Clinical Manifestations and Metabolic Outcomes of Seven Adults With Silver-Russell Syndrome

Clinical Manifestations and Metabolic Outcomes of Seven Adults With Silver-Russell Syndrome Abstract Context There is little information on the long-term natural history of Silver-Russell syndrome (SRS). Objective To describe the phenotypes and metabolic status in adults with SRS. Design Clinical and metabolic evaluations in adults with a molecular diagnosis of SRS. Participants Seven patients (aged 18 to 46 years; mean age, 26.9 years) were studied. Two had chromosome 7 maternal uniparental disomy, three had 11p15 loss of methylation, and two had 11p15 duplication. Setting Single tertiary university center. Main Outcome Measures Netchine-Harbison (NH) clinical score, oral glucose tolerance test, lipid profiles, bone mineral density (BMD; lumbar spine at L1 to L4 and total body), lean body mass (LBM), absolute fat mass (kg), fat mass percentage, fat mass index (FMI), and trunk/limb fat ratio were evaluated. Results The NH score declined in all but two patients during adulthood, and all patients but one displayed relative macrocephaly. Two patients were underweight, four patients had a normal body mass index, and one was obese. Two patients had glucose intolerance and hyperinsulinemia; two showed a high total cholesterol level with low high-density lipoprotein (HDL) cholesterol levels. BMD was within the normal range, whereas a high fat mass percentage, FMI, and trunk/limb fat ratio and a low LBM were found. The trunk/limb fat ratio showed an inverse relation with HDL cholesterol levels. Conclusions The diagnosis of SRS seems to be reliable in adults, although some clinical signs become less pronounced with age. Glucose, lipids, and body composition should be monitored over time. Silver-Russell syndrome (SRS) is a heterogeneous syndrome characterized by severe intrauterine and postnatal growth retardation and typical dysmorphic features; it has an incidence between 1 in 70,000 and 1 in 100,000 live births (1). The most common genetic abnormalities are 11p15 ICR1 loss of methylation (11p15, LOM) and maternal uniparental disomy of chromosome 7 (mUPD7), which occur in 30% to 60% and 5% to 10% of cases, respectively (2); single cases carry other chromosome abnormalities, including duplications of maternal 11p15 material (3, 4). In a substantial proportion of patients (40%), the molecular cause remains unknown, and SRS remains primarily a clinical diagnosis based on the Netchine-Harbison (NH) scoring system (2, 5). Indeed, a targeted next-generation sequencing approach in patients referred for SRS testing increases the mutation rate as well as other diagnoses overlapping SRS (6–9). The management of children with SRS requires a multidisciplinary approach. Specific issues include body asymmetry, failure to thrive and growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycemia, motor and speech delay, and psychosocial challenges (2). Indeed, there is little information on the long-term natural history of SRS, changes in clinical phenotype, and metabolic consequences in adulthood (10–13). On the other hand, it is well recognized that being small for gestational age (SGA) at birth increases the risk for metabolic concerns in adulthood (12, 14). Hypertension, dilated cardiomyopathy, and type 2 diabetes mellitus have been reported in a few cases (10–13). Here, we report the phenotypes and the metabolic assessment of seven adult Italian patients with a clinical diagnosis of SRS, confirmed by molecular genetic analysis. Methods The study group comprised seven patients with a mean age [± standard deviation (SD)] of 26.9 ± 9.1 years (range, 18 to 46 years) who were voluntarily recruited by the Italian Association of Silver Russell Syndrome (AISRS Onlus). Birth data were obtained from available hospital records. Clinical score was evaluated according to the NH scoring system (2). According to the latter, macrocephaly was defined as an occipital-frontal circumference ≥ 1.5 SD above weight and/or height (2, 5). Each patient was examined by the same two pediatric endocrinologists (G.P. and N.D.) with experience in the field of SRS. Height was measured to the nearest 0.1 cm (Harpenden stadiometer), weight to the nearest 0.1 kg (TANITA Corporation, Tokyo, Japan). Waist circumference was evaluated midway between the lower margin of the lowest rib and the upper margin of the iliac crest at the end of a normal expiration. A standard 2-hour oral glucose tolerance test was administered by using a 1.75-g/kg glucose load. Bone mineral density (BMD; lumbar spine at L1 to L4, total body, femoral neck), lean body mass (LBM, in kg), and fat body mass expressed as percentage, fat mass index (FMI, in kg/m2) and trunk fat/limb fat ratio were measured by dual-energy x-ray absorptiometry (DXA; Lunar Prodigy, version 13, GE Healthcare, Madison, WI). Quality control was performed daily. Data for body composition were compared with published normative data (15, 16). To compare our patients with short healthy controls, we examined the body composition data for the shortest healthy young adults (six males and five females; mean age, 17 years) available in our DXA institutional database (mean height, 151.6 ± 3.3 cm in females and 159.8 ± 2.4 cm in males). After 15 minutes of rest, diastolic and systolic blood pressure were measured in the sitting position, using the nondominant arm, with an automatic device (Carescape, Dinamap technology Vital Signs 100, GE Healthcare). Fasting levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured by using a homogeneous enzymatic colorimetric assay (Roche, Milan, Italy). Bone-specific alkaline phosphatase cross-linked carboxy-terminal telopeptide of type 1 collagen were analyzed by using two enzyme-linked immunosorbent assay (ELISA) kits (METRA BAP ELISA kit; Quidel Corp., San Diego, CA) and (Serum Crosslaps; Immunodiagnostics System, Frankfurt, Germany) both automatized on a DSX automated ELISA processing system (Dynex Technologies; Technogenetics, Milan, Italy). Vitamin 25(OH)D (ng/mL) and parathyroid hormone (pg/mL) were determined by using chemiluminescence (Roche); adiponectin (ng/dL) was measured by using an ELISA kit (total human adiponectin ELISA; Teco Medical Group, Sissach, Switzerland) on a DSX automated ELISA processing system (Dynex Technologies; Technogenetics). Hormonal parameters were evaluated by chemiluminescent assay (Roche). Criteria for metabolic syndrome were defined according to the National Cholesterol Education Program (17) in presence of at least three of the following risk factors: waist circumference ≥ 88 cm in women and ≥ 102 cm in men; triglycerides ≥ 150 mg/dL; HDL cholesterol < 50 mg/dL in women and < 40 mg/dL in men; fasting glucose ≥ 100 mg/dL; systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg. Written informed consent was obtained from all participants, and permission was authorized for the publication of their photographs. Patients Patient 1 This female patient was born to healthy parents and was normally delivered at 39 weeks of gestation. Birth weight was 2500 g (−1.76 SD) (18), length was 46 cm (−1.77 SD), and occipito-frontal circumference was 35 cm (+0.96 SD). Because of growth impairment, feeding difficulty, and poor weight gain with distinctive craniofacial features (Fig. 1), SRS was hypothesized at the age of 3 months. Molecular analysis revealed mUPD7. Her development was normal, and she met all developmental milestones at the appropriate times. During childhood, she had a dental brace tailored because of crowded teeth, and she experienced tics during school age. Because her height was always above −2.5 SD (19) (−2.1 SD from 2 to 6 years and −1.9 from 7 to 9 years according to available measurements obtained from clinical records), no growth hormone (GH) therapy was started. She experienced menarche at 13 years of age, with a subsequently regular menstrual cycle. Figure 1. View largeDownload slide Patient 1 at ages (a) 1 y, (b) 2 y, and (c) 16 y. Note that the clinical manifestations are less obvious with age. Figure 1. View largeDownload slide Patient 1 at ages (a) 1 y, (b) 2 y, and (c) 16 y. Note that the clinical manifestations are less obvious with age. At age 21 years, she is a medical student, has a good social life, and practices ballet three times a week. Last examination revealed a weight of 38.4 kg, height of 153.7 cm (−1.4 SD), body mass index (BMI) of 16.3 kg/m2 (−2.8 SD), and an occipital-frontal circumference of 53.5 cm (−0.5 SD), with a relative macrocephaly (Table 1). A slightly triangular face and a prominent forehead were evident; she has micrognathia and comparatively large teeth. She also has clinodactyly of her fifth finger and wears glasses owing to myopia. Table 1. Clinical Characteristics and Body Composition of Seven Adults With SRS Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Age, y 21 26 25 46 29 18 23 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Sex Female Male Female Female Female Male Female Gestational age, wk 39 38 39 41 40 31 32 Birth weight SD −1.8 −3 −3.2 −2.7 −3.5 −3 −2.2 Birth length SD −1.77 −3.15 −4.2 Unknown −4.6 Unknown Unknown Height, cm 153.7 150.9 137.5 149.5 136.7 141.2 145.3 Height SD −1.4 −3.6 −4,1 −2.1 −4.3 −5 −2.8 SH SD −1.8 −3.2 −4.2 −2.6 −4.2 −4.6 −2.9 SH/H 0.53 0.54 0.54 0.53 0.55 0.55 0.54 Occipito-frontal circumference SD −0.5 2.3 −1,2 −0.5 0.5 1.4 −1.9 BMI SD −2.8 −2 2.5 0.3 −1.7 0 −0.6 Fat mass, kg 9.5 12.8 33.1 22.3 10.7 15.1 17.5 Fat mass, %a 26 31 55.1 45.7 31 36.6 41.5 FM, kg/m2b 4 5.6 17.4 10 5.7 7.6 8.5 Trunk fat, g 3588 7515 15,466 8929 4401 7841 8231 Limb fat, g 14,356 4340 16,900 12,700 5642 6446 8593 Trunk/limb fat ratioc 0.24 1.73 0.91 0.7 0.78 1.2 0.95 Lean mass, kgd 27 28.5 26.3 26.6 21.7 26.2 24.6 BMD  L1–L4 Z-score 1.2 0.7 0.7 −0.9 1.1 −2 0.1  L1–L4, g/cm2 1.234 1.191 1.261 0.980 1.185 0.943 1.131  TB Z-score 1 −0.1 1 −0.5 1.5 −1.8 0.1  TB, g/cm2 1.060 1.036 1.261 0.872 1.093 0.981 1.053  Left hip Z-score 1.1 0.6 1.6 −0.5 −0.4 0.7  Left hip, g/cm2 1.060 1.074 1.179 0.872 0.865 1.020 Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Age, y 21 26 25 46 29 18 23 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Sex Female Male Female Female Female Male Female Gestational age, wk 39 38 39 41 40 31 32 Birth weight SD −1.8 −3 −3.2 −2.7 −3.5 −3 −2.2 Birth length SD −1.77 −3.15 −4.2 Unknown −4.6 Unknown Unknown Height, cm 153.7 150.9 137.5 149.5 136.7 141.2 145.3 Height SD −1.4 −3.6 −4,1 −2.1 −4.3 −5 −2.8 SH SD −1.8 −3.2 −4.2 −2.6 −4.2 −4.6 −2.9 SH/H 0.53 0.54 0.54 0.53 0.55 0.55 0.54 