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

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.

Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years’ Experience in the UK

“…Appropriate monitoring and counseling can be provided, and cryopreservation of sperm might be considered. There are reports of testicular adrenal rest tumors with poor control in some of these conditions too [ 46 , 47 ]. Patients with triple A syndrome often present with additional features such as alacrima (93% of all patients, 64% of them within the first 36 months of life), achalasia (86% of all patients with an average age of 6.4 years), dermatological symptoms (71% of all patients), and neurological symptom (72% of all patients) [ 48 ].…”

Disorders of Sex Development: Classification, Review, and Impact on Fertility

“…As the StAR protein plays a crucial role in steroidogenesis by accelerating the transport of cholesterol to the inner mitochondrial membrane, where the cytochrome P450scc enzyme is found, mutations of StAR [107,108], as well as of the P450scc enzyme [106,109,110] or the CYP11A1 gene that encodes it (chromosome 15), are causes of this disorder. Recently, Kallali et al [111] studied three siblings with partial P450scc deficiency, highlighting the importance of an accurate diagnosis in primary adrenal insufficiency to ensure adequate counseling and management, particularly of TARTs. Piya et al [112] also presented a patient with ambiguous genitalia, a salt-loss crisis within two weeks after birth, and low cortisol levels, with a mutation or absence of exon 1 of StAR.…”

Atypical Presentation of Testicular Adrenal Rest Tumor (TART) Leading to Bilateral Partial Orchiectomy in a 31-Year-Old Adult Revealing Primary Adrenal Insufficiency with CYP11A1 Deficiency

“…TARTs were mainly described in defects in 21-hydroxylase, which are the most frequent enzymatic blocks representing 90 to 94% of CAH [ 1 , 3 ]. TARTs can be present in other blocks, such as in 17alpha hydroxylase, P450Scc, 3 beta-hydroxysteroid dehydrogenase, and 11 beta-hydroxylase deficiencies [ 4 ]. TARTs can never occur in adrenal insufficiency of autoimmune origin, despite high rates of ACTH [ 4 ].…”