (4.8–12.7)  11  0.2, 4.0  0.02  ALT, mU/L  83.5 (11–216)  12  36.5 (13–287)  10  −20, 86  0.31  AST, mU/L  51 (20–120)  12  44.5 (16–134)  10  −30, 38  0.71  HDL cholesterol, mg/dL  21.0 (6–42)  11  40.5 (14.6–50.0)  12  −24.7, −11.0  0.001  Leptin, ng/mL  0.3 (0–4.0)  10  3.0 (0.8–12.6)  11  −5.1, −0.8  0.0003  Fasting glucose, mg/dL  125 (74–283)  13  93 (84–277)  13  −10, 85  0.26  Fasting insulin, µU/mL  55.2 (8.7–290)  11  14.7 (1.9–85.0)  11  4, 136  0.03  Total body fat,b (%)  8.5 (0.04–25.0)  10  17.2 (6.5–27.0)  12  −13.4, −0.1  0.04  Lower Extremity fat,b %  6.3 (4.0–12.9)  7  15.7 (5.2–26.9)  9  −13.3, −1.8  0.01  Upper Extremity fat,b %  10.4 (3.0–13.7)  6  19.3 (12.3–32.2)  10  −18.5, −2.3  0.001  Truncal fat,b %  7.8 (3.9–14.2)  7  17.8 (8.1–30.2)  10  −17.7, −1.6  0.01  Type of lipodystrophy    13    25    0.01   Generalized  11  7   Partial  1  8   Unspecified  1  6   None  0  4  Diabetes mellitus, %  85  13  36  22  14, 68  0.01  Hypertension, %  50  10  50  12  −36, 36  1.00  Hypertriglyceridemia, %  100  12  46.2  13  19, 77  0.005  Joint contractures, %  89  9  62  13  −11, 55  0.33  Cardiomyopathy, %  70  10  59  22  −24, 39  0.70  Valvular disease, %  80  10  63  19  −19, 43  0.43  Scoliosis, %  38  8  29  7  −34, 47  1.00  Mottled skin, %  100  11  89  18  −16, 33  0.29  Hepatomegaly, %  100  11  50  10  13, 76  0.01  Acanthosis nigricans, %  40  10  0  12  6, 69  0.03  Small atrophic breasts, %  100  4  89  9  −39, 43  1.0    GLPS  Total n  APSb  Total n  95% CI of the Differences  P Value  Females, %  50  14  63  27  −41, 17  0.50  Age reported, y  14 (8–55)  14  23.0 (7–53)  26  −14, −2  0.01  BMI, kg/m2  14.6 (11.4–25.1)  12  15.4 (10.1–19.6)  20  −3.3, 1.1  0.39  Fasting TG, mg/dL  776 (238–10,623)  13  121 (34–3000)  14  214, 2022  0.0007  HbA1c, %  8.0 (5.2–10.7)  13  5.3 (4.8–12.7)  11  0.2, 4.0  0.02  ALT, mU/L  83.5 (11–216)  12  36.5 (13–287)  10  −20, 86  0.31  AST, mU/L  51 (20–120)  12  44.5 (16–134)  10  −30, 38  0.71  HDL cholesterol, mg/dL  21.0 (6–42)  11  40.5 (14.6–50.0)  12  −24.7, −11.0  0.001  Leptin, ng/mL  0.3 (0–4.0)  10  3.0 (0.8–12.6)  11  −5.1, −0.8  0.0003  Fasting glucose, mg/dL  125 (74–283)  13  93 (84–277)  13  −10, 85  0.26  Fasting insulin, µU/mL  55.2 (8.7–290)  11  14.7 (1.9–85.0)  11  4, 136  0.03  Total body fat,b (%)  8.5 (0.04–25.0)  10  17.2 (6.5–27.0)  12  −13.4, −0.1  0.04  Lower Extremity fat,b %  6.3 (4.0–12.9)  7  15.7 (5.2–26.9)  9  −13.3, −1.8  0.01  Upper Extremity fat,b %  10.4 (3.0–13.7)  6  19.3 (12.3–32.2)  10  −18.5, −2.3  0.001  Truncal fat,b %  7.8 (3.9–14.2)  7  17.8 (8.1–30.2)  10  −17.7, −1.6  0.01  Type of lipodystrophy    13    25    0.01   Generalized  11  7   Partial  1  8   Unspecified  1  6   None  0  4  Diabetes mellitus, %  85  13  36  22  14, 68  0.01  Hypertension, %  50  10  50  12  −36, 36  1.00  Hypertriglyceridemia, %  100  12  46.2  13  19, 77  0.005  Joint contractures, %  89  9  62  13  −11, 55  0.33  Cardiomyopathy, %  70  10  59  22  −24, 39  0.70  Valvular disease, %  80  10  63  19  −19, 43  0.43  Scoliosis, %  38  8  29  7  −34, 47  1.00  Mottled skin, %  100  11  89  18  −16, 33  0.29  Hepatomegaly, %  100  11  50  10  13, 76  0.01  Acanthosis nigricans, %  40  10  0  12  6, 69  0.03  Small atrophic breasts, %  100  4  89  9  −39, 43  1.0  Median and range are presented for continuous variables. P values are from the Wilcoxon rank sum test or Fisher’s exact test. Confidence intervals are Hodges–Lehmann confidence interval for median differences (GLPS-APS) and binomial confidence interval for differences in percentage. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; HbA1c, hemoglobin A1c; BMI, body mass index; TG, triglyceride. a Patients with APS had the following heterozygous LMNA mutations: p.P4R (n = 6), p.R133L (n = 4), p.D136H (n = 3), p.C588R (n = 2), p.D300N (n = 2), p.E138K (n = 2), p.E111K (n = 1), p.E159K (n = 1), p.R644C (n = 1), p.L140R (n = 1), p.A57P (n = 1), p.P485R (n = 1), p.L59V (n = 1), p.T506* (n = 1). Patients with APS with the following heterozygous LMNA mutations had generalized lipodystrophy: p.R133L (two patients), p.R644C (one patient), p.T506del (one patient), and p.D136H (three patients). b Body fat was estimated by dual-energy x-ray absorptiometry (DXA). View Large Discussion Our study highlights distinctive characteristic features of this novel syndrome associated with the heterozygous LMNA p.T10I mutation such as early childhood onset of generalized lipodystrophy, rather than at birth, along with other progeroid features (Table 1). These patients had severe metabolic complications such as hypertriglyceridemia, diabetes, hepatomegaly, and acanthosis nigricans early in life, with higher levels of serum triglycerides and insulin, as well as lower levels of serum leptin and HDL cholesterol than others with APS, suggesting more severe complications of lipodystrophy. In contrast, generalized lipodystrophy was noted in only one fourth of the other patients with APS. Both groups had similar prevalence of mottled skin pigmentation, joint contractures, and cardiomyopathy. Particularly notable in patients with heterozygous LMNA p.T10I mutation was the need for cardiac transplantation at ages 13, 32, and 47 years in three patients and severe aortic stenosis in another. Additionally, the patient reported by Cardona-Hernández et al. (14) died of congestive heart failure at age 17.7 years (personal communication). Clinical features of the patients with heterozygous LMNA p.T10I mutation are also very different from those with HGPS. Even though some patients with HGPS have been reported to have generalized loss of subcutaneous fat, occurrence of diabetes, hypertriglyceridemia, acanthosis nigricans, and hepatomegaly are unusual (4, 5). Instead, patients with HGPS have severe failure to thrive, alopecia, skeletal dysplasia including acro-osteolysis, hearing loss, and exacerbated cardiovascular disease, including cardiac electrical defects, atherosclerosis, vascular stiffening, and calcification, and die at an average age of 14.6 years, predominantly from myocardial infarction or stroke (4, 5). Because patients with heterozygous LMNA p.T10I mutation have unique and relatively homogeneous clinical features, we propose that they should be designated as having a novel syndrome called generalized lipodystrophy-associated progeroid syndrome (GLPS). We think that recognition of GLPS and molecular confirmation would be important