Occipito-frontal circumference SD −0.5 2.3 −1,2 −0.5 0.5 1.4 −1.9 BMI SD −2.8 −2 2.5 0.3 −1.7 0 −0.6 Fat mass, kg 9.5 12.8 33.1 22.3 10.7 15.1 17.5 Fat mass, %a 26 31 55.1 45.7 31 36.6 41.5 FM, kg/m2b 4 5.6 17.4 10 5.7 7.6 8.5 Trunk fat, g 3588 7515 15,466 8929 4401 7841 8231 Limb fat, g 14,356 4340 16,900 12,700 5642 6446 8593 Trunk/limb fat ratioc 0.24 1.73 0.91 0.7 0.78 1.2 0.95 Lean mass, kgd 27 28.5 26.3 26.6 21.7 26.2 24.6 BMD  L1–L4 Z-score 1.2 0.7 0.7 −0.9 1.1 −2 0.1  L1–L4, g/cm2 1.234 1.191 1.261 0.980 1.185 0.943 1.131  TB Z-score 1 −0.1 1 −0.5 1.5 −1.8 0.1  TB, g/cm2 1.060 1.036 1.261 0.872 1.093 0.981 1.053  Left hip Z-score 1.1 0.6 1.6 −0.5 −0.4 0.7  Left hip, g/cm2 1.060 1.074 1.179 0.872 0.865 1.020 Abbreviations: FM, fat mass; H, height; SH, sitting height; TB, total body. a Mean value of fat mass percentage calculated according to Imboden et al. (15): women: age 20–29 y, 31.4% ± 8.5%; age 40–49 y, 39.2 ± 9.7; men: age 20–29 y, 21.1± 8.3. b Mean FMI value according to Imboden et al. (16): women: age 20–29 y, 7.6 ± 3.6 kg/m2; age 40–49 y, 11 ± 5.1 kg/m2; men: age 20–29 y, 5.6 ± 3 kg/m2. c Mean value of trunk/limb ratio calculated according to Imboden et al. (15): women: age 20–29 y, 0.96 ± 0.25; age 40–49 y, 1.12 ± 0.39; men: age 20–29 y, 1.24 ± 0.29. d Mean lean mass calculated according to Imboden et al. (16): women: age 20–29 y, 43 ± 6.1 kg; age 40–49 y, 42.9 ± 7 kg; men: age 20–29 y, 65 ± 11 kg. View Large Table 1. Clinical Characteristics and Body Composition of Seven Adults With SRS Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Age, y 21 26 25 46 29 18 23 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Sex Female Male Female Female Female Male Female Gestational age, wk 39 38 39 41 40 31 32 Birth weight SD −1.8 −3 −3.2 −2.7 −3.5 −3 −2.2 Birth length SD −1.77 −3.15 −4.2 Unknown −4.6 Unknown Unknown Height, cm 153.7 150.9 137.5 149.5 136.7 141.2 145.3 Height SD −1.4 −3.6 −4,1 −2.1 −4.3 −5 −2.8 SH SD −1.8 −3.2 −4.2 −2.6 −4.2 −4.6 −2.9 SH/H 0.53 0.54 0.54 0.53 0.55 0.55 0.54 Occipito-frontal circumference SD −0.5 2.3 −1,2 −0.5 0.5 1.4 −1.9 BMI SD −2.8 −2 2.5 0.3 −1.7 0 −0.6 Fat mass, kg 9.5 12.8 33.1 22.3 10.7 15.1 17.5 Fat mass, %a 26 31 55.1 45.7 31 36.6 41.5 FM, kg/m2b 4 5.6 17.4 10 5.7 7.6 8.5 Trunk fat, g 3588 7515 15,466 8929 4401 7841 8231 Limb fat, g 14,356 4340 16,900 12,700 5642 6446 8593 Trunk/limb fat ratioc 0.24 1.73 0.91 0.7 0.78 1.2 0.95 Lean mass, kgd 27 28.5 26.3 26.6 21.7 26.2 24.6 BMD  L1–L4 Z-score 1.2 0.7 0.7 −0.9 1.1 −2 0.1  L1–L4, g/cm2 1.234 1.191 1.261 0.980 1.185 0.943 1.131  TB Z-score 1 −0.1 1 −0.5 1.5 −1.8 0.1  TB, g/cm2 1.060 1.036 1.261 0.872 1.093 0.981 1.053  Left hip Z-score 1.1 0.6 1.6 −0.5 −0.4 0.7  Left hip, g/cm2 1.060 1.074 1.179 0.872 0.865 1.020 Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Age, y 21 26 25 46 29 18 23 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Sex Female Male Female Female Female Male Female Gestational age, wk 39 38 39 41 40 31 32 Birth weight SD −1.8 −3 −3.2 −2.7 −3.5 −3 −2.2 Birth length SD −1.77 −3.15 −4.2 Unknown −4.6 Unknown Unknown Height, cm 153.7 150.9 137.5 149.5 136.7 141.2 145.3 Height SD −1.4 −3.6 −4,1 −2.1 −4.3 −5 −2.8 SH SD −1.8 −3.2 −4.2 −2.6 −4.2 −4.6 −2.9 SH/H 0.53 0.54 0.54 0.53 0.55 0.55 0.54 Occipito-frontal circumference SD −0.5 2.3 −1,2 −0.5 0.5 1.4 −1.9 BMI SD −2.8 −2 2.5 0.3 −1.7 0 −0.6 Fat mass, kg 9.5 12.8 33.1 22.3 10.7 15.1 17.5 Fat mass, %a 26 31 55.1 45.7 31 36.6 41.5 FM, kg/m2b 4 5.6 17.4 10 5.7 7.6 8.5 Trunk fat, g 3588 7515 15,466 8929 4401 7841 8231 Limb fat, g 14,356 4340 16,900 12,700 5642 6446 8593 Trunk/limb fat ratioc 0.24 1.73 0.91 0.7 0.78 1.2 0.95 Lean mass, kgd 27 28.5 26.3 26.6 21.7 26.2 24.6 BMD  L1–L4 Z-score 1.2 0.7 0.7 −0.9 1.1 −2 0.1  L1–L4, g/cm2 1.234 1.191 1.261 0.980 1.185 0.943 1.131  TB Z-score 1 −0.1 1 −0.5 1.5 −1.8 0.1  TB, g/cm2 1.060 1.036 1.261 0.872 1.093 0.981 1.053  Left hip Z-score 1.1 0.6 1.6 −0.5 −0.4 0.7  Left hip, g/cm2 1.060 1.074 1.179 0.872 0.865 1.020 Abbreviations: FM, fat mass; H, height; SH, sitting height; TB, total body. a Mean value of fat mass percentage calculated according to Imboden et al. (15): women: age 20–29 y, 31.4% ± 8.5%; age 40–49 y, 39.2 ± 9.7; men: age 20–29 y, 21.1± 8.3. b Mean FMI value according to Imboden et al. (16): women: age 20–29 y, 7.6 ± 3.6 kg/m2; age 40–49 y, 11 ± 5.1 kg/m2; men: age 20–29 y, 5.6 ± 3 kg/m2. c Mean value of trunk/limb ratio calculated according to Imboden et al. (15): women: age 20–29 y, 0.96 ± 0.25; age 40–49 y, 1.12 ± 0.39; men: age 20–29 y, 1.24 ± 0.29. d Mean lean mass calculated according to Imboden et al. (16): women: age 20–29 y, 43 ± 6.1 kg; age 40–49 y, 42.9 ± 7 kg; men: age 20–29 y, 65 ± 11 kg. View Large Patient 2 This male patient was a second child, born after 38 weeks of gestation via vaginal delivery. His birth weight was 2000 g (−3.0 SD), birth length was 43 cm (−3.15 SD), and occipital-frontal circumference was 33 cm (−1.2 SD). He displayed failure to thrive and feeding difficulties since the first months of life, leading to nutritional support via a nasogastric tube until age 8 years. At age 2 years, he had an episode of symptomatic fasting hypoglycemia. He had a mild motor delay and was not able to walk alone until 2.5 years of age. His cognitive development was good, and he never had any difficulties at school. He obtained a diploma as a qualified accountant. He has a busy social life, enjoys relatively good health, and works as a municipal employee. At the last evaluation, at 27 years of age, his height was 150.9 cm (−3.6 SD)—with a sitting height of 82.8 cm (−3.2 SD) and a sitting height/height ratio of 0.54 (+2 SD) (20)—and his weight was 43.3 kg, with a BMI of 18.9 kg/m2 (−2 SD). The clinical examination documented relative macrocephaly, with a head occipital-frontal circumference of 57.3 cm (+2.3 SD). He had normal pubertal development with a bilateral testicular volume of 15 mL. He also had clinodactyly of the fifth finger, and no body asymmetry was observed. He has experienced excessive sweating since the first months of life. Molecular tests revealed mUPD7. Patient 3 This female patient was born at 39 weeks of gestation. Her birth weight was 1850 g (−3.2 SD), birth length was 40 cm (−4.2 SD), and occipital-frontal circumference was 34 cm (+0.12 SD), with relative macrocephaly. In her first years of life, she displayed feeding difficulties and failure to thrive. From age 6 years onward, however, she has been overweight. She had menarche at age 11 years, followed by regular menses. She also displayed chronic otitis media in childhood and cholesteatoma in the left ear at age 14 years. At last evaluation at age 25 years, her height was 137.5 cm (−4.1 SD), sitting height was 74.7 cm (−4.2 SD)—with a sitting height/height ratio of 0.54 (+1 SD)—and weight was 61 kg, with a BMI of 32.3 kg/m2 (+2.5 SD). She also had relative macrocephaly, with an occipital-frontal circumference of 52.5 cm (−1.2 SD), fifth-finger clinodactyly, and body asymmetry (leg length discrepancy of 1.5 cm; arm and facial asymmetry). Her facial appearance is shown in Fig. 2. Her neuropsychological development was normal, and she recently graduated as a social worker. Molecular tests were performed at age 24 years and showed 11p15 LOM. Figure 2. View largeDownload slide Patient 3 at ages (a) 1 y, (b) 2 y, and (c) 24 y. Figure 2. View largeDownload slide Patient 3 at ages (a) 1 y, (b) 2 y, and (c) 24 y. Patient 4 After an uncomplicated pregnancy, this female patient was born in 1970 after 41 weeks of gestation by natural delivery and had a birth weight of 2300 g (−2.7 SD). Data on length and occipito-frontal circumference, as well as on clinical outcome at birth, are lacking. However, her parents reported that she was born SGA in terms of both weight and length and had relative macrocephaly. In the first months of life, she had feeding difficulties and failure to thrive. Her cognitive development was normal. As a child, she enjoyed relatively good health. Since leaving school, she has worked as a post office employee. At age 40 years, she had a son, who is currently 6 years old and in good health. Her pregnancy was characterized by cervical incompetence. She experienced menopause at age 44 years. The patient has experienced significant dental overcrowding and misalignment, requiring orthodontic treatment and multiple tooth extractions. Methylation study revealed 11p15 LOM. At the time of examination, the patient was 46 years old and 149.5 cm tall (−2.1 SD). Her BMI was 23 kg/m2 (+0.3 SD), and her occipito-frontal circumference was 53.5 cm (−0.5 SD) (Table 1). She had leg length and arm asymmetry. She reports eating normal-sized adult portions and having difficulty maintaining her weight. Patient 5 This female patient was born to healthy nonconsanguineous parents at 40 weeks of gestational age. Her birth weight was 1850 g (−3.5 SD), her birth length was 40 cm (−4.6 SD), and relative macrocephaly was documented at birth. Poor fetal growth was first noted in the 30th week of gestation. She had severe feeding difficulties during the first years of life. However, a nasogastric tube for feeding was not inserted. Because of her short stature, GH therapy was started when she was age 7 years and was continued until she was age 9 years. She experienced precocious puberty with menarche at age 9 years, and gonadotropin-releasing hormone analog treatment was performed from age 9 to 10 years. She had significant dental overcrowding and misalignment, which led to orthodontic treatment and multiple teeth extractions. Micrognathia was also pronounced. She graduated with a degree in sports science and is now working in a call center as an operator. She had a miscarriage at 10 weeks of pregnancy at age 29 years. Molecular analysis performed at age 24 years showed 11p15 LOM. At the last evaluation, at age 29 years, her height was 136.7 cm (−4.3 SD), her BMI was 18.2 kg/m2 (−1.7 SD), she had persistent relative macrocephaly, and her head circumference was +0.5 SD (Table 1). She had leg length, foot, and facial asymmetry. Patient 6 This male patient was prematurely born at the 31st gestational week via cesarean delivery due to intrauterine growth restriction (IUGR), oligohydramnios, and fetal distress. At birth, he was SGA and displayed relative macrocephaly and the typical clinical manifestations of SRS, including a prominent forehead, a triangular face, low-set ears, and fifth-digit clinodactyly. No body asymmetry was observed. Developmental milestones were delayed (he walked at 2.5 years of age and pronounced his first