Primary adrenal insufficiency (PAI) is a disorder issued from a deficient production of glucocorticoids and/or mineralocorticoids that are normally synthesized in the adrenal cortex [1-3]. Cholesterol side-chain cleavage enzyme (P450scc) is an enzyme that initiates steroid hormone biosynthesis and is encoded by the
A 13-day-old female infant was hospitalized to Seoul National University Bundang Hospital with chief complaints of decreased oral intake and feeding cyanosis. She was delivered at 38 weeks of gestation, weighing 2.2 kg, without any perinatal complications. She was the second child of healthy non-consanguineous parents. Newborn screening for inborn error of metabolism showed a normal level of 17-alpha-hydroxyprogesterone (17-OHP). At admission, the patient’s height was 47 cm (–0.7 000 standard deviation score [SDS]), and weight was 2.0 kg (–2.6 SDS). On physical examination, her external genitalia appeared normal. Blood tests revealed hyperkalemia (9.5 mmol/L) and hyponatremia (125 mmol/L). She had elevated adrenocorticotropic hormone (ACTH) (531 pg/mL; reference range, 0-60), and increased plasma renin activity (84.5 ng/mL/h; reference range, 2.0-35.0). A standard-dose ACTH stimulation test (using 0.125 mg of synacthen [ACTH-(1-24)]) showed poor responses of cortisol and 17-OHP (Table 1). Adrenal imaging by ultrasonography revealed normal-sized adrenals. After the diagnosis of glucocorticoid and mineralocorticoid deficiency was made, hydrocortisone with 0.8 mg three times per day (15.0 mg/m2/d), and 9α- fludrocortisone with 0.1 mg once daily were prescribed to the patient.
The patient’s karyotype was 46,XX. Whole exome sequencing was done on a NextSeq 500 system (Illumina Inc.,) with 2×150 paired-end reads. Reads were aligned to the human genome build 37 (Hg19). A novel homozygous frameshift variant of
While taking hydrocortisone and 9α-fludrocortisone, she showed catch-up growth and a stable clinical course without adrenal crisis. On her latest visit (5 years and 3 months of age), she was prescribed hydrocortisone, 3.3 mg three times per day (12.0 mg/m2/d), and 9α-fludrocortisone (0.1 mg daily). Her height was 104.0 cm (–1.4 SDS), and her weight was 23.3 kg (–1.5 SDS). She had normal plasma renin activity (0.9 ng/mL/h; reference range, 1.0–6.5) but had high ACTH levels (715 pg/mL; reference range, 0–60) without hypoglycemia or electrolyte imbalance (blood glucose 87 mg/dL, sodium 139 mmol/L, and potassium 4.3 mmol/L, respectively) (Table 1).
P450scc deficiency is an extremely rare cause of PAI and results from defects in the
To our knowledge, approximately 60 cases of P450scc deficiency caused by
The diagnosis of PAI in pediatric patients is often delayed as many symptoms and signs of PAI are nonspecific. In cases of normal 17-OHP levels, genetic analysis can be helpful in diagnosing rare causes of PAI, including CLAH, X-inked adrenoleukodystrophy, and P450scc deficiency as in this case who developed symptoms early in their infancy [3,5,12,13]. In conclusion, the diagnosis of P450scc deficiency in our case was established through a comprehensive genetic analysis that combined exome sequencing and a SNP array. This underscores the critical role of genetic analysis in uncovering the rare etiologies underlying PAI. Furthermore, our case serves as an illustrative example of the potential for UPD to reveal recessive disorders such as
The authors declare that they do not have any conflicts of interest.
The authors thank the patient and her parents, who consigned to participate in this report.
Conception and design: CWC, JK. Acquisition of data: YJK, SC, HYK, YHJ, JMK, CWC, JK. Analysis and interpretation of data: HWK, JMK. Drafting the article: YJK, SC. Critical revision of the article: YJK, HWK, JK. Final approval of the version to be published: YJK, SC, HYK, YHJ, JMK, CWC, JK.
Clinical and hormonal data
|Items||Baseline||Latest visit||Normal age range (basal)|
|Age||13 days||5 yrs and 3 mos||NS|
|Height, cm (SDS)||47 (–0.7 )||47 (–0.7 )||NS|
|Weight, kg (SDS)||2.0 (–2.6 )||47 (–0.7 )||NS|
|External genitalia||Normal female||Normal female||NS|
|Blood glucose, mg/dL||71||87||70-110|
|Cortisol, μg/dL (basal/post ACTH)||3.5/8.2||11.0/ND||2-11|
|17OH-Progesterone, ng/mL (basal/post ACTH)||0.5/1.2||ND||0.1-0.8|
|Plasma renin activity, ng/mL/h||84.5||0.9||2.0-35.0|
SDS, standard deviation score; ACTH, adrenocorticotropic hormone; ND, Not done; NS, not significant.