ESPE Abstracts (2014) 82 P-D-2-2-274

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 Ponmania,b, Abigail Atterburyb, Senthil Seniappanc, Nadia Schoenmakersd, Adeline K Nicholasd, Krishna Chatterjeed & Mehul Dattanib


aQueens Hospital Romford, London, UK; bGreat Ormond Street Hospital, London, UK; cAlderhey Children’s Hospital, Liverpool, UK; dUniversity of Cambridge Metabolic Laboratories, Cambridge, 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.

Objective and hypotheses: We report a kindred with three siblings born to unrelated parents manifesting with two different forms of CAH. The older siblings presented in the neonatal period with salt losing CAH due to compound heterozygosity in CYP21A2 gene (maternally derived intron 2 splice mutation, paternally-derived p.Ile172Asn). The third sibling, presented at the age of 7 years with premature pubarche, has a simple virilising form of CAH. CH was diagnosed in both older siblings by neonatal screening. Next generation sequencing recently demonstrated compound mutations in the thyroglobulin gene (TG): p.R277X and p.T1397Rfs*30.

Method: 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, hirsutism, primary amenorrhoea, voice changes, and polycystic ovarian disease, due to poor compliance with medication. Her 13-year-old brother is currently on hydrocortisone, fludrocortisone and thyroxine (height SDS: −0.90, weight SDS: +1.39, BMI SDS: +2.63). His compliance is also erratic, and he is being treated with GnRH analogue for gonadotrophin-dependent precocious puberty.

Results: Abdominal MRI in the older sibling revealed bilaterally enlarged adrenals with a probable right adrenal adenoma, probably due to chronic ACTH stimulation.

Conclusion: 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.