words at 3 years of age). Molecular analysis showed a maternally inherited duplication of chromosome 11p15. GH therapy was started at age 7 years and was withdrawn at age 11 years because of glucose intolerance. He currently displays selective mutism and mild cognitive delay, and he is assisted by a teaching-support specialist. On last physical examination at age 18 years, his height was 141.2 cm (−5 SD), weight was 42.5 kg, BMI was 21.3 kg/m2 (0 SD), and occipito-frontal circumference was 56.5 cm (+1.4 SD) (Table 1). He wears glasses because of astigmatism. Patient 7 This female patient was born prematurely (at 32 weeks of gestational age) by cesarean delivery. Her birth weight was 950 g (−2.2 SD). Although her birth length and occipito-frontal circumference were not available, a measurement compatible with macrocephaly was reported at ages 1 to 3 years. She had menarche at age 11 years, followed by regular menses. She has an ectopic kidney, incidentally detected by abdominal ultrasonography. She has had two pregnancies characterized by cervical incompetence: In the 28th week of her first pregnancy, she delivered a still-born baby; in her second pregnancy she delivered in the 24th week, and the baby died after a few hours. Molecular tests performed in adulthood revealed a duplication of chromosome 11. Current examination, at age 23 years, revealed a weight of 43.5 kg, height of 145.3 cm (−2.8 SD), BMI of 20.6 kg/m2 (–0.6 SD), and an occipito-frontal circumference of 51.5 cm (−1.9 SD) (Table 1). Results NH clinical score The clinical diagnosis was confirmed by molecular genetic analysis: three patients had 11p15 LOM, two had mUPD7, and two had 11p15 duplication. Clinical characteristics and body composition of the patients are listed in Table 1. All patients but one were born SGA (mean birth weight, −2.76 SD ± 0.6; mean birth length, −3.43 SD ± 1.2). Body asymmetry was found in patients with 11p15 LOM (patients 3, 4, and 5) (Table 2). Table 2. Childhood and Adulthood NH Scores and Molecular Findings in Seven Patients With SRS Variablea Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 NH score in childhood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X X X X X X  Total (n) 4 5 6 6 6 5 5 NH score in adulthood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X  Total (n) 4 5 5 5 5 4 4 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Variablea Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 NH score in childhood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X X X X X X  Total (n) 4 5 6 6 6 5 5 NH score in adulthood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X  Total (n) 4 5 5 5 5 4 4 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication a (1) SGA: birth weight and/or birth length ≤ −2 SD, (2) postnatal growth failure, (3) relative macrocephaly at birth (head circumference ≥ 1.5 SD for birth weight and length), (4) protruding forehead, (5) body asymmetry, (6) feeding difficulties and/or low BMI (≤−2 SD). View Large Table 2. Childhood and Adulthood NH Scores and Molecular Findings in Seven Patients With SRS Variablea Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 NH score in childhood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X X X X X X  Total (n) 4 5 6 6 6 5 5 NH score in adulthood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X  Total (n) 4 5 5 5 5 4 4 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Variablea Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 NH score in childhood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X X X X X X  Total (n) 4 5 6 6 6 5 5 NH score in adulthood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X  Total (n) 4 5 5 5 5 4 4 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication a (1) SGA: birth weight and/or birth length ≤ −2 SD, (2) postnatal growth failure, (3) relative macrocephaly at birth (head circumference ≥ 1.5 SD for birth weight and length), (4) protruding forehead, (5) body asymmetry, (6) feeding difficulties and/or low BMI (≤−2 SD). View Large At the time of diagnosis, all patients showed typical facial features of SRS: frontal bosses, relative macrocephaly, triangular facies, and micrognathia. Mean adult height was −3.3 SD ± 1.2, and only two patients (patients 5 and 6) received short-term GH therapy. One patient (patient 5) developed precocious puberty. Two women (patients 4 and 7) who had a pregnancy had cervical incompetence requiring cerclage. The NH clinical score declined in all but two of the seven patients during adulthood (Table 2). Two patients (patients 1 and 2), both mUPD7, were still underweight, four patients had a normal BMI, and one was obese; patient 6 had a cognitive delay. All patients but one displayed relative macrocephaly in adulthood. Metabolic and body composition findings Oral glucose tolerance testing showed glucose intolerance and hyperinsulinemia in two patients (Table 3). Two patients (patients 2 and 4) showed high total cholesterol levels with low HDL cholesterol levels. The obese patient (patient 3) had high waist/hip and waist/height ratios (21, 22). All patients showed normal triglyceride levels and blood pressure (23) (Table 4). None of our patients satisfied the criteria for metabolic syndrome. Bone turnover markers and calciotropic hormonal parameters (vitamin D, parathyroid hormone) are listed in Supplemental Table 1. Type 1 collagen values were higher in males compared with the reference values. BMD was within the normal range (mean Z-score for L1 to L4, 0.1 ± 1.2; mean Z-score for total body, 0.44 ± 0.9). A high body fat mass percentage (mean, 38.2% ± 10.2%; range, 26% to 55.7%), FMI (mean, 8.37 ± 4.47 kg/m2; range, 4.0 to 17.48 kg/m2), and trunk/limb fat ratio (mean, 0.93 ± 0.45; range, 0.24 to 1.73) and a low LBM (mean, 25.84 ± 2.16 kg; range, 21.7 to 28.5 kg) were found in comparison with published references in healthy adults (15, 16) (Table 1). The trunk/limb fat ratio did not correlate with different measures of adiposity (BMI SD, FMI, fat body mass percentage); however, it showed an inverse relation with HDL cholesterol levels (r = −0.78; P = 0.036) and a trend toward a direct relation with glucose 120’ (r = 0.67; P = 0.11). Table 3. Glucose Metabolism in Seven Adults With SRS Variable Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Glucose, mmol/L  T 0 min 4.5 4.4 5.4 4.8 4.8 5.3 5.4  T 30 7.0 7.5 7.4 6.5 6.9 11.2 8.1  T 60 min 7.5 7.1 9.4 4.8 4.7 11.5 6  T 90 min 6.4 7.4 9.6 4.5 6.7 9.3 6.1  T 120 min 5.6 8.4 7.7 3.8 4.8 9.4 7.5 Insulin, μU/mL  T 0 min 9.2 5.9 13.4 4.3 6.0 20.5 12.2  T 30 min 52.8 75.6 11.6 139.2 76.2 304.7 100.5  T 60 min 55.0 91.8 22.2 85.4 42.0 314.7 56.8  T 90 min 50.8 86.6 68.9 22.3 87.1 211.3 32.7  T 120 min 63.7 125.8 52.2 16.0 52.3 296.3 74.4 Variable Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Glucose, mmol/L  T 0 min 4.5 4.4 5.4 4.8 4.8 5.3 5.4  T 30 7.0 7.5 7.4 6.5 6.9 11.2 8.1  T 60 min 7.5 7.1 9.4 4.8 4.7 11.5 6  T 90 min 6.4 7.4 9.6 4.5 6.7 9.3 6.1  T 120 min 5.6 8.4 7.7 3.8 4.8 9.4 7.5 Insulin, μU/mL  T 0 min 9.2 5.9 13.4 4.3 6.0 20.5 12.2  T 30 min 52.8 75.6 11.6 139.2 76.2 304.7 100.5  T 60 min 55.0 91.8 22.2 85.4 42.0 314.7 56.8  T 90 min 50.8 86.6 68.9 22.3 87.1 211.3 32.7  T 120 min 63.7 125.8 52.2 16.0 52.3 296.3 74.4 Abbreviation: T, time. View Large Table 3. Glucose Metabolism in Seven Adults With SRS Variable Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Glucose, mmol/L  T 0 min 4.5 4.4 5.4 4.8 4.8 5.3 5.4  T 30 7.0 7.5 7.4 6.5 6.9 11.2 8.1  T 60 min 7.5 7.1 9.4 4.8 4.7 11.5 6  T 90 min 6.4 7.4 9.6 4.5 6.7 9.3 6.1  T 120 min 5.6 8.4 7.7 3.8 4.8 9.4 7.5 Insulin, μU/mL  T 0 min 9.2 5.9 13.4 4.3 6.0 20.5 12.2  T 30 min 52.8 75.6 11.6 139.2 76.2 304.7 100.5  T 60 min 55.0 91.8 22.2 85.4 42.0 314.7 56.8  T 90 min 50.8 86.6 68.9 22.3 87.1 211.3 32.7  T 120 min 63.7 125.8 52.2 16.0 52.3 296.3 74.4 Variable Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Glucose, mmol/L  T 0 min 4.5 4.4 5.4 4.8 4.8 5.3 5.4  T 30 7.0 7.5 7.4 6.5 6.9 11.2 8.1  T 60 min 7.5 7.1 9.4 4.8 4.7 11.5 6  T 90 min 6.4 7.4 9.6 4.5 6.7 9.3 6.1  T 120 min 5.6 8.4 7.7 3.8 4.8 9.4 7.5 Insulin, μU/mL  T 0 min 9.2 5.9 13.4 4.3 6.0 20.5 12.2  T 30 min 52.8 75.6 11.6 139.2 76.2 304.7 100.5  T 60 min 55.0 91.8 22.2 85.4 42.0 314.7 56.8  T 90 min 50.8 86.6 68.9 22.3 87.1 211.3 32.7  T 120 min 63.7 125.8 52.2 16.0 52.3 296.3 74.4 Abbreviation: T, time. View Large Table 4. Blood Pressure, Waist and Hip Circumferences, and Lipid Profiles in Seven Adults With SRS Variable Normal Ranges Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 TC, mmol/L <5.17 4.37 5.92 4.29 5.61 5.14 4.13 4.75 HDL cholesterol, mmol/L 1.68–2.58 2.27 1.03 2.14 1.52 1.71 1.24 1.19 LDL cholesterol, mmol/L Optimal value < 2.58
Intermediate risk > 3.88
High risk > 4.91 1.86 4.39 1.81 3.62 3.05 2.43 2.97 Triglycerides, mmol/L 0.78–4.13 1.16 1.76 1.55 1.11 1.47 1.58 1.63 Waist circumference, cm ≤88 in women
≤102 in men 59 73 83 73 62 72 65 Hip circumference, cm 89 81 110 101 78 82 88 Waist/hip circumference ratio <0.95 in men
<0.8 in women 0.66 0.9 0.75 0.72 0.79 0.87 0.73 Waist circumference/height ratio <0.58 0.38 0.48 0.6 0.48 0.45 0.5 0.44 SBP, mm Hg ≤135 101 109 125 113 115 101 DBP, mm Hg ≤85 65 63 83 78 66 57 Variable Normal Ranges Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 TC, mmol/L <5.17 4.37 5.92 4.29 5.61 5.14 4.13 4.75 HDL cholesterol, mmol/L 1.68–2.58 2.27 1.03 2.14 1.52 1.71 1.24 1.19 LDL cholesterol, mmol/L Optimal value < 2.58
Intermediate risk > 3.88
High risk > 4.91 1.86 4.39 1.81 3.62 3.05 2.43 2.97 Triglycerides, mmol/L 0.78–4.13 1.16 1.76 1.55 1.11 1.47 1.58 1.63 Waist circumference, cm ≤88 in women
≤102 in men 59 73 83 73 62 72 65 Hip circumference, cm 89 81 110 101 78 82 88 Waist/hip circumference ratio <0.95 in men
<0.8 in women 0.66 0.9 0.75 0.72 0.79 0.87 0.73 Waist circumference/height ratio <0.58 0.38 0.48 0.6 0.48 0.45 0.5 0.44 SBP, mm Hg ≤135 101 109 125 113 115 101 DBP, mm Hg ≤85 65 63 83 78 66 57 Abbreviations: DBP, diastolic blood pressure; LDL, low-density lipoprotein; SBP, systolic blood pressure; TC, total cholesterol. View Large Table 4. Blood Pressure, Waist and Hip Circumferences, and Lipid Profiles in Seven Adults With SRS Variable Normal Ranges Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 TC, mmol/L <5.17 4.37 5.92 4.29 5.61 5.14 4.13 4.75 HDL cholesterol, mmol/L 1.68–2.58 2.27 1.03 2.14 1.52 1.71 1.24 1.19 LDL cholesterol, mmol/L Optimal value < 2.58
Intermediate risk > 3.88
High risk > 4.91 1.86 4.39 1.81 3.62 3.05 2.43 2.97 Triglycerides, mmol/L 0.78–4.13 1.16 1.76 1.55 1.11 1.47 1.58 1.63 Waist circumference, cm ≤88 in women
