ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2013) 33 P6 | DOI: 10.1530/endoabs.33.P6

Severe 21-hydroxylase deficiency congenital adrenal hyperplasia and congenital hypothyroidism due to thyroglobulin mutations in a single family: two distinct genetic disorders with phenotypic variability within a single family

Caroline Ponmani1, Nadia Schoenmakers2, Gill Rumsby3, Adeline K Nicholas2, Krishna Chatterjee2 & Mehul Dattani1


1Great Ormond Street Hosiptal, London, UK; 2University of Cambridge, Cambridge, UK; 3University College London Hospital, London, UK.


Background: 21-Hydroxylase deficiency due to mutations in CYP21A2 represents the commonest form of congenital adrenal hyperplasia (CAH). Dyshormonogenetic congenital hypothyroidism (CH) may be due to TPO, TG, DUOX2, DUOXA2, IYD, SLC5A5 and SLC26A4 mutations.

Case report: Two of six children born to unrelated parents presented in the neonatal period with salt-losing CAH due to compound heterozygosity in CYP21A2 (maternally derived intron two splice mutation, paternally-derived p.Ile172Asn). Congenital hypothyroidism was diagnosed in both by neonatal screening. Next generation sequencing recently demonstrated compound mutations in the thyroglobulin gene (TG): p.R277X and p.T1397Rfs*30. A third sibling presented with pubic hair and body odour since 7 years of age, and had a simple virilising form of CAH (normal plasma renin, aldosterone and thyroid function; genetic analysis awaited), treated with hydrocortisone.

The oldest sibling, a female now aged 17, has learning difficulties and is short (height SDS −2.60) with severe obesity (BMI 52.5), insulin insensitivity, severe virilisation with marked hirsutism, primary amenorrhoea and voice changes, and polycystic ovarian disease, due to poor compliance with medication (currently on dexamethasone, 9-α-fludrocortisone, metformin, flutamide and thyroxine). Pelvic ultrasound and abdominal MRI revealed bilaterally enlarged adrenals with a probable right adrenal adenoma, probably due to chronic ACTH stimulation. Her 13-year-old brother is currently on hydrocortisone, fludrocortisone and thyroxine (height SDS −0.90, weight SDS +1.39, and BMI SDS +2.63). His compliance is also erratic, and he is being treated with GnRH analogue for gonadotrophin-dependent precocious puberty.

Conclusions: In this unusual pedigree, three siblings manifested two different forms of CAH, and the older siblings show inheritance of two distinct genetic disorders, namely CAH and CH due to TG mutations. Finally, this case illustrates the importance of optimal disease control in CAH; poor compliance with chronically elevated ACTH concentrations may have resulted in an adrenal adenoma in the older sibling.