because even among investigators who are experienced in characterizing various types of lipodystrophy, some patients were misdiagnosed as having “idiopathic” or “acquired” generalized lipodystrophy (17, 20), HGPS, Seip syndrome (13), and even juvenile dermatomyositis (23). The major morbidity in GLPS seems to be due to progressive cardiomyopathy with predominant valvular involvement, as well as interstitial fibrosis, and in later adulthood even coronary artery disease. The underlying mechanisms of other diverse clinical features such as mottled skin pigmentation, joint contractures, focal segmental glomerulosclerosis, and myositis remain unclear. It is noteworthy that nearly all patients developed GLPS due to de novo mutation, suggesting that cytosine at position 29 may be a mutational hot spot for recurrent substitution with thymidine. This is peculiar, as cytosine at position 29 is not a part of mutation-prone CpG dinucleotides. The case of a father-to-daughter transmission of the variant suggests that affected males may have normal fertility. It is unclear whether females with GLPS may also be able to reproduce because only patient 6.1 is within reproductive age but also has severe comorbidities. Seven patients with GLPS who had severe metabolic abnormalities were treated with metreleptin therapy. All of them, except one who was noncompliant, responded exceptionally well, with improved metabolic parameters. Patient 8.1 had menarche at age 10 and regular menstruation subsequently after commencement of metreleptin therapy at age 9. Patient 6.1 commenced regular menstruation after metreleptin therapy but developed heart failure in the third decade of life despite 16 years of metreleptin treatment. Interestingly, rapamycin (sirolimus) and temsirolimus, which inhibit mammalian target of rapamycin, are under development for LMNA-associated cardiomyopathy (26–28), but leptin is known to activate mammalian target of rapamycin (29, 30). Because echocardiography in patient 6.1 at age 14, before metreleptin therapy, showed evidence of cardiomyopathy, and her father, patient 6.2, developed severe cardiomyopathy but was never treated with metreleptin, it is difficult to speculate whether metreleptin therapy has any untoward effects on cardiac function in patients with GLPS. Skin fibroblasts of patients with GLPS and HGPS show markedly abnormal nuclear morphology (3, 7). Although patients with HGPS may benefit from farnesyl transferase inhibitor therapy (31, 32) or by modulation of LMNA splicing (33) to reduce formation of farnesylated progerin, such approaches theoretically may not help patients with GLPS. Chemical inhibition of acyltransferase NAT10 by remodelin improves nuclear architecture and chromatin organization of human lamin A/C-depleted cells (34) and may have a potential therapeutic role for patients with GLPS. Other therapeutic approaches for GLPS patients may include helper-dependent adenoviral vector-mediated correction of p.T10I mutation (35) and antisense oligonucleotide-mediated “exon skipping.” (36). In conclusion, patients with GLPS have distinctive clinical features and significantly worse metabolic complications compared with other APS and HGPS patients. Patients with GLPS should undergo annual evaluation for metabolic complications and cardiomyopathy, which appear to be the major causes of morbidity. Although metreleptin therapy may be effective in ameliorating severe metabolic abnormalities in these patients, its effects on female reproductive function and cardiac function warrant further investigation. Abbreviations: APS atypical progeroid syndrome GLPS generalized lipodystrophy-associated progeroid syndrome HDL high-density lipoprotein HGPS Hutchinson–Gilford progeria syndrome LMNA lamin A/C. Acknowledgments We thank Pei-Yun Tseng and Jeongwoo Lee for illustrations and Claudia Quittner for help with evaluation of patients at the UT Southwestern Medical Center. Financial Support: This work was supported by National Institutes of Health Grants R01 DK105448 and R01 DK088114, Clinical and Transitional Science Award Grants UL1RR024982, UL1TR001105, and UL1TR000433, Centers Grant P30 DK089503, and National Institutes of Health Institutional Grant DK034933; by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases; by Grant 14-35-00 026 of the Russian Science Foundation; and by funding from the UT Southwestern Medical Foundation. Author Contributions: I.H., N.P., and A.G. designed the study, reviewed the data, provided figures and data collection, interpreted the data, and wrote the manuscript. 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Endocrine Society
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Copyright © 2018 Endocrine Society
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Abstract

Abstract Background Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson–Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality. Mutations in lamin A/C (LMNA) gene can cause several disorders, including familial partial lipodystrophy, muscular dystrophies, cardiomyopathies, neuropathy, and progeroid syndromes (1, 2). The progeroid syndromes associated with LMNA mutations include the autosomal-dominant Hutchinson–Gilford progeria syndrome (HGPS) (3–5) and atypical progeroid syndrome (APS) (6–14), as well as autosomal recessive, mandibuloacral dysplasia (15, 16). Most patients with HGPS have a characteristic phenotype and a recurrent de novo heterozygous LMNA c.1824C>T; p.G608= mutation that activates a cryptic splice site resulting in the deletion of 50 amino acids near its carboxyl terminus (3). Patients with APS have variable progeroid features such as short stature, beaked nose, premature graying, partial loss of hair, high-pitched voice, skin atrophy over the hands and feet, generalized lipodystrophy, skin pigmentation, and mandibular hypoplasia (7). Interestingly, 5 of 31 patients with APS reported so far also had a recurrent de novo heterozygous LMNA c.29C>T; p.T10I mutation (7, 12–14), suggesting that this subset of patients could have another distinct progeroid disorder. All five patients had childhood onset of generalized lipodystrophy with variable metabolic, cardiac, cutaneous, and other similar clinical manifestations. In this study, we report nine new patients and follow-up of two previously reported patients with heterozygous LMNA p.T10I mutation, comparing clinical features and disease burden of all