≤102 in men 59 73 83 73 62 72 65 Hip circumference, cm 89 81 110 101 78 82 88 Waist/hip circumference ratio <0.95 in men
<0.8 in women 0.66 0.9 0.75 0.72 0.79 0.87 0.73 Waist circumference/height ratio <0.58 0.38 0.48 0.6 0.48 0.45 0.5 0.44 SBP, mm Hg ≤135 101 109 125 113 115 101 DBP, mm Hg ≤85 65 63 83 78 66 57 Variable Normal Ranges Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 TC, mmol/L <5.17 4.37 5.92 4.29 5.61 5.14 4.13 4.75 HDL cholesterol, mmol/L 1.68–2.58 2.27 1.03 2.14 1.52 1.71 1.24 1.19 LDL cholesterol, mmol/L Optimal value < 2.58
Intermediate risk > 3.88
High risk > 4.91 1.86 4.39 1.81 3.62 3.05 2.43 2.97 Triglycerides, mmol/L 0.78–4.13 1.16 1.76 1.55 1.11 1.47 1.58 1.63 Waist circumference, cm ≤88 in women
≤102 in men 59 73 83 73 62 72 65 Hip circumference, cm 89 81 110 101 78 82 88 Waist/hip circumference ratio <0.95 in men
<0.8 in women 0.66 0.9 0.75 0.72 0.79 0.87 0.73 Waist circumference/height ratio <0.58 0.38 0.48 0.6 0.48 0.45 0.5 0.44 SBP, mm Hg ≤135 101 109 125 113 115 101 DBP, mm Hg ≤85 65 63 83 78 66 57 Abbreviations: DBP, diastolic blood pressure; LDL, low-density lipoprotein; SBP, systolic blood pressure; TC, total cholesterol. View Large FMI was significantly higher in patients (P = 0.004) than in short healthy controls (9.1 ± 5.2 kg/m2 vs. 6.0 ± 0.6 kg/m2 in females, respectively; 6.6 ± 1.4 kg/m2 vs. 4.5 ± 1.4 kg/m2 in males, respectively). In addition, the patients with SRS showed mean trunk fat significantly higher than that in healthy controls: 8.1 ± 4.7 kg vs. 6.0 ± 0.5 kg in females, respectively, and 7.7 ± 0.2 kg vs. 5.5 ± 1.9 kg in males, respectively. The latter findings suggest that both female and male patients with SRS have almost 2 kg more trunk fat than do controls. This represents a further 35% of the truncal fat mass in female patients with SRS and 41% more in male patients with SRS compared with controls. Lean mass index (LMI) showed a trend toward lower values in patients with SRS (P = 0.07), with an LMI of 12.0 ± 1.0 kg/m2 in female patients with SRS compared with 12.2 ± 0.5 kg /m2 in controls and LMI of 12.7 ± 0.5 kg/m2 in male patients with SRS with 14.9 ± 1.5 kg/m2 in controls. Discussion Few long-term follow-up studies have been conducted in patients with SRS, and the clinical phenotype as well as the metabolic outcomes of this condition during adulthood remain to be defined (12, 24). Although several studies have shown that children who are SGA at birth are prone to later development of metabolic disorders, including insulin resistance and diabetes, hypercholesterolemia, and cardiovascular diseases (14, 25), little has been reported in patients with SRS, who are generally born SGA and as having IUGR. Here, we report the clinical features and the metabolic profiles of seven adult patients with a molecular diagnosis of SRS, re-evaluated at a mean age of 26.9 ± 9.1 years. The diagnosis of SRS at birth or during childhood could be straightforward based on validated clinical criteria (5), recently highlighted by the first international consensus statement (2). Nevertheless, SRS is a heterogeneous condition, and its differential diagnosis could be a challenge already in children presenting with IUGR, in which the underlying molecular abnormalities could not be confirmed (2, 6, 7, 9), or in those born appropriate for gestational age with mUPD7 (26, 27). Therefore, the diagnosis of missed SRS or SRS-like conditions may be even more difficult in adults. Because the criteria and scores for the diagnosis of SRS were validated for patients aged 1.05 to 20.06 years, with a mean age of 6.61 years (5), we asked whether the clinical characteristics of these patients could be maintained over time and specifically after age 20 years. It is worth pointing out, however, that the clinical features of relative macrocephaly, protruding forehead (although less pronounced), and body asymmetry were maintained after 20 years, suggesting that their identification in an adult born SGA or with IUGR with an adult height of less than −2 SD should prompt physicians to consider a missed diagnosis of SRS during childhood. In adults suspected of having SRS, it is also advisable to check for early-childhood photographs. Indeed, feeding difficulties and low BMI did not appear to be typical features of adults with SRS but were consistently present during the first year of life. However, the BMI of most of these patients remained between −2.8 to 0 SD, except for one patient with severe obesity, who showed high waist/hip and waist/height ratios, risk factors for cardiovascular disease (21, 22). It is known that patients born SGA are at risk for insulin resistance and cardiovascular disease, which seems to be related to the rate of weight gain occurring during the first years of life and to the adverse prenatal metabolic environment (25, 28). In addition to adult weight, weight catch-up growth during childhood is a strong determinant of body composition, and patients with SGA and catch-up growth have been reported to have significantly higher fat mass percentage % and lower LBM than controls (28). Our patients displayed a low LBM and a high fat mass percentage, FMI, trunk fat percentage, and trunk fat/limb ratio (the latter being a surrogate of central adiposity) compared with a small group of short controls, suggesting that patients with SRS have an abnormal body composition. Thus, total and visceral fat mass should be adequately defined in patients with SRS as compared with healthy controls (15, 16), where BMI and waist circumference are commonly included in the definition of the cardiovascular risk profile (17, 29), and raise the question about the role of DXA values in the assessment of the cardiovascular risks in adults with SRS. To our knowledge, there are only two case reports and one long-term study addressing metabolic health in SRS (10–12). In particular, a 69-year-old man originally reported by Russell in 1953, is the oldest patient with SRS ever reported (11, 30). The patient enjoyed a relatively good life, was married, and had a daughter. He had hypercholesterolemia, developed type 2 diabetes mellitus at age 56 years, and developed osteopenia and hypogonadotropic hypogonadism later in life (11). Takenouchi et al. (10) described three young adults with SRS (early 20s) with 11p15 LOM who developed type 2 diabetes, hyperlipidemia, and hypertension, respectively. In addition, the recent long-term study available on metabolic status of patients with SRS showed no metabolic differences between patients treated with GH and SGA patients without SRS before, during, and through 2 years after the discontinuation of GH; none of the patients with SRS developed diabetes or metabolic syndrome at the mean age of 18 years (12). Our findings of glucose intolerance and hyperinsulinemia in two patients at ages 18 and 27 years, respectively, suggests that these patients can develop early abnormalities in glucose metabolism. In addition, although glucose intolerance and hypercholesterolemia were found to be independent of BMI, FMI, total percentage body fat, and molecular findings, both HDL cholesterol level and glucose intolerance were related to the trunk/limb fat ratio. Regarding BMD, DXA examination of these adults with SRS, performed for the first time at three skeletal sites (spine, femur, and total body), showed normal bone mineralization. These findings deserve further follow-up because DXA technique may underestimate bone mass in short/small persons. Hence, limitations of our study include the small number of patients and their relatively young age. In conclusion, the recognition of SRS features after achievement of adult height is crucial for the identification of patients with classical phenotype in order to establish a real prevalence of this rare condition; it is essential for genetic counseling, and it enables these patients to benefit from the early management of their metabolic complications. Although the scoring system for the diagnosis of SRS has been validated for children and adolescents, the diagnosis of SRS seems to also be reliable in adults; however, some clinical signs may become less pronounced with age, suggesting the need for further validation. The increase in central adiposity detected by DXA deserves further studies, and long-term follow-up in a larger number of patients with SRS is mandatory to understand the natural history of this disease and improve the management of these patients. Abbreviations: Abbreviations: BMD bone mineral density BMI body mass index DXA dual-energy x-ray absorptiometry ELISA enzyme-linked immunosorbent assay FMI fat mass index GH growth hormone HDL high-density lipoprotein IUGR intrauterine growth restriction LBM lean body mass LMI lean mass index LOM loss of methylation NH Netchine-Harbison SD standard deviation SGA small for gestational age SRS Silver-Russell syndrome Acknowledgments We thank Luana Pennisi, Silvia Mariotti, and Margherita Scola from the Italian Association of Families with Silver-Russell Syndrome (AISRS Onlus) for their great support, and all patients and their families. We also thank our nurse staff for their daily commitments in the care of patients with SRS and other endocrine conditions. Financial Support: Ministero Dell’Istruzione, dell’Università e della Ricerca, PRIN 2015, number 2015JHLY35 Author Contributions: G.P. designed the study, examined the clinical phenotypes of the patients, takes care of patient follow-up, collected the data, and drafted and revised the manuscript; M.G. helped in evaluating the clinical phenotypes of the patients; V.C. performed genetic counseling; F.N. reviewed and revised the manuscript; G.C. performed laboratory tests and participated in drafting the manuscript; S.N. helped in data collection; S.G. and S.R. performed molecular analysis and genetic counseling; M.M. designed the study, examined the clinical phenotypes of the patients, and reviewed and revised the manuscript; N.D. performed body composition assessment and data analysis and reviewed and revised the manuscript. Disclosure Summary: The authors have nothing to disclose. References 1. Wakeling EL . Silver-Russell syndrome . Arch Dis Child . 2011 ; 96 ( 12 ): 1156 – 1161 . 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Clinical Manifestations and Metabolic Outcomes of Seven Adults With Silver-Russell Syndrome

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Oxford University Press
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Copyright © 2018 Endocrine Society
ISSN
0021-972X
