Duplication of 17q11.2 and Features of Albright Hereditary Osteodystrophy Secondary to Methylation Defects within the GNAS Cluster: Coincidence or Causal?

We report a case of Albright hereditary osteodystrophy (AHO) in a three-year-old girl with a microduplication at 17q11.2. The child developed obesity within the first 6 months of life. A diagnosis of Albright was made at age 2 years when biochemical evidence of parathyroid resistance was found. No mutations were identified in guanine nucleotide-binding protein G (s) subunit alpha (GNAS1). Subsequent investigations revealed methylation disturbance at GNAS1A, neuroendocrine secretory protein antisense (NESPAS) and neuroendocrine secretory protein 55 (NESP55) confirming a diagnosis of pseudohypothyroidism type 1B. A deletion of NESP55 and uniparental disomy chromosome 20 were excluded which suggested that the features of AHO arose through a purely epigenetic mechanism. Further investigation revealed a de novo microduplication at 17q11.2 encompassing the neurofibromatosis type 1 (NF1) gene. The combination of two rare de novo events in the same child raises the possibility that duplication of a gene within the 17q11.2 region may have triggered abnormal methylation in the GNAS cluster region on chromosome 20. 1. Clinical Summary The child, a girl, was the third child born to healthy non consanguineous parents at 38 weeks of gestation by Elective Lower Segment Caesarean Section weighing 3.01 kilograms. There were no neonatal issues apart from mild jaundice that did not require phototherapy treatment, and family history was noncontributory. At 3 months of age she was noted to be on the 99.9th centile for height and weight, which was to remain an ongoing concern, and she developed a large appetite with little satiety from early infancy. Development was initially felt to be mildly delayed globally, and at 18 months she was behind in gross motor and communication development. However, at 2.5 years her development was reported as being within normal limits. The child had been attending her local paediatrician for weight management and dietetic input. Two separate TSH measurements were elevated with a normal Free T4 on both occasions. This prompted referral to a tertiary endocrinology service at 2 years of age for endocrinology assessment of elevated TSH in the context of obesity. At the initial endocrinology review, her weight was 20？kg (>99.6th centile), height was 93？cm (>99.6th centile), and body mass index (BMI) was 23.2 (>99.6th centile for age and gender). Clinical examination revealed a round facies, a flat occiput and central obesity. Phenotypic appearances suggested a possible diagnosis of AHO, without any evidence of the skeletal manifestations, either