these patients to those with other APS patients to define unique characteristics of this novel progeroid syndrome. Case Reports Patients 1.1 to 4.1 were evaluated at the University of Texas Southwestern Medical Center; patients 5.1 to 7.1 at the National Institutes of Health; patient 8.1 at the University of Michigan; patient 9.1 at Moscow, Russia; and patient 10.1 at Rio de Janeiro, Brazil. Patients 6.1 and 6.2 were also evaluated at the University of Pennsylvania. The research protocol was approved by the respective Institutional Review Boards, and all participants provided written informed consent. Anthropometric and metabolic data of these patients are presented in Tables 1 and 2, respectively. Their pedigrees are shown in Supplemental Fig. 1. Unique clinical features of each patient are briefly summarized below. Table 1. Clinical Features of Patients With GLPS as a Result of Heterozygous LMNA p.T10I Mutation Variables  Patient No.  1.1  2.1  3.1  4.1  5.1  6.1  6.2  7.1  8.1  9.1  10.1  Age at report,a y  10  16  8.5  15  8  33  55  13  16  10  12  Age of onset of lipodystrophy, y  5  10  5.5  5  0.5  14  35  10  7  4  6  Sex  F  M  M  M  M  F  M  M  F  F  F  Ethnicity  White  White  White  White  White  White  White  Black  Black  White  Mixed  Nationality  American  American  American  Kazakhstan  Spain  American  American  American  American  Russian  Brazilian  Height, m  1.44  1.41  1.26  1.62  1.40  1.50  1.69  1.55  1.48  1.36  1.50  Height, z score  0.86  −1.11  −0.33  −1.02  2.10  −2.01  NA  0.78  −2.25  −0.31  −0.16  Weight, kg  24.9  33.5  20.9  39.6  27.5  34.4  71.6  38.8  32.3  21.1  32.2  BMI, kg/m2  11.8  16.8  13.5  15.2  14  15.2  25.1  14.8  14.8  11.4  14.3  DM (age of onset, y)  Y (9)  Y (13)  N  Y (12)  Y (7)  Y (13)  Y (47)  Y (11)  Y (7)  N  Y (12)  Acanthosis nigricans  N  Y  N  N  Y  N  N  NR  Y  N  Y  HTN (age of onset, y)  Y (10)  Y (NR)  N  NR  NR  N  Y  Y  N  N  N  Joint contractures  Y  Y  Y  Y  NR  Y  N  Y  Y  Y  N  Cardiomyopathy  N  N  N  Y  Y  Y  Y  Y  Y  Y  N  Valvular disease  Y  Y  N  Y  Y  Y  Y  N  Y  Y  N  Micrognathia  Y  Y  Y  Y  NR  Y  N  NR  Y  NR  Y  Mottled skin  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Atrophic skin  NR  Y  Y  Y  NR  Y  Y  Y  Y  Y  Y  Beaked nose  Y  NR  Y  NR  NR  Y  N  NR  N  NR  Y  Thin lips  Y  NR  NR  NR  NR  Y  Y  NR  NR  Y  Y  Receding hairline  NR  Y  NR  NR  NR  Y  N  NR  Y  NR  Y  Loss of hair  Y  N  N  NR  N  NR  Y  NR  Y  NR  Y  Hepatomegaly  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Splenomegaly  N  Y  N  Y  Y  N  N  N  Y  Y  Y  Underdeveloped breasts  Y  NA  NA  NA  NA  Y  NA  NA  Y  NA  Y  Spinal deformities  Y  N  N  NR  NR  N  N  Y  N  Y  Y  Variables  Patient No.  1.1  2.1  3.1  4.1  5.1  6.1  6.2  7.1  8.1  9.1  10.1  Age at report,a y  10  16  8.5  15  8  33  55  13  16  10  12  Age of onset of lipodystrophy, y  5  10  5.5  5  0.5  14  35  10  7  4  6  Sex  F  M  M  M  M  F  M  M  F  F  F  Ethnicity  White  White  White  White  White  White  White  Black  Black  White  Mixed  Nationality  American  American  American  Kazakhstan  Spain  American  American  American  American  Russian  Brazilian  Height, m  1.44  1.41  1.26  1.62  1.40  1.50  1.69  1.55  1.48  1.36  1.50  Height, z score  0.86  −1.11  −0.33  −1.02  2.10  −2.01  NA  0.78  −2.25  −0.31  −0.16  Weight, kg  24.9  33.5  20.9  39.6  27.5  34.4  71.6  38.8  32.3  21.1  32.2  BMI, kg/m2  11.8  16.8  13.5  15.2  14  15.2  25.1  14.8  14.8  11.4  14.3  DM (age of onset, y)  Y (9)  Y (13)  N  Y (12)  Y (7)  Y (13)  Y (47)  Y (11)  Y (7)  N  Y (12)  Acanthosis nigricans  N  Y  N  N  Y  N  N  NR  Y  N  Y  HTN (age of onset, y)  Y (10)  Y (NR)  N  NR  NR  N  Y  Y  N  N  N  Joint contractures  Y  Y  Y  Y  NR  Y  N  Y  Y  Y  N  Cardiomyopathy  N  N  N  Y  Y  Y  Y  Y  Y  Y  N  Valvular disease  Y  Y  N  Y  Y  Y  Y  N  Y  Y  N  Micrognathia  Y  Y  Y  Y  NR  Y  N  NR  Y  NR  Y  Mottled skin  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Atrophic skin  NR  Y  Y  Y  NR  Y  Y  Y  Y  Y  Y  Beaked nose  Y  NR  Y  NR  NR  Y  N  NR  N  NR  Y  Thin lips  Y  NR  NR  NR  NR  Y  Y  NR  NR  Y  Y  Receding hairline  NR  Y  NR  NR  NR  Y  N  NR  Y  NR  Y  Loss of hair  Y  N  N  NR  N  NR  Y  NR  Y  NR  Y  Hepatomegaly  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Y  Splenomegaly  N  Y  N  Y  Y  N  N  N  Y  Y  Y  Underdeveloped breasts  Y  NA  NA  NA  NA  Y  NA  NA  Y  NA  Y  Spinal deformities  Y  N  N  NR  NR  N  N  Y  N  Y  Y  Abbreviations: BMI, body mass index; DM, diabetes mellitus; F, female; HTN, hypertension; M, male; N, no; NA, not applicable; NR, not reported; Y, yes. a Age at which patient was last seen by investigators. View Large Table 2. Metabolic Parameters of Patients With GLPS as a Result of Heterozygous LMNA p.T10I Mutation Variables  Patient No.  1.1  2.1  3.1  4.1  5.1  6.1  6.2  7.1  8.1  9.1  10.1  Triglycerides, mg/dL  580  571  293  445  335  7420  238  2238  10,623  1134  2056  Cholesterol, mg/dL  145  145  125  164  165  740  172  173  NR  225  145  HDL cholesterol, mg/dL  22  23  21  42  32  18  31  NR  23  19  28  HbA1C, %  6.4  5.4  5.3  10.7  6.3  8  5.2  10.4  9.3  5.5  11.5  Glucose, mg/dL  125  87  74  176  111  283  87  218  277  83  102  Insulin, µU/mL  55.7  208  8.7  15.6  55.9  26.8  46.4  55.2  NR  218.9  47.1  Leptin, ng/mL  NR  1  0.6  0.1  0.4  1.48  4  1.62  0  0.5  1  ALT, IU/L  70  92  11  31  216  97  56  119  27  103  146  AST, IU/L  35  50  22  31  120  70  31  66  20  66  71  Proteinuria, g/d  0.926  0.099  NR  0.271  0.518  10.099  0.110  2.12  0.30  NA  0.420  Body fat,a %  13.6  14.4  13.6  6.6  NR  3.1  25  8.3  4.3  4.0  4.5  Variables  Patient No.  1.1  2.1  3.1  4.1  5.1  6.1  6.2  7.1  8.1  9.1  10.1  Triglycerides, mg/dL  580  571  293  445  335  7420  238  2238  10,623  1134  2056  Cholesterol, mg/dL  145  145  125  164  165  740  172  173  NR  225  145  HDL cholesterol, mg/dL  22  23  21  42  32  18  31  NR  23  19  28  HbA1C, %  6.4  5.4  5.3  10.7  6.3  8  5.2  10.4  9.3  5.5  11.5  Glucose, mg/dL  125  87  74  176  111  283  87  218  277  83  102  Insulin, µU/mL  55.7  208  8.7  15.6  55.9  26.8  46.4  55.2  NR  218.9  47.1  Leptin, ng/mL  NR  1  0.6  0.1  0.4  1.48  4  1.62  0  0.5  1  ALT, IU/L  70  92  11  31  216  97  56  119  27  103  146  AST, IU/L  35  50  22  31  120  70  31  66  20  66  71  Proteinuria, g/d  0.926  0.099  NR  0.271  0.518  10.099  0.110  2.12  0.30  NA  0.420  Body fat,a %  13.6  14.4  13.6  6.6  NR  3.1  25  8.3  4.3  4.0  4.5  For patients who were treated with metreleptin, the data reported are before the initiation of therapy. