Characterization of the<i>CYP11A1</i>Nonsynonymous Variant p.E314K in Children Presenting With Adrenal Insufficiency

Kolli, Vipula; Kim, Hannah; Torky, Ahmed; Lao, Qizong; Tatsi, Christina; Mallappa, Ashwini; Merke, Deborah P.

doi:10.1210/jc.2018-01661

Cited by 28 publications

(20 citation statements)

References 22 publications

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“…Consistent with previous reports, pubertal development (although delayed in the two older brothers) was normal in the sibship, with normal testicular volumes and Leydig cell function (19,24,25,26).…”

Section: Discussionsupporting

confidence: 91%

“…The partial nature of P450scc deficiency in this family is consistent with most of the published cases with similar genetic findings (19,24,25,26).…”

Section: Discussionsupporting

confidence: 90%

“…Classic deficiency presents with severe earlyonset adrenal insufficiency in the neonatal period and female external genitalia in 46,XY individuals (11,13,14,15,16,17,18,19). Partial defects result in late-onset adrenal insufficiency or glucocorticoid insufficiency alone, associated with either normal genitalia or variable degrees of underandrogenisation (11,15,19,20,21,22,23,24,25).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Maharaj and colleagues reported that the missense mutation rs6161, c.940G>A, p.Glu314Lys, previously predicted to be a benign variant, results in PAI in the context of compound heterozygosity when combined with variations harboring disruptive changes (26). In all, 28 cases of P450scc deficiency related to the presence of the rs6161, c.940G>A, p.Glu314Lys variant have been described, 19 by Maharaj et al (26) and 9 from other centres (19,24,25).…”

Section: Introductionmentioning

confidence: 99%

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

Kallali

Gray²,

Mehdi

et al. 2020

European Journal of Endocrinology

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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.

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Section: Discussionsupporting

confidence: 91%

“…The partial nature of P450scc deficiency in this family is consistent with most of the published cases with similar genetic findings (19,24,25,26).…”

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Kallali

Gray²,

Mehdi

et al. 2020

European Journal of Endocrinology

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“…As with NCLAH, long‐term monitoring of sex hormone production and fertility is warranted at puberty and in adulthood. Fertility has been reported in men, although raised gonadotrophins are sometimes seen, and testicular adrenal rest tumours (TART) can occur if glucocorticoid insufficiency is poorly controlled . Sperm banking might also be considered.…”

Section: Nonclassic Steroidogenic Disorders: Star and Cyp11a1mentioning

confidence: 99%

Primary adrenal insufficiency: New genetic causes and their long‐term consequences

Buonocore

Achermann

2019

Clinical Endocrinology

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Primary adrenal insufficiency (PAI) is a potentially life‐threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, more than 30 other physical and genetics cause of PAI have been reported. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about recurrence risk in siblings and relatives. Here, we describe some recent insights into the genetics of adrenal insufficiency and associated molecular mechanisms. We discuss (a) the role of the nuclear receptors DAX‐1 (NR0B1) and steroidogenic factor‐1 (SF‐1, NR5A1) in human adrenal and reproductive dysfunction; (b) multisystem growth restriction syndromes due to gain‐of‐function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1; (c) nonclassic forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed‐onset adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI; and (d) a new sphingolipidosis causing PAI due to defects in sphingosine‐1‐phosphate lyase‐1 (SGPL1). Reaching a specific diagnosis can have life‐long implications for management. In some situations, milder or nonclassic forms of these conditions can first present in adulthood and may have been labelled, “Addison's disease.”

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Disorders of Testosterone Synthesis

Sugandhi

2024

Children With Differences in Sex Development

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Characterization of theCYP11A1Nonsynonymous Variant p.E314K in Children Presenting With Adrenal Insufficiency

Cited by 28 publications

References 22 publications

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

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

Primary adrenal insufficiency: New genetic causes and their long‐term consequences

Disorders of Testosterone Synthesis

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