ESPE Abstracts (2018) 89 P-P2-318

SOX3 Gene Duplication Associated with Midline CNS Malformations, Hypopituitarism and Neurodevelopmental Abnormalities: 5 Unrelated Cases

Garima Chawlaa, Aparna K.R. Nambisanb, Ved B. Aryaa, Nadia Muhi-Iddinc, Katia Vamvakitid, Michal Ajzensztejne, Tony Hulsee, Charles R. Buchanana & Ritika R. Kapoora


aKing’s College Hospital NHS Foundation Trust, London, UK; bNorth Middlesex Hospital NHS Trust, London, UK; cEast Sussex Healthcare NHS Trust, Eastbourne, UK; dWestern Sussex Hospital NHS Trust, Worthing, UK; eGuys and St Thomas Hospitals NHS Trust, London, UK


Introduction: Duplications of SOX3 at Xq27.1 are known to be associated with a spectrum of midline defects, isolated/multiple pituitary hormone deficiencies and learning difficulties. We report 5 cases of SOX3 duplication with hypopituitarism and differing presentations. 1)Male neonate presented with poor feeding and prolonged jaundice. Investigations revealed central hypothyroidism and inadequate cortisol response to Synacthen. Appropriate hormone replacement was commenced. MRI showed pituitary hypoplasia and ectopic posterior pituitary. Array CGH revealed maternally inherited duplication of SOX3. He has a maternal cousin with hypopituitarism and another with spina bifida. At 10.7 years, he is of normal stature with severe expressive language delay. 2)15yr old boy was referred with short stature (Ht -1.78SDS) and pubertal delay. He had brachycephaly, learning difficulties and hyposmia. Investigations revealed GH deficiency (low serum IGF1, peak GH 6.1mcg/l on glucagon stimulation test). MRI showed partial agenesis of corpus callosum and absent septum pellucidum. Array CGH identified maternally inherited duplication of SOX3. Testicular volumes failed to progress to mature volume. Aged 20 yrs he is on full testosterone replacement. 3)Male infant noted on antenatal scans to have lumbar meningomyelocoele. Post-natal imaging showed hydrocephalus and agenesis of corpus callosum. He had micropenis, small testes; normal thyroid function and cortisol response to Synacthen at week 1 of life. Array CGH revealed de novo duplication of SOX3 and part of chromosome 6. At 2 years of age, serum IGF1 measured 4.89 nmol/L (RR: 3.67-14.8) & GH was 4.4mcg/L with cortisol of 452 nmol/L on glucagon stimulation. He has bilateral optic atrophy and left temporal lobe epilepsy with severe developmental delay. 4) 4.9yr old boy presented with short stature (Ht -3.52SDS) and mild developmental delay. Examination revealed clinodactyly, hypoplastic right thumb and hyperextensible fingers. CGH array revealed maternally derived Xq27.1 duplication including SOX3. Endocrine assessment is normal (fT4: 16pmol/l, peak GH: 26.2 mcg/l and cortisol: 612 nmol/l). MRI brain is pending. 5) 5yr old boy was referred with developmental delay and obesity. CGH array showed duplication of Xq27 to Xq28 including SOX3. Investigations revealed borderline fT4 (12.6pmol/l), normal TSH and undetectable GH on glucagon stimulation with normal cortisol levels. MRI brain showed anterior pituitary hypoplasia and ectopic posterior pituitary. Thyroxine and GH replacement have been initiated.

Conclusion: These cases expand our knowledge of the clinical phenotype associated with SOX3 duplication in boys. Array CGH is recommended in boys with hypopituitarism and intellectual disability.