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; HbA1c, hemoglobin A1c; NR, not reported. a Body fat from dual-energy x-ray absorptiometry. View Large Patient 1.1 This 11-year-old white female presented with failure to thrive since birth and remained at the 10th percentile for weight during childhood (Fig. 1A). At age 9, generalized absence of subcutaneous fat and mottled skin hyperpigmentation around the neck, axillae, and groin were noted. She had birdlike facies with dental crowding, a receding hairline, and anteverted ears. She had mild scoliosis and joint contractures, especially at the knees. Hypertriglyceridemia, mild diabetes mellitus, hypertension, and proteinuria were also noted. An echocardiogram showed normal cardiac function with mild mitral and aortic regurgitation. At age 10, she started metreleptin therapy resulting in marked lowering of fasting serum triglycerides from 1026 mg/dL to 118 mg/dL after 4 months. Figure 1. View largeDownload slide Phenotypic and anthropometric features of patients with GLPS with heterozygous LMNA p.T10I mutation. All patients have generalized lipodystrophy with notable micrognathia and prominent scapulae. (A) Lateral and (B) posterior views of patient 1.1, a 9-year-old white girl with generalized loss of subcutaneous fat, extremely thin arms and legs, and mildly protuberant abdomen. She has a progeroid appearance with sharp features along with curly hair. (C) Lateral and (D) posterior views of patient 3.1, an 8-year-old white boy with generalized fat loss and muscular extremities. He also has a receding chin and protuberant abdomen. (E) Anterior view of the neck of patient 7.1, a 13-year-old African-American male with mottled skin pigmentation. (F) Anterior view of the abdomen and (G) left axilla of patient 9.1, a 10-year-old white girl showing mottled pigmentation and abdominal protuberance. (H) Anterior view of left thigh of patient 10.1 showing marked loss of subcutaneous fat and eruptive xanthomas. (I) Right axilla of patient 10.1 with eruptive xanthomas, mottled skin, acanthosis nigricans, and marked fat loss. (J) Skinfold thickness of three female patients (1.1, 6.1, and 9.1) marked by filled diamonds, squares, and inverted triangles, respectively, as measured with standard calipers. The gray bars show 10th to 90th percentile values of normal age-matched girls with the median value marked by a horizontal line. (K) Skinfold thickness of two male GLPS patients (2.1 and 3.1) marked by filled circles and triangles, respectively. The gray bars show the 10th and 90th percentile values of normal age-matched boys with the median value marked by a horizontal line. All patients have markedly decreased skinfold thickness at all anatomic sites indicating generalized loss of subcutaneous fat. This appears to be even more pronounced in the upper and lower extremities. Figure 1. View largeDownload slide Phenotypic and anthropometric features of patients with GLPS with heterozygous LMNA p.T10I mutation. All patients have generalized lipodystrophy with notable micrognathia and prominent scapulae. (A) Lateral and (B) posterior views of patient 1.1, a 9-year-old white girl with generalized loss of subcutaneous fat, extremely thin arms and legs, and mildly protuberant abdomen. She has a progeroid appearance with sharp features along with curly hair. (C) Lateral and (D) posterior views of patient 3.1, an 8-year-old white boy with generalized fat loss and muscular extremities. He also has a receding chin and protuberant abdomen. (E) Anterior view of the neck of patient 7.1, a 13-year-old African-American male with mottled skin pigmentation. (F) Anterior view of the abdomen and (G) left axilla of patient 9.1, a 10-year-old white girl showing mottled pigmentation and abdominal protuberance. (H) Anterior view of left thigh of patient 10.1 showing marked loss of subcutaneous fat and eruptive xanthomas. (I) Right axilla of patient 10.1 with eruptive xanthomas, mottled skin, acanthosis nigricans, and marked fat loss. (J) Skinfold thickness of three female patients (1.1, 6.1, and 9.1) marked by filled diamonds, squares, and inverted triangles, respectively, as measured with standard calipers. The gray bars show 10th to 90th percentile values of normal age-matched girls with the median value marked by a horizontal line. (K) Skinfold thickness of two male GLPS patients (2.1 and 3.1) marked by filled circles and triangles, respectively. The gray bars show the 10th and 90th percentile values of normal age-matched boys with the median value marked by a horizontal line. All patients have markedly decreased skinfold thickness at all anatomic sites indicating generalized loss of subcutaneous fat. This appears to be even more pronounced in the upper and lower extremities. Patient 2.1 This 16-year-old white male presented at age 11.3 years with remarkable loss of adiposity, especially from the face and the extremities. He had micrognathia and curly hair that was reportedly straight at birth. His skin was atrophic with mottled hyperpigmentation and mild acanthosis nigricans. He had joint contractures of the phalangeal joints, wrists, and ankles, as well as hammer toes. Abdominal ultrasound showed hepatosplenomegaly with severe hepatic steatosis. Oral glucose tolerance test revealed mild diabetes and his fasting serum triglycerides were 571 mg/dL. Echocardiogram showed trivial pulmonary and tricuspid regurgitation. Mild motor neuropathy was reported on a nerve conduction study. Metreleptin therapy was started at age 11.6 years; however, he was noncompliant. At age 14, he developed worsening of diabetes (hemoglobin A1c, 9.2%) and extreme hypertriglyceridemia (serum triglycerides, 6640 mg/dL) with eruptive xanthomas, and insulin therapy was initiated. At age 16 years, with improved compliance to metreleptin, gemfibrozil, and insulin therapy, his fasting serum triglycerides were 1287 mg/dL and hemoglobin A1c was 8.3%. Patient 3.1 This 8.5-year-old white male presented with failure to thrive despite having voracious appetite and generalized absence of subcutaneous fat (Fig. 1C and 1D). He had significant dental crowding due to micrognathia. Superficial veins and mottled hyperpigmentation on the trunk were prominent features. He had contractures of the phalangeal joints and knees and