Long-term outcome of partial P450 side-chain cleavage enzyme deficiency in three brothers: the importance of early diagnosis

Kallali, W., Gray, E., Mehdi, M. Z., Lindsay, R. , Metherell, L. A., Buonocore, F., Suntharalingham, J. P., Achermann, J. C. and Donaldson, M. (2020) Long-term outcome of partial P450 side-chain cleavage enzyme deficiency in three brothers: the importance of early diagnosis. European Journal of Endocrinology, 182(3), K15-K24. (doi: 10.1530/eje-19-0696) (PMID:31917682)

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Abstract

Objective CYP11A1 mutations cause P450 side-chain cleavage (scc) deficiency, a rare form of congenital adrenal hyperplasia with a wide clinical spectrum. We detail the phenotype and evolution in a male sibship identified by HaloPlex targeted capture array. Family study The youngest of three brothers from a non-consanguineous Scottish family presented with hyperpigmentation at 3.7 years. Investigation showed grossly impaired glucocorticoid function with ACTH elevation, moderately impaired mineralocorticoid function, and normal external genitalia. The older brothers were found to be pigmented also, with glucocorticoid impairment but normal electrolytes. Linkage studies in 2002 showed that all three brothers had inherited the same critical regions of the maternal X chromosome suggesting an X-linked disorder, but analysis of NR0B1 (DAX-1, adrenal hypoplasia) and ABCD1 (adrenoleukodystrophy) were negative. In 2016, next-generation sequencing revealed compound heterozygosity for the rs6161 variant in CYP11A1 (c.940G>A, p.Glu314Lys), together with a severely disruptive frameshift mutation (c.790_802del, K264Lfs*5). The brothers were stable on hydrocortisone and fludrocortisone replacement, testicular volumes (15–20 mL), and serum testosterone levels (24.7, 33.3, and 27.2 nmol/L) were normal, but FSH (41.2 µ/L) was elevated in the proband. The latter had undergone left orchidectomy for suspected malignancy at the age of 25 years and was attending a fertility clinic for oligospermia. Initial histology was reported as showing nodular Leydig cell hyperplasia. However, histological review using CD56 staining confirmed testicular adrenal rest cell tumour (TART). Conclusion This kinship with partial P450scc deficiency demonstrates the importance of precise diagnosis in primary adrenal insufficiency to ensure appropriate counselling and management, particularly of TART.

Item Type:Articles
Additional Information:Funding: J C A is a Wellcome Trust Senior Research Fellow in Clinical Science (grants 098513/Z/12/Z and 209328/Z/17/Z) with research support from Great Ormond Street Hospital Children’s Charity (grant V2518) and the National Institute for Health Research, Great Ormond Street Hospital Biomedical Research Centre (grant IS-BRC-1215-20012). L A M is supported by funding from Barts Charity (grant MGU0438) and MRC (Project Grant MR/K020455/1).
Keywords:Endocrinology, diabetes and metabolism, endocrinology, general medicine.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kallali, Dr Wafa and Donaldson, Dr Malcolm and Lindsay, Dr Robert and Gray, Mr Ewan
Authors: Kallali, W., Gray, E., Mehdi, M. Z., Lindsay, R., Metherell, L. A., Buonocore, F., Suntharalingham, J. P., Achermann, J. C., and Donaldson, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Health Economics and Health Technology Assessment
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:European Journal of Endocrinology
Publisher:Bioscientifica
ISSN:0804-4643
ISSN (Online):1479-683X
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in European Journal of Endocrinology 182:K15-K24
Publisher Policy:Reproduced under a Creative Commons License

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