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1945-7197
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10.1210/jc.2017-02589
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Abstract

Abstract Context There is little information on the long-term natural history of Silver-Russell syndrome (SRS). Objective To describe the phenotypes and metabolic status in adults with SRS. Design Clinical and metabolic evaluations in adults with a molecular diagnosis of SRS. Participants Seven patients (aged 18 to 46 years; mean age, 26.9 years) were studied. Two had chromosome 7 maternal uniparental disomy, three had 11p15 loss of methylation, and two had 11p15 duplication. Setting Single tertiary university center. Main Outcome Measures Netchine-Harbison (NH) clinical score, oral glucose tolerance test, lipid profiles, bone mineral density (BMD; lumbar spine at L1 to L4 and total body), lean body mass (LBM), absolute fat mass (kg), fat mass percentage, fat mass index (FMI), and trunk/limb fat ratio were evaluated. Results The NH score declined in all but two patients during adulthood, and all patients but one displayed relative macrocephaly. Two patients were underweight, four patients had a normal body mass index, and one was obese. Two patients had glucose intolerance and hyperinsulinemia; two showed a high total cholesterol level with low high-density lipoprotein (HDL) cholesterol levels. BMD was within the normal range, whereas a high fat mass percentage, FMI, and trunk/limb fat ratio and a low LBM were found. The trunk/limb fat ratio showed an inverse relation with HDL cholesterol levels. Conclusions The diagnosis of SRS seems to be reliable in adults, although some clinical signs become less pronounced with age. Glucose, lipids, and body composition should be monitored over time. Silver-Russell syndrome (SRS) is a heterogeneous syndrome characterized by severe intrauterine and postnatal growth retardation and typical dysmorphic features; it has an incidence between 1 in 70,000 and 1 in 100,000 live births (1). The most common genetic abnormalities are 11p15 ICR1 loss of methylation (11p15, LOM) and maternal uniparental disomy of chromosome 7 (mUPD7), which occur in 30% to 60% and 5% to 10% of cases, respectively (2); single cases carry other chromosome abnormalities, including duplications of maternal 11p15 material (3, 4). In a substantial proportion of patients (40%), the molecular cause remains unknown, and SRS remains primarily a clinical diagnosis based on the Netchine-Harbison (NH) scoring system (2, 5). Indeed, a targeted next-generation sequencing approach in patients referred for SRS testing increases the mutation rate as well as other diagnoses overlapping SRS (6–9). The management of children with SRS requires a multidisciplinary approach. Specific issues include body asymmetry, failure to thrive and growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycemia, motor and speech delay, and psychosocial challenges (2). Indeed, there is little information on the long-term natural history of SRS, changes in clinical phenotype, and metabolic consequences in adulthood (10–13). On the other hand, it is well recognized that being small for gestational age (SGA) at birth increases the risk for metabolic concerns in adulthood (12, 14). Hypertension, dilated cardiomyopathy, and type 2 diabetes mellitus have been reported in a few cases (10–13). Here, we report the phenotypes and the metabolic assessment of seven adult Italian patients with a clinical diagnosis of SRS, confirmed by molecular genetic analysis. Methods The study group comprised seven patients with a mean age [± standard deviation (SD)] of 26.9 ± 9.1 years (range, 18 to 46 years) who were voluntarily recruited by the Italian Association of Silver Russell Syndrome (AISRS Onlus). Birth data were obtained from available hospital records. Clinical score was evaluated according to the NH scoring system (2). According to the latter, macrocephaly was defined as an occipital-frontal circumference ≥ 1.5 SD above weight and/or height (2, 5). Each patient was examined by the same two pediatric endocrinologists (G.P. and N.D.) with experience in the field of SRS. Height was measured to the nearest 0.1 cm (Harpenden stadiometer), weight to the nearest 0.1 kg (TANITA Corporation, Tokyo, Japan). Waist circumference was evaluated midway between the lower margin of the lowest rib and the upper margin of the iliac crest at the end of a normal expiration. A standard 2-hour oral glucose tolerance test was administered by using a 1.75-g/kg glucose load. Bone mineral density (BMD; lumbar spine at L1 to L4, total body, femoral neck), lean body mass (LBM, in kg), and fat body mass expressed as percentage, fat mass index (FMI, in kg/m2) and trunk fat/limb fat ratio were measured by dual-energy x-ray absorptiometry (DXA; Lunar Prodigy, version 13, GE Healthcare, Madison, WI). Quality control was performed daily. Data for body composition were compared with published normative data (15, 16). To compare our patients with short healthy controls, we examined the body composition data for the shortest healthy young adults (six males and five females; mean age, 17 years) available in our DXA institutional database (mean height, 151.6 ± 3.3 cm in females and 159.8 ± 2.4 cm in males). After 15 minutes of rest, diastolic and systolic blood pressure were measured in the sitting position, using the nondominant arm, with an automatic device (Carescape, Dinamap technology Vital Signs 100, GE Healthcare). Fasting levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured by using a homogeneous enzymatic colorimetric assay (Roche, Milan, Italy). Bone-specific alkaline phosphatase cross-linked carboxy-terminal telopeptide of type 1 collagen were analyzed by using two enzyme-linked immunosorbent assay (ELISA) kits (METRA BAP ELISA kit; Quidel Corp., San Diego, CA) and (Serum Crosslaps; Immunodiagnostics System, Frankfurt, Germany) both automatized on a DSX automated ELISA processing system (Dynex Technologies; Technogenetics, Milan, Italy). Vitamin 25(OH)D (ng/mL) and parathyroid hormone (pg/mL) were determined by using chemiluminescence (Roche); adiponectin (ng/dL) was measured by using an ELISA kit (total human adiponectin ELISA; Teco Medical Group, Sissach, Switzerland) on a DSX automated ELISA processing system (Dynex Technologies; Technogenetics). Hormonal parameters were evaluated by chemiluminescent assay (Roche). Criteria for metabolic syndrome were defined according to the National Cholesterol Education Program (17) in presence of at least three of the following risk factors: waist circumference ≥ 88 cm in women and ≥ 102 cm in men; triglycerides ≥ 150 mg/dL; HDL cholesterol < 50 mg/dL in women and < 40 mg/dL in men; fasting glucose ≥ 100 mg/dL; systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg. Written informed consent was obtained from all participants, and permission was authorized for the publication of their photographs. Patients Patient 1 This female patient was born to healthy parents and was normally delivered at 39 weeks of gestation. Birth weight was 2500 g (−1.76 SD) (18), length was 46 cm (−1.77 SD), and occipito-frontal circumference was 35 cm (+0.96 SD). Because of growth impairment, feeding difficulty, and poor weight gain with distinctive craniofacial features (Fig. 1), SRS was hypothesized at the age of 3 months. Molecular analysis revealed mUPD7. Her development was normal, and she met all developmental milestones at the appropriate times. During childhood, she had a dental brace tailored because of crowded teeth, and she experienced tics during school age. Because her height was always above −2.5 SD (19) (−2.1 SD from 2 to 6 years and −1.9 from 7 to 9 years according to available measurements obtained from clinical records), no growth hormone (GH) therapy was started. She experienced menarche at 13 years of age, with a subsequently regular menstrual cycle. Figure 1. View largeDownload slide Patient 1 at ages (a) 1 y, (b) 2 y, and (c) 16 y. Note that the clinical manifestations are less obvious with age. Figure 1. View largeDownload slide Patient 1 at ages (a) 1 y, (b) 2 y, and (c) 16 y. Note that the clinical manifestations are less obvious with age. At age 21 years, she is a medical student, has a good social life, and practices ballet three times a week. Last examination revealed a weight of 38.4 kg, height of 153.7 cm (−1.4 SD), body mass index (BMI) of 16.3 kg/m2 (−2.8 SD), and an occipital-frontal circumference of 53.5 cm (−0.5 SD), with a relative macrocephaly (Table 1). A slightly triangular face and a prominent forehead were evident; she has micrognathia and comparatively large teeth. She also has clinodactyly of her fifth finger and wears glasses owing to myopia. Table 1. Clinical Characteristics and Body Composition of Seven Adults With SRS Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Age, y 21 26 25 46 29 18 23 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Sex Female Male Female Female Female Male Female Gestational age, wk 39 38 39 41 40 31 32 Birth weight SD −1.8 −3 −3.2 −2.7 −3.5 −3 −2.2 Birth length SD −1.77 −3.15 −4.2 Unknown −4.6 Unknown Unknown Height, cm 153.7 150.9 137.5 149.5 136.7 141.2 145.3 Height SD −1.4 −3.6 −4,1 −2.1 −4.3 −5 −2.8 SH SD −1.8 −3.2 −4.2 −2.6 −4.2 −4.6 −2.9 SH/H 0.53 0.54 0.54 0.53 0.55 0.55 0.54 Occipito-frontal circumference SD −0.5 2.3 −1,2 −0.5 0.5 1.4 −1.9 BMI SD −2.8 −2 2.5 0.3 −1.7 0 −0.6 Fat mass, kg 9.5 12.8 33.1 22.3 10.7 15.1 17.5 Fat mass, %a 26 31 55.1 45.7 31 36.6 41.5 FM, kg/m2b 4 5.6 17.4 10 5.7 7.6 8.5 Trunk fat, g 3588 7515 15,466 8929 4401 7841 8231 Limb fat, g 14,356 4340 16,900 12,700 5642 6446 8593 Trunk/limb fat ratioc 0.24 1.73 0.91 0.7 0.78 1.2 0.95 Lean mass, kgd 27 28.5 26.3 26.6 21.7 26.2 24.6 BMD  L1–L4 Z-score 1.2 0.7 0.7 −0.9 1.1 −2 0.1  L1–L4, g/cm2 1.234 1.191 1.261 0.980 1.185 0.943 1.131  TB Z-score 1 −0.1 1 −0.5 1.5 −1.8 0.1  TB, g/cm2 1.060 1.036 1.261 0.872 1.093 0.981 1.053  Left hip Z-score 1.1 0.6 1.6 −0.5 −0.4 0.7  Left hip, g/cm2 1.060 1.074 1.179 0.872 0.865 1.020 Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Age, y 21 26 25 46 29 18 23 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Sex Female Male Female Female Female Male Female Gestational age, wk 39 38 39 41 40 31 32 Birth weight SD −1.8 −3 −3.2 −2.7 −3.5 −3 −2.2 Birth length SD −1.77 −3.15 −4.2 Unknown −4.6 Unknown Unknown Height, cm 153.7 150.9 137.5 149.5 136.7 141.2 145.3 Height SD −1.4 −3.6 −4,1 −2.1 −4.3 −5 −2.8 SH SD −1.8 −3.2 −4.2 −2.6 −4.2 −4.6 −2.9 SH/H 0.53 0.54 0.54 