hepatomegaly. Echocardiographic evaluation was normal. Patient 4.1 This patient from Kazakhstan (previously reported as APS 800.3) (7, 17) had generalized loss of fat at age 5 and joint contractures of ankles, knees, and hips. He received metreleptin therapy for only 10 months at age 15 years, which improved diabetes and hypertriglyceridemia (18). Echocardiogram revealed severe concentric left ventricular hypertrophy and aortic stenosis with heavily calcified aortic and mitral valves. Subsequently, he had worsening of hyperglycemia and hypertriglyceridemia due to noncompliance with insulin. He developed a foot infection leading to sepsis and death at age 17 years. Patient 5.1 This 15-year-old male from Spain (previously reported as APS 1700.4) (7) initially presented with acanthosis nigricans at the age of 6 months and was treated with metreleptin since age 8 years with marked improvement in diabetes and hyperlipidemia. He had cardiac transplantation at age 13 years for progressively worsening dilated cardiomyopathy and valvular disease (19). The explanted heart showed extensive areas of myocardial sclerosis in both ventricles with normal coronary arteries (19). Patient 6.1 This 33-year-old white female (previously reported as NIH-1) developed extreme hypertriglyceridemia (>19,000 mg/dL) with painful, eruptive xanthomas on the face, trunk, and extremities at age 12 years, requiring plasmapheresis for ∼24 months (20). She also had severe diabetes with insulin resistance and primary amenorrhea and was diagnosed with “acquired” generalized lipodystrophy at age 14 years. She had pinched facies with sunken cheeks. The skin was mottled in appearance with patchy areas of hyperpigmentation and hypopigmentation on the neck and trunk. Liver biopsy showed severe steatohepatitis with mild inflammation, as well as fibrosis. Kidney biopsy performed for proteinuria (>2 g daily) revealed focal segmental glomerulosclerosis. At age 17 years, metreleptin therapy was initiated with a remarkable metabolic response and onset of menarche at age 17 (21, 22). However, by age 30 years, she developed mild to moderate regurgitation of the aortic, mitral, and tricuspid valves and moderate-to-severe calcification of the aortic and mitral valves. She also required a cardiac resynchronization therapy device for wide left bundle branch block. At age 32 years, the left ventricular ejection fraction declined to 15%, and she received cardiac transplantation at age 33. Pathology of the explanted heart revealed heavily calcified mitral and aortic valves, left ventricular myocyte hypertrophy with interstitial fibrosis, and mild calcific coronary atherosclerosis with minimal luminal occlusion (Fig. 2). Despite metreleptin, posttransplantation steroid therapy worsened hyperglycemia and hypertriglyceridemia, resulting in acute pancreatitis 2 months afterward. With strict dietary intervention, she was able to stabilize serum triglyceride levels. Figure 2. View largeDownload slide Photomicrographs showing histopathology of the explanted heart of patient 6.1. Magnifications are given in the right-hand upper corner. (A) Hematoxylin and eosin staining showing expanding subendocardial fibrotic changes (shown by blue arrow). (B) Trichrome staining of section of left ventricle showing fibrotic changes (blue) of the cardiac myocytes. (C) Hematoxylin and eosin staining showing mild myocyte hypertrophy (examples of enlarged, hyperchromatic, slightly bizarre nuclei circled) and fibrosis (shown by arrows) of the left ventricle. (D) Hematoxylin and eosin staining highlighting an atherosclerotic plaque with foam cells (blue arrow), calcifications (green arrows), and inflammatory cells (black arrow) in the left circumflex coronary artery. Figure 2. View largeDownload slide Photomicrographs showing histopathology of the explanted heart of patient 6.1. Magnifications are given in the right-hand upper corner. (A) Hematoxylin and eosin staining showing expanding subendocardial fibrotic changes (shown by blue arrow). (B) Trichrome staining of section of left ventricle showing fibrotic changes (blue) of the cardiac myocytes. (C) Hematoxylin and eosin staining showing mild myocyte hypertrophy (examples of enlarged, hyperchromatic, slightly bizarre nuclei circled) and fibrosis (shown by arrows) of the left ventricle. (D) Hematoxylin and eosin staining highlighting an atherosclerotic plaque with foam cells (blue arrow), calcifications (green arrows), and inflammatory cells (black arrow) in the left circumflex coronary artery. Patient 6.2 This 55-year-old white male is the father of patient 6.1 (Supplemental Fig. 1). He was an unusually thin child who had mottled skin pigmentation on his abdomen, which resolved around age 13 years. At age 35 years, he was noted to have sunken cheeks and muscular arms and legs. Abdominal ultrasound showed fatty liver and increased intra-abdominal fat. At age 38, he had a myocardial infarction and required coronary stents. At age 47 years, he required cardiac transplantation for deteriorating “cardiomyopathy.” Pathology of the explanted heart revealed myocardium with patchy interstitial fibrosis and myocyte hypertrophy, myxoid degeneration of mitral and tricuspid valves, and moderate-to-severe calcific coronary atherosclerosis. After transplantation, he developed mild steroid-induced diabetes mellitus with the highest fasting serum triglycerides of 493 mg/dL. Patient 7.1 This 13-year-old African American male had gradual generalized loss of subcutaneous fat between ages 10 and 12 years. He had micrognathia and sunken cheeks. His skin was mottled with patches of hypopigmentation and hyperpigmentation (Fig. 1E), noted since birth on the neck, torso, and the extremities. He had mild thoracic scoliosis and kyphosis, as well as mildly limited joint mobility. He developed hypertriglyceridemia, diabetes mellitus, and severe insulin resistance at age 11 years. An abdominal ultrasound revealed severe hepatic steatosis, and a biopsy confirmed steatohepatitis without fibrosis. An echocardiogram at age 13 years revealed possible noncompaction cardiomyopathy without valvular abnormalities. Metreleptin therapy for 1 year improved his hemoglobin A1c from 10.4% to 5.7% and he was able to discontinue insulin therapy; his serum triglycerides declined from 2238 mg/dL to 112 mg/dL. Patient 8.1 This 16-year-old female of African-American ethnicity developed decreased muscle strength at age 4, and at age 6 years