Steroid Hormone Profiles and Molecular Diagnostic Tools in Pediatric Patients With non-CAH Primary Adrenal Insufficiency

Abstract

Background There is a significant challenge of attributing specific diagnoses to patients with primary adrenal insufficiency of unknown etiology other than congenital adrenal hyperplasia (non-CAH PAI). Specific diagnoses per se may guide personalized treatment or may illuminate pathophysiology. Objective Investigation of the efficacy of steroid hormone profiles and high-throughput sequencing methods in establishing the etiology in non-CAH PAI of unknown origin. Design Paediatric patients with non-CAH PAI whose etiology could not be established by clinical and biochemical characteristics were enrolled. Genetic analysis was performed using targetedgene panel sequencing (TPS) and whole-exome sequencing (WES). Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. Setting Eighteen pediatric endocrinology clinics. Patients Forty-one patients (17 females, median age: 3 months, range: 0-8 years) with non-CAH PAI of unknown etiology. Results A genetic diagnosis was obtained in 29 (70.7%) patients by TPS. Further molecular diagnosis could not be achieved by WES. Compared to healthy control group, patients showed lower steroid concentrations, most significantly in cortisone, cortisol, and corticosterone (p<0.0001, area under the ROC curve: 0.96, 0.88, 0.87, respectively). Plasma cortisol<4 ng/mL, cortisone<11 ng/mL, and corticosterone<0.11 ng/mL had >95% specificity to ensure the diagnosis of non-CAH PAI of unknown etiology. Conclusion Steroid hormone profiles are highly sensitive for the diagnosis of non-CAH PAI of unknown etiology, while they are unlikely to point out a specific molecular diagnosis. TPS is an optimal approach in the molecular diagnosis of these patients with high efficacy, while little additional benefit is expected from WES.

A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review

“…Thirty-two patients (64% of the 50 patients) presented with biochemical evidence of PAI, with a male to female preponderance of approximately 1.7:1 (overall male to female preponderance in the syndrome being 1.3:1) ( Fig. 3 and Table 1 ) ( 2 , 3 , 4 , 6 , 7 , 8 , 9 , 10 , 17 , 18 , 19 , 20 , 21 ). The median age of PAI presentation among boys was 1 year (range, 0–6.5 years) and for girls 0.55 years (range, 0.17–11 years).…”

“…Most patients presented with PAI in the first 2 years of life (81%; median age, 1 year; range, 0–11 years). Ten of the children with glucocorticoid deficiency had additional mineralocorticoid deficiency (31%) ( 4 , 6 , 7 , 8 , 20 , 21 ). The majority had PAI with concomitant nephrotic syndrome, and in most cases (12 out of 27 patients), nephrotic syndrome preceded adrenal insufficiency by a median time of 0.3 years (range, 0.08–10.2 years).…”

“…In the remaining seven patients, nephrotic syndrome developed after the PAI diagnosis by a median time of 1.9 years (range, 0.08–12.5 years), highlighting the need for surveillance of evolving disease. In 13 children where adrenal imaging was reported, 69% were noted to have adrenal calcifications ( 2 , 3 , 4 , 5 , 7 , 9 , 20 , 21 ). In addition, five further patients had detectable adrenal calcifications on ultrasonography, although a biochemical diagnosis of adrenal failure was not provided ( 2 , 3 , 5 ) ( Table 1 ).…”

“…Primary hypothyroidism, with mildly raised thyroid-stimulating hormone (TSH) and low free-T4, has been reported in 17 patients ( Table 3 ) ( 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 20 , 21 ). Goitres are not a usual feature of disease (reported in only one individual) and normal parenchyma is seen on thyroid ultrasound imaging ( 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 21 ).…”

“…Since the initial descriptions of the syndrome in 2017, several case series and reports have been published, totalling 50 patients ( 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 16 , 17 , 18 , 19 , 20 , 21 ). It is clear that the endocrine phenotype within this rare disease extends beyond PAI, and in contrast to other disorders of sphingolipid metabolism, SPLIS is associated with multiple endocrinopathies.…”