0.53 0.55 0.55 0.54 Occipito-frontal circumference SD −0.5 2.3 −1,2 −0.5 0.5 1.4 −1.9 BMI SD −2.8 −2 2.5 0.3 −1.7 0 −0.6 Fat mass, kg 9.5 12.8 33.1 22.3 10.7 15.1 17.5 Fat mass, %a 26 31 55.1 45.7 31 36.6 41.5 FM, kg/m2b 4 5.6 17.4 10 5.7 7.6 8.5 Trunk fat, g 3588 7515 15,466 8929 4401 7841 8231 Limb fat, g 14,356 4340 16,900 12,700 5642 6446 8593 Trunk/limb fat ratioc 0.24 1.73 0.91 0.7 0.78 1.2 0.95 Lean mass, kgd 27 28.5 26.3 26.6 21.7 26.2 24.6 BMD  L1–L4 Z-score 1.2 0.7 0.7 −0.9 1.1 −2 0.1  L1–L4, g/cm2 1.234 1.191 1.261 0.980 1.185 0.943 1.131  TB Z-score 1 −0.1 1 −0.5 1.5 −1.8 0.1  TB, g/cm2 1.060 1.036 1.261 0.872 1.093 0.981 1.053  Left hip Z-score 1.1 0.6 1.6 −0.5 −0.4 0.7  Left hip, g/cm2 1.060 1.074 1.179 0.872 0.865 1.020 Abbreviations: FM, fat mass; H, height; SH, sitting height; TB, total body. a Mean value of fat mass percentage calculated according to Imboden et al. (15): women: age 20–29 y, 31.4% ± 8.5%; age 40–49 y, 39.2 ± 9.7; men: age 20–29 y, 21.1± 8.3. b Mean FMI value according to Imboden et al. (16): women: age 20–29 y, 7.6 ± 3.6 kg/m2; age 40–49 y, 11 ± 5.1 kg/m2; men: age 20–29 y, 5.6 ± 3 kg/m2. c Mean value of trunk/limb ratio calculated according to Imboden et al. (15): women: age 20–29 y, 0.96 ± 0.25; age 40–49 y, 1.12 ± 0.39; men: age 20–29 y, 1.24 ± 0.29. d Mean lean mass calculated according to Imboden et al. (16): women: age 20–29 y, 43 ± 6.1 kg; age 40–49 y, 42.9 ± 7 kg; men: age 20–29 y, 65 ± 11 kg. View Large Table 1. Clinical Characteristics and Body Composition of Seven Adults With SRS Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Age, y 21 26 25 46 29 18 23 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Sex Female Male Female Female Female Male Female Gestational age, wk 39 38 39 41 40 31 32 Birth weight SD −1.8 −3 −3.2 −2.7 −3.5 −3 −2.2 Birth length SD −1.77 −3.15 −4.2 Unknown −4.6 Unknown Unknown Height, cm 153.7 150.9 137.5 149.5 136.7 141.2 145.3 Height SD −1.4 −3.6 −4,1 −2.1 −4.3 −5 −2.8 SH SD −1.8 −3.2 −4.2 −2.6 −4.2 −4.6 −2.9 SH/H 0.53 0.54 0.54 0.53 0.55 0.55 0.54 Occipito-frontal circumference SD −0.5 2.3 −1,2 −0.5 0.5 1.4 −1.9 BMI SD −2.8 −2 2.5 0.3 −1.7 0 −0.6 Fat mass, kg 9.5 12.8 33.1 22.3 10.7 15.1 17.5 Fat mass, %a 26 31 55.1 45.7 31 36.6 41.5 FM, kg/m2b 4 5.6 17.4 10 5.7 7.6 8.5 Trunk fat, g 3588 7515 15,466 8929 4401 7841 8231 Limb fat, g 14,356 4340 16,900 12,700 5642 6446 8593 Trunk/limb fat ratioc 0.24 1.73 0.91 0.7 0.78 1.2 0.95 Lean mass, kgd 27 28.5 26.3 26.6 21.7 26.2 24.6 BMD  L1–L4 Z-score 1.2 0.7 0.7 −0.9 1.1 −2 0.1  L1–L4, g/cm2 1.234 1.191 1.261 0.980 1.185 0.943 1.131  TB Z-score 1 −0.1 1 −0.5 1.5 −1.8 0.1  TB, g/cm2 1.060 1.036 1.261 0.872 1.093 0.981 1.053  Left hip Z-score 1.1 0.6 1.6 −0.5 −0.4 0.7  Left hip, g/cm2 1.060 1.074 1.179 0.872 0.865 1.020 Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Age, y 21 26 25 46 29 18 23 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Sex Female Male Female Female Female Male Female Gestational age, wk 39 38 39 41 40 31 32 Birth weight SD −1.8 −3 −3.2 −2.7 −3.5 −3 −2.2 Birth length SD −1.77 −3.15 −4.2 Unknown −4.6 Unknown Unknown Height, cm 153.7 150.9 137.5 149.5 136.7 141.2 145.3 Height SD −1.4 −3.6 −4,1 −2.1 −4.3 −5 −2.8 SH SD −1.8 −3.2 −4.2 −2.6 −4.2 −4.6 −2.9 SH/H 0.53 0.54 0.54 0.53 0.55 0.55 0.54 Occipito-frontal circumference SD −0.5 2.3 −1,2 −0.5 0.5 1.4 −1.9 BMI SD −2.8 −2 2.5 0.3 −1.7 0 −0.6 Fat mass, kg 9.5 12.8 33.1 22.3 10.7 15.1 17.5 Fat mass, %a 26 31 55.1 45.7 31 36.6 41.5 FM, kg/m2b 4 5.6 17.4 10 5.7 7.6 8.5 Trunk fat, g 3588 7515 15,466 8929 4401 7841 8231 Limb fat, g 14,356 4340 16,900 12,700 5642 6446 8593 Trunk/limb fat ratioc 0.24 1.73 0.91 0.7 0.78 1.2 0.95 Lean mass, kgd 27 28.5 26.3 26.6 21.7 26.2 24.6 BMD  L1–L4 Z-score 1.2 0.7 0.7 −0.9 1.1 −2 0.1  L1–L4, g/cm2 1.234 1.191 1.261 0.980 1.185 0.943 1.131  TB Z-score 1 −0.1 1 −0.5 1.5 −1.8 0.1  TB, g/cm2 1.060 1.036 1.261 0.872 1.093 0.981 1.053  Left hip Z-score 1.1 0.6 1.6 −0.5 −0.4 0.7  Left hip, g/cm2 1.060 1.074 1.179 0.872 0.865 1.020 Abbreviations: FM, fat mass; H, height; SH, sitting height; TB, total body. a Mean value of fat mass percentage calculated according to Imboden et al. (15): women: age 20–29 y, 31.4% ± 8.5%; age 40–49 y, 39.2 ± 9.7; men: age 20–29 y, 21.1± 8.3. b Mean FMI value according to Imboden et al. (16): women: age 20–29 y, 7.6 ± 3.6 kg/m2; age 40–49 y, 11 ± 5.1 kg/m2; men: age 20–29 y, 5.6 ± 3 kg/m2. c Mean value of trunk/limb ratio calculated according to Imboden et al. (15): women: age 20–29 y, 0.96 ± 0.25; age 40–49 y, 1.12 ± 0.39; men: age 20–29 y, 1.24 ± 0.29. d Mean lean mass calculated according to Imboden et al. (16): women: age 20–29 y, 43 ± 6.1 kg; age 40–49 y, 42.9 ± 7 kg; men: age 20–29 y, 65 ± 11 kg. View Large Patient 2 This male patient was a second child, born after 38 weeks of gestation via vaginal delivery. His birth weight was 2000 g (−3.0 SD), birth length was 43 cm (−3.15 SD), and occipital-frontal circumference was 33 cm (−1.2 SD). He displayed failure to thrive and feeding difficulties since the first months of life, leading to nutritional support via a nasogastric tube until age 8 years. At age 2 years, he had an episode of symptomatic fasting hypoglycemia. He had a mild motor delay and was not able to walk alone until 2.5 years of age. His cognitive development was good, and he never had any difficulties at school. He obtained a diploma as a qualified accountant. He has a busy social life, enjoys relatively good health, and works as a municipal employee. At the last evaluation, at 27 years of age, his height was 150.9 cm (−3.6 SD)—with a sitting height of 82.8 cm (−3.2 SD) and a sitting height/height ratio of 0.54 (+2 SD) (20)—and his weight was 43.3 kg, with a BMI of 18.9 kg/m2 (−2 SD). The clinical examination documented relative macrocephaly, with a head occipital-frontal circumference of 57.3 cm (+2.3 SD). He had normal pubertal development with a bilateral testicular volume of 15 mL. He also had clinodactyly of the fifth finger, and no body asymmetry was observed. He has experienced excessive sweating since the first months of life. Molecular tests revealed mUPD7. Patient 3 This female patient was born at 39 weeks of gestation. Her birth weight was 1850 g (−3.2 SD), birth length was 40 cm (−4.2 SD), and occipital-frontal circumference was 34 cm (+0.12 SD), with relative macrocephaly. In her first years of life, she displayed feeding difficulties and failure to thrive. From age 6 years onward, however, she has been overweight. She had menarche at age 11 years, followed by regular menses. She also displayed chronic otitis media in childhood and cholesteatoma in the left ear at age 14 years. At last evaluation at age 25 years, her height was 137.5 cm (−4.1 SD), sitting height was 74.7 cm (−4.2 SD)—with a sitting height/height ratio of 0.54 (+1 SD)—and weight was 61 kg, with a BMI of 32.3 kg/m2 (+2.5 SD). She also had relative macrocephaly, with an occipital-frontal circumference of 52.5 cm (−1.2 SD), fifth-finger clinodactyly, and body asymmetry (leg length discrepancy of 1.5 cm; arm and facial asymmetry). Her facial appearance is shown in Fig. 2. Her neuropsychological development was normal, and she recently graduated as a social worker. Molecular tests were performed at age 24 years and showed 11p15 LOM. Figure 2. View largeDownload slide Patient 3 at ages (a) 1 y, (b) 2 y, and (c) 24 y. Figure 2. View largeDownload slide Patient 3 at ages (a) 1 y, (b) 2 y, and (c) 24 y. Patient 4 After an uncomplicated pregnancy, this female patient was born in 1970 after 41 weeks of gestation by natural delivery and had a birth weight of 2300 g (−2.7 SD). Data on length and occipito-frontal circumference, as well as on clinical outcome at birth, are lacking. However, her parents reported that she was born SGA in terms of both weight and length and had relative macrocephaly. In the first months of life, she had feeding difficulties and failure to thrive. Her cognitive development was normal. As a child, she enjoyed relatively good health. Since leaving school, she has worked as a post office employee. At age 40 years, she had a son, who is currently 6 years old and in good health. Her pregnancy was characterized by cervical incompetence. She experienced menopause at age 44 years. The patient has experienced significant dental overcrowding and misalignment, requiring orthodontic treatment and multiple tooth extractions. Methylation study revealed 11p15 LOM. At the time of examination, the patient was 46 years old and 149.5 cm tall (−2.1 SD). Her BMI was 23 kg/m2 (+0.3 SD), and her occipito-frontal circumference was 53.5 cm (−0.5 SD) (Table 1). She had leg length and arm asymmetry. She reports eating normal-sized adult portions and having difficulty maintaining her weight. Patient 5 This female patient was born to healthy nonconsanguineous parents at 40 weeks of gestational age. Her birth weight was 1850 g (−3.5 SD), her birth length was 40 cm (−4.6 SD), and relative macrocephaly was documented at birth. Poor fetal growth was first noted in the 30th week of gestation. She had severe feeding difficulties during the first years of life. However, a nasogastric tube for feeding was not inserted. Because of her short stature, GH therapy was started when she was age 7 years and was continued until she was age 9 years. She experienced precocious puberty with menarche at age 9 years, and gonadotropin-releasing hormone analog treatment was performed from age 9 to 10 years. She had significant dental overcrowding and misalignment, which led to orthodontic treatment and multiple teeth extractions. Micrognathia was also pronounced. She graduated with a degree in sports science and is now working in a call center as an operator. She had a miscarriage at 10 weeks of pregnancy at age 29 years. Molecular analysis performed at age 24 years showed 11p15 LOM. At the last evaluation, at age 29 years, her height was 136.7 cm (−4.3 SD), her BMI was 18.2 kg/m2 (−1.7 SD), she had persistent relative macrocephaly, and her head circumference was +0.5 SD (Table 1). She had leg length, foot, and facial asymmetry. Patient 6 This male patient was prematurely born at the 31st gestational week via cesarean delivery due to intrauterine growth restriction (IUGR), oligohydramnios, and fetal distress. At birth, he was SGA and displayed relative macrocephaly and the typical clinical manifestations of SRS, including a prominent forehead, a triangular face, low-set ears, and fifth-digit clinodactyly. No body asymmetry was observed. Developmental milestones were delayed (he walked at 2.5 years of age and