she was diagnosed with juvenile dermatomyositis based on clinical features and elevated serum creatine kinase (477 U/L; normal range, 25 to 240 U/L) and was treated with methotrexate (23). Serum antinuclear, anti–double-stranded DNA, Rh factor, and anticardiolipin antibodies were negative. Subsequently, serum antinuclear antibody titer was 1:160 with speckled pattern. Later, she developed progressive contractures of the phalangeal joints, wrists, left elbow, and right shoulder with calcium deposits. Around age 7 years, she started losing subcutaneous fat, gradually resulting in generalized lipodystrophy and diabetes mellitus. She had a small midface, high-arched palate, and micrognathia with crowding of teeth. She had mottled skin and eruptive xanthomas. At age 9 years, she developed acute pancreatitis with serum triglycerides of 10,623 mg/dL and diabetic ketoacidosis. Metreleptin treatment was started at age 9 years (23). She had menarche at age 10 years but was diagnosed with polycystic ovarian syndrome associated with hirsutism and clitoromegaly. An echocardiogram showed a small secundum atrial septal defect. Abdominal imaging study revealed nephromegaly and bilateral kidney cysts. Patient 9.1 This 10-year-old white female from Russia had failure to thrive since 2 months of age. Around age 4 years, she had generalized loss of fat, mandibular hypoplasia, and low-set, deformed ears. She had mottled skin on the torso and extremities (Fig. 1F and 1G). Her lower extremities appeared hypertrophic. She had scoliosis and flexion contractures of all interphalangeal joints, elbows, and knees. At age 6 years, she complained of intermittent epigastric pain likely due to acute pancreatitis with extreme hypertriglyceridemia (serum triglycerides 1134 mg/dL). She had normal glucose tolerance, but with extreme hyperinsulinemia. An echocardiogram revealed pulmonary hypertension with pulmonary artery pressure of 36 mm Hg, along with nonsignificant pulmonary and tricuspid regurgitation. Patient 10.1 This 12-year-old female of mixed African-European origin from Brazil reported gradual loss of subcutaneous fat since age 6 despite increased appetite. She was noted to have hypertriglyceridemia at age 9 years. She had generalized loss of subcutaneous fat, including the palms and soles, and acanthosis nigricans in the axillae and neck. The liver was palpable at 6 cm below the right costal margin. The skin was atrophic with mottled hypopigmentation over the trunk and extremities. She had loss of the hair in frontal region, micrognathia, beaked nose with thin lips, and birdlike face. She had lumbar lordosis but no joint contractures. Abdominal ultrasonography showed hepatosplenomegaly and hepatic steatosis, and a liver biopsy revealed steatohepatitis stage 3 with grade 1a fibrosis. At age 12 years, she developed severe hyperglycemia (hemoglobin A1c 11.5%) and hypertriglyceridemia (serum triglycerides 2056 mg/dL) despite high doses of insulin (180 U/d), fibrate, and pioglitazone therapy and suffered from acute pancreatitis. She had eruptive xanthomas on the neck, trunk, and lower limbs and Tanner stage 3 pubic hair, but with no menarche or breast development. Materials and Methods Anthropometry Anthropometric measurements Height, body weight, and skinfold thickness were measured by standard procedures as reported previously (7). Dual-energy x-ray absorptiometry Whole-body fat and regional fat in the head, trunk, and upper and lower extremities were determined using a Hologic QDR-2000 densitometer (Hologic, Waltham, MA) or GE Lunar Prodigy (General Electric, Madison, WI). Magnetic resonance imaging Magnetic resonance imaging studies were performed using a 1.5-Tesla imaging device (Philips Medical Systems, Best, Netherlands) and version 5.2-2 viewing software as reported previously (7). Metabolic assessments and genetic analysis Biochemical analyses Plasma glucose was measured by the glucose oxidase method with a glucose analyzer. Serum insulin and leptin levels were determined by immunoassays using commercial laboratories or kits (EMD Millipore, Billerica, MA). Serum cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and chemistry as well as blood hemoglobin A1C were analyzed as part of a systematic multichannel analysis. Mutational analyses The exons and exon–intron boundaries of the LMNA gene were sequenced according to Chen et al. (24). For patients 6.1 and 6.2, DNA was extracted from the whole blood on the QIAsymphony SP system with the use of a QIAsymphony DSP DNA kit as specified by the manufacture (Qiagen, Germantown, MD). LipidSeq, a custom targeted lipid gene panel focusing on known lipodystrophy genes (25), was used for analysis using Illumina MiSeq platform with subsequent confirmation by Sanger sequencing. A targeted next generation sequencing panel was used to genotype patient 10.1. Results The same heterozygous pathogenic LMNA mutation c.29C>T (g.156084738C>T; GRCh37/hg19), which translates to p.Thr10Ile in lamin A/C (NM_170707.3), was identified in all 11 patients, occurring de novo except in patient 6.1, who inherited it from her father, patient 6.2. We then compared clinical features and laboratory data of all these and 3 other previously reported patients with heterozygous LMNA p.T10I mutation to 26 other previously reported patients with APS with many different heterozygous LMNA variants. All patients with heterozygous LMNA p.T10I mutation had generalized lipodystrophy except for patient 6.2, who was assessed to have partial lipodystrophy, and patient 8.1, where the degree of lipodystrophy was not specified. Compared with other patients with APS, the patients with the heterozygous LMNA p.T10I mutation had significantly increased prevalence of generalized lipodystrophy, diabetes mellitus, hypertriglyceridemia, hepatomegaly, and acanthosis nigricans despite being significantly younger (Table 3). Generalized lack of body fat was also noticed on skinfold thickness measurements in five patients with p.T10I mutation (Fig. 1H and 1I) and in a previously reported patient (7), and on whole-body magnetic resonance imaging (Supplemental Fig. 2). Dual-energy x-ray absorptiometry scans further confirmed significantly reduced total and regional body fat in patients with heterozygous LMNA p.T10I mutation (Table 3). Patients with heterozygous LMNA p.T10I mutation also had markedly lower levels of serum leptin and HDL cholesterol and had higher levels of triglycerides