ESPE Abstracts

Case report: We describe a male with tall stature (final height 210.5cm), macrocephaly (63.5cm, +5.5SD), obesity (BMI 44.6 kg/m²) and mild learning difficulties. Birth weight was 4.6kg (+2.3SD). He had slightly delayed developmental milestones. He was referred at the age of 5 for tall stature (+6.2SD), with a head circumference on the 98^th centile, growing at a rate of 10cm/yr. He had thick doughy skin, a mild squint, somewhat coarse features, large hands, feet and ears, but no clear arachnodactyly. He developed hip pain from the age of 6 with restriction of movement and abnormalities on imaging. He had a right hip subluxation and avascular necrosis aged 8 and a left femoral neck fracture aged 9, requiring multiple orthopaedic interventions and a total hip replacement aged 18. He developed obesity from young age. His height continued on the same centile and he reached near final height aged 16-17. Parents are consanguineous Pakistani. Father is 195cm, mother 161cm. TFTs, gonadotropins, testosterone, oestradiol, IGF1, IGFBP3, HbA1c, and urine homocysteine were normal. GH was normally suppressed in OGTT. Brain and pituitary gland were normal on MRI, and bone mineral density was normal. The skeletal survey showed mild arachnodactyly and prominent supraorbital ridges, but was insufficient to make a diagnosis. Ophthalmological and cardiac assessments were normal. Microarray, karyotype and FraX were normal. Sanger sequencing showed a common NSD1 variant c.7636G>A(p.Ala2546Thr) in the patient and his father, not suggestive of Sotos Syndrome. NSD1 MLPA analysis was normal. Eventually, a tall stature gene panel (DIS3L2, DNMT3A, EZH2, GPC3, NFIX, NSD1, OFD1, PTEN, ZBTB20) showed a heterozygous pathogenic loss-of-function missense variant in EZH2 (enhancer of zeste homolog 2), c.1876G>A (p.Val626Met), once previously described, confirming Weaver syndrome. Testing of the father is in progress.

Discussion: EHZ2 is part of the Polycomb Repressive Complex 2 (PRC2) and can modify histones. Loss-of-function EZH2 variants result in reduced H3K27 histone methyltransferase activity, and so suppress the activity of genes essential for normal growth, such as cell cycle genes. Weaver syndrome is characterized by tall stature, macrocephaly, mild intellectual disability, characteristic facial features (hypertelorism, retrognathia with stuck-on chin appearance, large ears), camptodactyly, kyphoscoliosis, advanced bone age, soft and doughy skin, umbilical hernia, abnormal muscle tone and hoarse, low-pitched cry. Joint stiffness can be seen, and congenital hip abnormalities have been described once before. Early genetic diagnosis is essential to avoid multiple investigations.