pronounced his first words at 3 years of age). Molecular analysis showed a maternally inherited duplication of chromosome 11p15. GH therapy was started at age 7 years and was withdrawn at age 11 years because of glucose intolerance. He currently displays selective mutism and mild cognitive delay, and he is assisted by a teaching-support specialist. On last physical examination at age 18 years, his height was 141.2 cm (−5 SD), weight was 42.5 kg, BMI was 21.3 kg/m2 (0 SD), and occipito-frontal circumference was 56.5 cm (+1.4 SD) (Table 1). He wears glasses because of astigmatism. Patient 7 This female patient was born prematurely (at 32 weeks of gestational age) by cesarean delivery. Her birth weight was 950 g (−2.2 SD). Although her birth length and occipito-frontal circumference were not available, a measurement compatible with macrocephaly was reported at ages 1 to 3 years. She had menarche at age 11 years, followed by regular menses. She has an ectopic kidney, incidentally detected by abdominal ultrasonography. She has had two pregnancies characterized by cervical incompetence: In the 28th week of her first pregnancy, she delivered a still-born baby; in her second pregnancy she delivered in the 24th week, and the baby died after a few hours. Molecular tests performed in adulthood revealed a duplication of chromosome 11. Current examination, at age 23 years, revealed a weight of 43.5 kg, height of 145.3 cm (−2.8 SD), BMI of 20.6 kg/m2 (–0.6 SD), and an occipito-frontal circumference of 51.5 cm (−1.9 SD) (Table 1). Results NH clinical score The clinical diagnosis was confirmed by molecular genetic analysis: three patients had 11p15 LOM, two had mUPD7, and two had 11p15 duplication. Clinical characteristics and body composition of the patients are listed in Table 1. All patients but one were born SGA (mean birth weight, −2.76 SD ± 0.6; mean birth length, −3.43 SD ± 1.2). Body asymmetry was found in patients with 11p15 LOM (patients 3, 4, and 5) (Table 2). Table 2. Childhood and Adulthood NH Scores and Molecular Findings in Seven Patients With SRS Variablea Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 NH score in childhood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X X X X X X  Total (n) 4 5 6 6 6 5 5 NH score in adulthood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X  Total (n) 4 5 5 5 5 4 4 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Variablea Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 NH score in childhood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X X X X X X  Total (n) 4 5 6 6 6 5 5 NH score in adulthood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X  Total (n) 4 5 5 5 5 4 4 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication a (1) SGA: birth weight and/or birth length ≤ −2 SD, (2) postnatal growth failure, (3) relative macrocephaly at birth (head circumference ≥ 1.5 SD for birth weight and length), (4) protruding forehead, (5) body asymmetry, (6) feeding difficulties and/or low BMI (≤−2 SD). View Large Table 2. Childhood and Adulthood NH Scores and Molecular Findings in Seven Patients With SRS Variablea Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 NH score in childhood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X X X X X X  Total (n) 4 5 6 6 6 5 5 NH score in adulthood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X  Total (n) 4 5 5 5 5 4 4 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication Variablea Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 NH score in childhood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X X X X X X  Total (n) 4 5 6 6 6 5 5 NH score in adulthood  SGA X X X X X X  Postnatal growth failure X X X X X X X  Relative macrocephaly at birth X X X X X X X  Protruding forehead X X X X X X X  Body asymmetry X X X  Feeding difficulties and/or low BMI X X  Total (n) 4 5 5 5 5 4 4 Molecular findings mUPD7 mUPD7 11p15 LOM 11p15 LOM 11p15 LOM 11 duplication 11 duplication a (1) SGA: birth weight and/or birth length ≤ −2 SD, (2) postnatal growth failure, (3) relative macrocephaly at birth (head circumference ≥ 1.5 SD for birth weight and length), (4) protruding forehead, (5) body asymmetry, (6) feeding difficulties and/or low BMI (≤−2 SD). View Large At the time of diagnosis, all patients showed typical facial features of SRS: frontal bosses, relative macrocephaly, triangular facies, and micrognathia. Mean adult height was −3.3 SD ± 1.2, and only two patients (patients 5 and 6) received short-term GH therapy. One patient (patient 5) developed precocious puberty. Two women (patients 4 and 7) who had a pregnancy had cervical incompetence requiring cerclage. The NH clinical score declined in all but two of the seven patients during adulthood (Table 2). Two patients (patients 1 and 2), both mUPD7, were still underweight, four patients had a normal BMI, and one was obese; patient 6 had a cognitive delay. All patients but one displayed relative macrocephaly in adulthood. Metabolic and body composition findings Oral glucose tolerance testing showed glucose intolerance and hyperinsulinemia in two patients (Table 3). Two patients (patients 2 and 4) showed high total cholesterol levels with low HDL cholesterol levels. The obese patient (patient 3) had high waist/hip and waist/height ratios (21, 22). All patients showed normal triglyceride levels and blood pressure (23) (Table 4). None of our patients satisfied the criteria for metabolic syndrome. Bone turnover markers and calciotropic hormonal parameters (vitamin D, parathyroid hormone) are listed in Supplemental Table 1. Type 1 collagen values were higher in males compared with the reference values. BMD was within the normal range (mean Z-score for L1 to L4, 0.1 ± 1.2; mean Z-score for total body, 0.44 ± 0.9). A high body fat mass percentage (mean, 38.2% ± 10.2%; range, 26% to 55.7%), FMI (mean, 8.37 ± 4.47 kg/m2; range, 4.0 to 17.48 kg/m2), and trunk/limb fat ratio (mean, 0.93 ± 0.45; range, 0.24 to 1.73) and a low LBM (mean, 25.84 ± 2.16 kg; range, 21.7 to 28.5 kg) were found in comparison with published references in healthy adults (15, 16) (Table 1). The trunk/limb fat ratio did not correlate with different measures of adiposity (BMI SD, FMI, fat body mass percentage); however, it showed an inverse relation with HDL cholesterol levels (r = −0.78; P = 0.036) and a trend toward a direct relation with glucose 120’ (r = 0.67; P = 0.11). Table 3. Glucose Metabolism in Seven Adults With SRS Variable Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Glucose, mmol/L  T 0 min 4.5 4.4 5.4 4.8 4.8 5.3 5.4  T 30 7.0 7.5 7.4 6.5 6.9 11.2 8.1  T 60 min 7.5 7.1 9.4 4.8 4.7 11.5 6  T 90 min 6.4 7.4 9.6 4.5 6.7 9.3 6.1  T 120 min 5.6 8.4 7.7 3.8 4.8 9.4 7.5 Insulin, μU/mL  T 0 min 9.2 5.9 13.4 4.3 6.0 20.5 12.2  T 30 min 52.8 75.6 11.6 139.2 76.2 304.7 100.5  T 60 min 55.0 91.8 22.2 85.4 42.0 314.7 56.8  T 90 min 50.8 86.6 68.9 22.3 87.1 211.3 32.7  T 120 min 63.7 125.8 52.2 16.0 52.3 296.3 74.4 Variable Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Glucose, mmol/L  T 0 min 4.5 4.4 5.4 4.8 4.8 5.3 5.4  T 30 7.0 7.5 7.4 6.5 6.9 11.2 8.1  T 60 min 7.5 7.1 9.4 4.8 4.7 11.5 6  T 90 min 6.4 7.4 9.6 4.5 6.7 9.3 6.1  T 120 min 5.6 8.4 7.7 3.8 4.8 9.4 7.5 Insulin, μU/mL  T 0 min 9.2 5.9 13.4 4.3 6.0 20.5 12.2  T 30 min 52.8 75.6 11.6 139.2 76.2 304.7 100.5  T 60 min 55.0 91.8 22.2 85.4 42.0 314.7 56.8  T 90 min 50.8 86.6 68.9 22.3 87.1 211.3 32.7  T 120 min 63.7 125.8 52.2 16.0 52.3 296.3 74.4 Abbreviation: T, time. View Large Table 3. Glucose Metabolism in Seven Adults With SRS Variable Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Glucose, mmol/L  T 0 min 4.5 4.4 5.4 4.8 4.8 5.3 5.4  T 30 7.0 7.5 7.4 6.5 6.9 11.2 8.1  T 60 min 7.5 7.1 9.4 4.8 4.7 11.5 6  T 90 min 6.4 7.4 9.6 4.5 6.7 9.3 6.1  T 120 min 5.6 8.4 7.7 3.8 4.8 9.4 7.5 Insulin, μU/mL  T 0 min 9.2 5.9 13.4 4.3 6.0 20.5 12.2  T 30 min 52.8 75.6 11.6 139.2 76.2 304.7 100.5  T 60 min 55.0 91.8 22.2 85.4 42.0 314.7 56.8  T 90 min 50.8 86.6 68.9 22.3 87.1 211.3 32.7  T 120 min 63.7 125.8 52.2 16.0 52.3 296.3 74.4 Variable Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Glucose, mmol/L  T 0 min 4.5 4.4 5.4 4.8 4.8 5.3 5.4  T 30 7.0 7.5 7.4 6.5 6.9 11.2 8.1  T 60 min 7.5 7.1 9.4 4.8 4.7 11.5 6  T 90 min 6.4 7.4 9.6 4.5 6.7 9.3 6.1  T 120 min 5.6 8.4 7.7 3.8 4.8 9.4 7.5 Insulin, μU/mL  T 0 min 9.2 5.9 13.4 4.3 6.0 20.5 12.2  T 30 min 52.8 75.6 11.6 139.2 76.2 304.7 100.5  T 60 min 55.0 91.8 22.2 85.4 42.0 314.7 56.8  T 90 min 50.8 86.6 68.9 22.3 87.1 211.3 32.7  T 120 min 63.7 125.8 52.2 16.0 52.3 296.3 74.4 Abbreviation: T, time. View Large Table 4. Blood Pressure, Waist and Hip Circumferences, and Lipid Profiles in Seven Adults With SRS Variable Normal Ranges Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 TC, mmol/L <5.17 4.37 5.92 4.29 5.61 5.14 4.13 4.75 HDL cholesterol, mmol/L 1.68–2.58 2.27 1.03 2.14 1.52 1.71 1.24 1.19 LDL cholesterol, mmol/L Optimal value < 2.58
Intermediate risk > 3.88
High risk > 4.91 1.86 4.39 1.81 3.62 3.05 2.43 2.97 Triglycerides, mmol/L 0.78–4.13 1.16 1.76 1.55 1.11 1.47 1.58 1.63 Waist circumference, cm ≤88 in women
≤102 in men 59 73 83 73 62 72 65 Hip circumference, cm 89 81 110 101 78 82 88 Waist/hip circumference ratio <0.95 in men
<0.8 in women 0.66 0.9 0.75 0.72 0.79 0.87 0.73 Waist circumference/height ratio <0.58 0.38 0.48 0.6 0.48 0.45 0.5 0.44 SBP, mm Hg ≤135 101 109 125 113 115 101 DBP, mm Hg ≤85 65 63 83 78 66 57 Variable Normal Ranges Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 TC, mmol/L <5.17 4.37 5.92 4.29 5.61 5.14 4.13 4.75 HDL cholesterol, mmol/L 1.68–2.58 2.27 1.03 2.14 1.52 1.71 1.24 1.19 LDL cholesterol, mmol/L Optimal value < 2.58
Intermediate risk > 3.88
High risk > 4.91 1.86 4.39 1.81 3.62 3.05 2.43 2.97 Triglycerides, mmol/L 0.78–4.13 1.16 1.76 1.55 1.11 1.47 1.58 1.63 Waist circumference, cm ≤88 in women
≤102 in men 59 73 83 73 62 72 65 Hip circumference, cm 89 81 110 101 78 82 88 Waist/hip circumference ratio <0.95 in men
<0.8 in women 0.66 0.9 0.75 0.72 0.79 0.87 0.73 Waist circumference/height ratio <0.58 0.38 0.48 0.6 0.48 0.45 0.5 0.44 SBP, mm Hg ≤135 101 109 125 113 115 101 DBP, mm Hg ≤85 65 63 83 78 66 57 Abbreviations: DBP, diastolic blood pressure; LDL, low-density lipoprotein; SBP, systolic blood pressure; TC, total cholesterol. View Large Table 4. Blood Pressure, Waist and Hip Circumferences, and Lipid Profiles in Seven Adults With SRS Variable Normal Ranges Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 TC, mmol/L <5.17 4.37 5.92 4.29 5.61 5.14 4.13 4.75 HDL cholesterol, mmol/L 1.68–2.58 2.27 1.03 2.14 1.52 1.71 1.24 1.19 LDL cholesterol, mmol/L Optimal value < 2.58