and insulin compared with other patients with APS (Table 3). The prevalence of other features such as mottled skin pigmentation, joint contractures, and cardiomyopathy, however, were not significantly different in the two groups. Age was not found to be a significant covariate. Table 3. Comparison of Clinical Features and Metabolic Parameters of Patients With GLPS With Heterozygous LMNA p.T10I Mutation and Others With APS   GLPS  Total n  APSb  Total n  95% CI of the Differences  P Value  Females, %  50  14  63  27  −41, 17  0.50  Age reported, y  14 (8–55)  14  23.0 (7–53)  26  −14, −2  0.01  BMI, kg/m2  14.6 (11.4–25.1)  12  15.4 (10.1–19.6)  20  −3.3, 1.1  0.39  Fasting TG, mg/dL  776 (238–10,623)  13  121 (34–3000)  14  214, 2022  0.0007  HbA1c, %  8.0 (5.2–10.7)  13  5.3 (4.8–12.7)  11  0.2, 4.0  0.02  ALT, mU/L  83.5 (11–216)  12  36.5 (13–287)  10  −20, 86  0.31  AST, mU/L  51 (20–120)  12  44.5 (16–134)  10  −30, 38  0.71  HDL cholesterol, mg/dL  21.0 (6–42)  11  40.5 (14.6–50.0)  12  −24.7, −11.0  0.001  Leptin, ng/mL  0.3 (0–4.0)  10  3.0 (0.8–12.6)  11  −5.1, −0.8  0.0003  Fasting glucose, mg/dL  125 (74–283)  13  93 (84–277)  13  −10, 85  0.26  Fasting insulin, µU/mL  55.2 (8.7–290)  11  14.7 (1.9–85.0)  11  4, 136  0.03  Total body fat,b (%)  8.5 (0.04–25.0)  10  17.2 (6.5–27.0)  12  −13.4, −0.1  0.04  Lower Extremity fat,b %  6.3 (4.0–12.9)  7  15.7 (5.2–26.9)  9  −13.3, −1.8  0.01  Upper Extremity fat,b %  10.4 (3.0–13.7)  6  19.3 (12.3–32.2)  10  −18.5, −2.3  0.001  Truncal fat,b %  7.8 (3.9–14.2)  7  17.8 (8.1–30.2)  10  −17.7, −1.6  0.01  Type of lipodystrophy    13    25    0.01   Generalized  11  7   Partial  1  8   Unspecified  1  6   None  0  4  Diabetes mellitus, %  85  13  36  22  14, 68  0.01  Hypertension, %  50  10  50  12  −36, 36  1.00  Hypertriglyceridemia, %  100  12  46.2  13  19, 77  0.005  Joint contractures, %  89  9  62  13  −11, 55  0.33  Cardiomyopathy, %  70  10  59  22  −24, 39  0.70  Valvular disease, %  80  10  63  19  −19, 43  0.43  Scoliosis, %  38  8  29  7  −34, 47  1.00  Mottled skin, %  100  11  89  18  −16, 33  0.29  Hepatomegaly, %  100  11  50  10  13, 76  0.01  Acanthosis nigricans, %  40  10  0  12  6, 69  0.03  Small atrophic breasts, %  100  4  89  9  −39, 43  1.0    GLPS  Total n  APSb  Total n  95% CI of the Differences  P Value  Females, %  50  14  63  27  −41, 17  0.50  Age reported, y  14 (8–55)  14  23.0 (7–53)  26  −14, −2  0.01  BMI, kg/m2  14.6 (11.4–25.1)  12  15.4 (10.1–19.6)  20  −3.3, 1.1  0.39  Fasting TG, mg/dL  776 (238–10,623)  13  121 (34–3000)  14  214, 2022  0.0007  HbA1c, %  8.0 (5.2–10.7)  13  5.3 (4.8–12.7)  11  0.2, 4.0  0.02  ALT, mU/L  83.5 (11–216)  12  36.5 (13–287)  10  −20, 86  0.31  AST, mU/L  51 (20–120)  12  44.5 (16–134)  10  −30, 38  0.71  HDL cholesterol, mg/dL  21.0 (6–42)  11  40.5 (14.6–50.0)  12  −24.7, −11.0  0.001  Leptin, ng/mL  0.3 (0–4.0)  10  3.0 (0.8–12.6)  11  −5.1, −0.8  0.0003  Fasting glucose, mg/dL  125 (74–283)  13  93 (84–277)  13  −10, 85  0.26  Fasting insulin, µU/mL  55.2 (8.7–290)  11  14.7 (1.9–85.0)  11  4, 136  0.03  Total body fat,b (%)  8.5 (0.04–25.0)  10  17.2 (6.5–27.0)  12  −13.4, −0.1  0.04  Lower Extremity fat,b %  6.3 (4.0–12.9)  7  15.7 (5.2–26.9)  9  −13.3, −1.8  0.01  Upper Extremity fat,b %  10.4 (3.0–13.7)  6  19.3 (12.3–32.2)  10  −18.5, −2.3  0.001  Truncal fat,b %  7.8 (3.9–14.2)  7  17.8 (8.1–30.2)  10  −17.7, −1.6  0.01  Type of lipodystrophy    13    25    0.01   Generalized  11  7   Partial  1  8   Unspecified  1  6   None  0  4  Diabetes mellitus, %  85  13  36  22  14, 68  0.01  Hypertension, %  50  10  50  12  −36, 36  1.00  Hypertriglyceridemia, %  100  12  46.2  13  19, 77  0.005  Joint contractures, %  89  9  62  13  −11, 55  0.33  Cardiomyopathy, %  70  10  59  22  −24, 39  0.70  Valvular disease, %  80  10  63  19  −19, 43  0.43  Scoliosis, %  38  8  29  7  −34, 47  1.00  Mottled skin, %  100  11  89  18  −16, 33  0.29  Hepatomegaly, %  100  11  50  10  13, 76  0.01  Acanthosis nigricans, %  40  10  0  12  6, 69  0.03  Small atrophic breasts, %  100  4  89  9  −39, 43  1.0  Median and range are presented for continuous variables. P values are from the Wilcoxon rank sum test or Fisher’s exact test. Confidence intervals are Hodges–Lehmann confidence interval for median differences (GLPS-APS) and binomial confidence interval for differences in percentage. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; HbA1c, hemoglobin A1c; BMI, body mass index; TG, triglyceride. a Patients with APS had the following heterozygous LMNA mutations: p.P4R (n = 6), p.R133L (n = 4), p.D136H (n = 3), p.C588R (n = 2), p.D300N (n = 2), p.E138K (n = 2), p.E111K (n = 1), p.E159K (n = 1), p.R644C (n = 1), p.L140R (n = 1), p.A57P (n = 1), p.P485R (n = 1), p.L59V (n = 1), p.T506* (n = 1). Patients with APS with the following heterozygous LMNA mutations had generalized lipodystrophy: p.R133L (two patients), p.R644C (one patient), p.T506del (one patient), and p.D136H (three patients). b Body fat was estimated by dual-energy x-ray absorptiometry (DXA). View Large Discussion Our study highlights distinctive characteristic features of this novel syndrome associated with the heterozygous LMNA p.T10I mutation such as early childhood onset of generalized lipodystrophy, rather than at birth, along with other progeroid features (Table 1). These patients had severe metabolic complications such as hypertriglyceridemia, diabetes, hepatomegaly, and acanthosis nigricans early in life, with higher levels of serum triglycerides and insulin, as well as lower levels of serum leptin and HDL cholesterol than others with APS, suggesting more severe complications of lipodystrophy. In contrast, generalized lipodystrophy was noted in only one fourth of the other patients with APS. Both groups had similar prevalence of mottled skin pigmentation, joint contractures, and cardiomyopathy. Particularly notable in patients with heterozygous LMNA p.T10I mutation was the need for cardiac transplantation at ages 13, 32, and 47 years in three patients and severe aortic stenosis in another. Additionally, the patient reported by Cardona-Hernández et al. (14) died of congestive heart failure at age 17.7 years (personal communication). Clinical features of the patients with heterozygous LMNA p.T10I mutation are also very different from those with HGPS. Even though some patients with HGPS have been reported to have generalized loss of subcutaneous fat, occurrence