Kallali, W;
Gray, E;
Mehdi, MZ;
Lindsay, RS;
Metherell, LA;
Buonocore, F;
Suntharalingham, JP;
... Donaldson, M; + view all
(2020)
Long-term outcome of partial P450 side-chain cleavage enzyme deficiency in three brothers: the importance of early diagnosis.
European Journal of Endocrinology
10.1530/EJE-19-0696.
(In press).
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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 rs6161variant 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 u/L) was elevated in the proband. The latter had undergone left orchidectomy for suspected malignancy aged 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.
| Type: | Article |
|---|---|
| Title: | Long-term outcome of partial P450 side-chain cleavage enzyme deficiency in three brothers: the importance of early diagnosis |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1530/EJE-19-0696 |
| Publisher version: | https://doi.org/10.1530/EJE-19-0696 |
| Language: | English |
| Additional information: | © 2019 The Authors 2019. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/deed.en_GB). |
| Keywords: | CYP11A1, P450 side-chain cleavage enzyme deficiency, primary adrenal insufficiency, testicular adrenal rest tumour |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10089521 |
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