Intermediate risk > 3.88
High risk > 4.91 1.86 4.39 1.81 3.62 3.05 2.43 2.97 Triglycerides, mmol/L 0.78–4.13 1.16 1.76 1.55 1.11 1.47 1.58 1.63 Waist circumference, cm ≤88 in women
≤102 in men 59 73 83 73 62 72 65 Hip circumference, cm 89 81 110 101 78 82 88 Waist/hip circumference ratio <0.95 in men
<0.8 in women 0.66 0.9 0.75 0.72 0.79 0.87 0.73 Waist circumference/height ratio <0.58 0.38 0.48 0.6 0.48 0.45 0.5 0.44 SBP, mm Hg ≤135 101 109 125 113 115 101 DBP, mm Hg ≤85 65 63 83 78 66 57 Variable Normal Ranges Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 TC, mmol/L <5.17 4.37 5.92 4.29 5.61 5.14 4.13 4.75 HDL cholesterol, mmol/L 1.68–2.58 2.27 1.03 2.14 1.52 1.71 1.24 1.19 LDL cholesterol, mmol/L Optimal value < 2.58
Intermediate risk > 3.88
High risk > 4.91 1.86 4.39 1.81 3.62 3.05 2.43 2.97 Triglycerides, mmol/L 0.78–4.13 1.16 1.76 1.55 1.11 1.47 1.58 1.63 Waist circumference, cm ≤88 in women
≤102 in men 59 73 83 73 62 72 65 Hip circumference, cm 89 81 110 101 78 82 88 Waist/hip circumference ratio <0.95 in men
<0.8 in women 0.66 0.9 0.75 0.72 0.79 0.87 0.73 Waist circumference/height ratio <0.58 0.38 0.48 0.6 0.48 0.45 0.5 0.44 SBP, mm Hg ≤135 101 109 125 113 115 101 DBP, mm Hg ≤85 65 63 83 78 66 57 Abbreviations: DBP, diastolic blood pressure; LDL, low-density lipoprotein; SBP, systolic blood pressure; TC, total cholesterol. View Large FMI was significantly higher in patients (P = 0.004) than in short healthy controls (9.1 ± 5.2 kg/m2 vs. 6.0 ± 0.6 kg/m2 in females, respectively; 6.6 ± 1.4 kg/m2 vs. 4.5 ± 1.4 kg/m2 in males, respectively). In addition, the patients with SRS showed mean trunk fat significantly higher than that in healthy controls: 8.1 ± 4.7 kg vs. 6.0 ± 0.5 kg in females, respectively, and 7.7 ± 0.2 kg vs. 5.5 ± 1.9 kg in males, respectively. The latter findings suggest that both female and male patients with SRS have almost 2 kg more trunk fat than do controls. This represents a further 35% of the truncal fat mass in female patients with SRS and 41% more in male patients with SRS compared with controls. Lean mass index (LMI) showed a trend toward lower values in patients with SRS (P = 0.07), with an LMI of 12.0 ± 1.0 kg/m2 in female patients with SRS compared with 12.2 ± 0.5 kg /m2 in controls and LMI of 12.7 ± 0.5 kg/m2 in male patients with SRS with 14.9 ± 1.5 kg/m2 in controls. Discussion Few long-term follow-up studies have been conducted in patients with SRS, and the clinical phenotype as well as the metabolic outcomes of this condition during adulthood remain to be defined (12, 24). Although several studies have shown that children who are SGA at birth are prone to later development of metabolic disorders, including insulin resistance and diabetes, hypercholesterolemia, and cardiovascular diseases (14, 25), little has been reported in patients with SRS, who are generally born SGA and as having IUGR. Here, we report the clinical features and the metabolic profiles of seven adult patients with a molecular diagnosis of SRS, re-evaluated at a mean age of 26.9 ± 9.1 years. The diagnosis of SRS at birth or during childhood could be straightforward based on validated clinical criteria (5), recently highlighted by the first international consensus statement (2). Nevertheless, SRS is a heterogeneous condition, and its differential diagnosis could be a challenge already in children presenting with IUGR, in which the underlying molecular abnormalities could not be confirmed (2, 6, 7, 9), or in those born appropriate for gestational age with mUPD7 (26, 27). Therefore, the diagnosis of missed SRS or SRS-like conditions may be even more difficult in adults. Because the criteria and scores for the diagnosis of SRS were validated for patients aged 1.05 to 20.06 years, with a mean age of 6.61 years (5), we asked whether the clinical characteristics of these patients could be maintained over time and specifically after age 20 years. It is worth pointing out, however, that the clinical features of relative macrocephaly, protruding forehead (although less pronounced), and body asymmetry were maintained after 20 years, suggesting that their identification in an adult born SGA or with IUGR with an adult height of less than −2 SD should prompt physicians to consider a missed diagnosis of SRS during childhood. In adults suspected of having SRS, it is also advisable to check for early-childhood photographs. Indeed, feeding difficulties and low BMI did not appear to be typical features of adults with SRS but were consistently present during the first year of life. However, the BMI of most of these patients remained between −2.8 to 0 SD, except for one patient with severe obesity, who showed high waist/hip and waist/height ratios, risk factors for cardiovascular disease (21, 22). It is known that patients born SGA are at risk for insulin resistance and cardiovascular disease, which seems to be related to the rate of weight gain occurring during the first years of life and to the adverse prenatal metabolic environment (25, 28). In addition to adult weight, weight catch-up growth during childhood is a strong determinant of body composition, and patients with SGA and catch-up growth have been reported to have significantly higher fat mass percentage % and lower LBM than controls (28). Our patients displayed a low LBM and a high fat mass percentage, FMI, trunk fat percentage, and trunk fat/limb ratio (the latter being a surrogate of central adiposity) compared with a small group of short controls, suggesting that patients with SRS have an abnormal body composition. Thus, total and visceral fat mass should be adequately defined in patients with SRS as compared with healthy controls (15, 16), where BMI and waist circumference are commonly included in the definition of the cardiovascular risk profile (17, 29), and raise the question about the role of DXA values in the assessment of the cardiovascular risks in adults with SRS. To our knowledge, there are only two case reports and one long-term study addressing metabolic health in SRS (10–12). In particular, a 69-year-old man originally reported by Russell in 1953, is the oldest patient with SRS ever reported (11, 30). The patient enjoyed a relatively good life, was married, and had a daughter. He had hypercholesterolemia, developed type 2 diabetes mellitus at age 56 years, and developed osteopenia and hypogonadotropic hypogonadism later in life (11). Takenouchi et al. (10) described three young adults with SRS (early 20s) with 11p15 LOM who developed type 2 diabetes, hyperlipidemia, and hypertension, respectively. In addition, the recent long-term study available on metabolic status of patients with SRS showed no metabolic differences between patients treated with GH and SGA patients without SRS before, during, and through 2 years after the discontinuation of GH; none of the patients with SRS developed diabetes or metabolic syndrome at the mean age of 18 years (12). Our findings of glucose intolerance and hyperinsulinemia in two patients at ages 18 and 27 years, respectively, suggests that these patients can develop early abnormalities in glucose metabolism. In addition, although glucose intolerance and hypercholesterolemia were found to be independent of BMI, FMI, total percentage body fat, and molecular findings, both HDL cholesterol level and glucose intolerance were related to the trunk/limb fat ratio. Regarding BMD, DXA examination of these adults with SRS, performed for the first time at three skeletal sites (spine, femur, and total body), showed normal bone mineralization. These findings deserve further follow-up because DXA technique may underestimate bone mass in short/small persons. Hence, limitations of our study include the small number of patients and their relatively young age. In conclusion, the recognition of SRS features after achievement of adult height is crucial for the identification of patients with classical phenotype in order to establish a real prevalence of this rare condition; it is essential for genetic counseling, and it enables these patients to benefit from the early management of their metabolic complications. Although the scoring system for the diagnosis of SRS has been validated for children and adolescents, the diagnosis of SRS seems to also be reliable in adults; however, some clinical signs may become less pronounced with age, suggesting the need for further validation. The increase in central adiposity detected by DXA deserves further studies, and long-term follow-up in a larger number of patients with SRS is mandatory to understand the natural history of this disease and improve the management of these patients. Abbreviations: Abbreviations: BMD bone mineral density BMI body mass index DXA dual-energy x-ray absorptiometry ELISA enzyme-linked immunosorbent assay FMI fat mass index GH growth hormone HDL high-density lipoprotein IUGR intrauterine growth restriction LBM lean body mass LMI lean mass index LOM loss of methylation NH Netchine-Harbison SD standard deviation SGA small for gestational age SRS Silver-Russell syndrome Acknowledgments We thank Luana Pennisi, Silvia Mariotti, and Margherita Scola from the Italian Association of Families with Silver-Russell Syndrome (AISRS Onlus) for their great support, and all patients and their families. We also thank our nurse staff for their daily commitments in the care of patients with SRS and other endocrine conditions. Financial Support: Ministero Dell’Istruzione, dell’Università e della Ricerca, PRIN 2015, number 2015JHLY35 Author Contributions: G.P. designed the study, examined the clinical phenotypes of the patients, takes care of patient follow-up, collected the data, and drafted and revised the manuscript; M.G. helped in evaluating the clinical phenotypes of the patients; V.C. performed genetic counseling; F.N. reviewed and revised the manuscript; G.C. performed laboratory tests and participated in drafting the manuscript; S.N. helped in data collection; S.G. and S.R. performed molecular analysis and genetic counseling; M.M. designed the study, examined the clinical phenotypes of the patients, and reviewed and revised the manuscript; N.D. performed body composition assessment and data analysis and reviewed and revised the manuscript. Disclosure Summary: The authors have nothing to disclose. References 1. Wakeling EL . Silver-Russell syndrome . Arch Dis Child . 2011 ; 96 ( 12 ): 1156 – 1161 . 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Mar 13, 2018

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