of diabetes, hypertriglyceridemia, acanthosis nigricans, and hepatomegaly are unusual (4, 5). Instead, patients with HGPS have severe failure to thrive, alopecia, skeletal dysplasia including acro-osteolysis, hearing loss, and exacerbated cardiovascular disease, including cardiac electrical defects, atherosclerosis, vascular stiffening, and calcification, and die at an average age of 14.6 years, predominantly from myocardial infarction or stroke (4, 5). Because patients with heterozygous LMNA p.T10I mutation have unique and relatively homogeneous clinical features, we propose that they should be designated as having a novel syndrome called generalized lipodystrophy-associated progeroid syndrome (GLPS). We think that recognition of GLPS and molecular confirmation would be important because even among investigators who are experienced in characterizing various types of lipodystrophy, some patients were misdiagnosed as having “idiopathic” or “acquired” generalized lipodystrophy (17, 20), HGPS, Seip syndrome (13), and even juvenile dermatomyositis (23). The major morbidity in GLPS seems to be due to progressive cardiomyopathy with predominant valvular involvement, as well as interstitial fibrosis, and in later adulthood even coronary artery disease. The underlying mechanisms of other diverse clinical features such as mottled skin pigmentation, joint contractures, focal segmental glomerulosclerosis, and myositis remain unclear. It is noteworthy that nearly all patients developed GLPS due to de novo mutation, suggesting that cytosine at position 29 may be a mutational hot spot for recurrent substitution with thymidine. This is peculiar, as cytosine at position 29 is not a part of mutation-prone CpG dinucleotides. The case of a father-to-daughter transmission of the variant suggests that affected males may have normal fertility. It is unclear whether females with GLPS may also be able to reproduce because only patient 6.1 is within reproductive age but also has severe comorbidities. Seven patients with GLPS who had severe metabolic abnormalities were treated with metreleptin therapy. All of them, except one who was noncompliant, responded exceptionally well, with improved metabolic parameters. Patient 8.1 had menarche at age 10 and regular menstruation subsequently after commencement of metreleptin therapy at age 9. Patient 6.1 commenced regular menstruation after metreleptin therapy but developed heart failure in the third decade of life despite 16 years of metreleptin treatment. Interestingly, rapamycin (sirolimus) and temsirolimus, which inhibit mammalian target of rapamycin, are under development for LMNA-associated cardiomyopathy (26–28), but leptin is known to activate mammalian target of rapamycin (29, 30). Because echocardiography in patient 6.1 at age 14, before metreleptin therapy, showed evidence of cardiomyopathy, and her father, patient 6.2, developed severe cardiomyopathy but was never treated with metreleptin, it is difficult to speculate whether metreleptin therapy has any untoward effects on cardiac function in patients with GLPS. Skin fibroblasts of patients with GLPS and HGPS show markedly abnormal nuclear morphology (3, 7). Although patients with HGPS may benefit from farnesyl transferase inhibitor therapy (31, 32) or by modulation of LMNA splicing (33) to reduce formation of farnesylated progerin, such approaches theoretically may not help patients with GLPS. Chemical inhibition of acyltransferase NAT10 by remodelin improves nuclear architecture and chromatin organization of human lamin A/C-depleted cells (34) and may have a potential therapeutic role for patients with GLPS. Other therapeutic approaches for GLPS patients may include helper-dependent adenoviral vector-mediated correction of p.T10I mutation (35) and antisense oligonucleotide-mediated “exon skipping.” (36). In conclusion, patients with GLPS have distinctive clinical features and significantly worse metabolic complications compared with other APS and HGPS patients. Patients with GLPS should undergo annual evaluation for metabolic complications and cardiomyopathy, which appear to be the major causes of morbidity. Although metreleptin therapy may be effective in ameliorating severe metabolic abnormalities in these patients, its effects on female reproductive function and cardiac function warrant further investigation. Abbreviations: APS atypical progeroid syndrome GLPS generalized lipodystrophy-associated progeroid syndrome HDL high-density lipoprotein HGPS Hutchinson–Gilford progeria syndrome LMNA lamin A/C. Acknowledgments We thank Pei-Yun Tseng and Jeongwoo Lee for illustrations and Claudia Quittner for help with evaluation of patients at the UT Southwestern Medical Center. Financial Support: This work was supported by National Institutes of Health Grants R01 DK105448 and R01 DK088114, Clinical and Transitional Science Award Grants UL1RR024982, UL1TR001105, and UL1TR000433, Centers Grant P30 DK089503, and National Institutes of Health Institutional Grant DK034933; by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases; by Grant 14-35-00 026 of the Russian Science Foundation; and by funding from the UT Southwestern Medical Foundation. Author Contributions: I.H., N.P., and A.G. designed the study, reviewed the data, provided figures and data collection, interpreted the data, and wrote the manuscript. M.U., E.S., C.M.V., E.C., R.J.B., J.P., Y.T., A.T., S.R.S.S., E.K., M.K.T., J.W.I., A.M., P.L., A.F.G.-M., M.G.T., D.J.R., R.A.H., and E.A.O. provided data and interpretation and wrote the manuscript. B.A.-H. provided data analysis and statistics. Disclosure Summary: A.G. and E.A.O. are co-holders of a patent for use of metreleptin in patients with lipodystrophy. A.G. does not receive any monetary benefits, and E.A.O. has not received any monetary benefits so far from the patent. A.G. is a consultant to and receives research support from Aegerion Pharmaceuticals. E.A.O. received grant support from Aegerion Pharmaceuticals, manufacturer of Metreleptin, and worked as a consultant for this company as well as previous owners of Metreleptin. The remaining authors have nothing to disclose. References 1. Jacob KN, Garg A. Laminopathies: multisystem dystrophy syndromes. Mol Genet Metab . 2006; 87( 4): 289– 302. Google Scholar CrossRef Search ADS PubMed  2. 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Mar 1, 2018

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