ESPE Abstracts

Background: Multiple autosomal recessive genes have been linked to primary adrenal insufficiency (PAI). Recently, sphingosine-1-phosphate lyase 1 (SGPL1) gene mutations were recognized as a cause of sphingolipidosis with multisystemic manifestations, including PAI. Sphingosine phosphate lyase (SGPL1) insufficiency syndrome (SPLIS) is characterized by steroid-resistant nephrotic syndrome, primary adrenal insufficiency (PAI), neurological deterioration, immunodeficiency, and other endocrine abnormalities. Autosomal recessive SGPL1 gene variants have been linked to SPLIS, with undefined genotype-phenotype correlation and intrafamilial variability. The intracellular enzyme SGPL, mediates sphingolipid degradation, crucial for cell migration, survival, and proliferation. The exact mechanism of adrenal insufficiency remains unknown; however, it was hypothesized that accumulation of sphingolipid intermediates such as the bioactive S1P interferes with steroid biosynthesis.

Case report: a 9-year-old boy, born to consanguineous Pakistani parents, with mute past medical history. He presented with abdominal pain, thinness, distended abdomen, mildly hyperpigmented palmar creases and oral mucosa. Laboratory tests showed low cortisol and elevated ACTH levels, consistent with glucocorticoid deficiency (ACTH 1676 pg/ml, cortisol 6.31 mcg/dl), normal levels of renin and aldosterone, lymphopenia, and hypogammaglobulinemia. Radiological investigations revealed generalized lymphadenopathy, mostly abdominal, and ileitis. No blasts were detected on peripheral blood. Addison disease, adrenal tuberculosis, and adrenoleukodystrophy were excluded. Treatment with hydrocortisone and empirical antibiotics was started. During the last follow up, at the age of 9.9 years he showed subclinical hypothyroidism with TSH 9.49 mcUI/mL, FT4 1.27 ng/dl, negative anti-TPO antibodies, low levels of DHEAS 2.6 µg/dl (normal values 24-247), low levels of testosterone and Delta4-Andreostenedione with normal electrolytes sodium 137 mEq/L, Potassium 4.71 mEq/L.

Results: Next-generation sequencing targeted panels for PAI in the trio, detecting the homozygous missense variant c.946G>A in the SGPL1 gene, chromosome 10q22.1, that corresponds to p.Ala316Thr in the protein, with biparental segregation, classified as a variant of uncertain significance.

Conclusion: Subjects with SGPL1 gene mutations have varying degrees of adrenal insufficiency, isolated glucocorticoid deficiency as in this patient but also total primary adrenal deficiency. This novel homozygous variant is characterized by predominant immunological and endocrinological anomalies with isolated glucocorticoid deficiency and subclinical hypothyroidism, with normal renal and neurological function.