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

Abstract

Sphingosine-1-phosphate lyase (SGPL1) insufficiency syndrome (SPLIS) is an autosomal recessive multi-system disorder, which mainly incorporates steroid-resistant nephrotic syndrome and primary adrenal insufficiency. Further variable endocrine manifestations are described. We aimed to comprehensively annotate the endocrinopathies associated with pathogenic SGPL1 variants and assess for genotype-phenotype correlations by retrospectively reviewing reports of endocrine disease within our patient cohort and all published cases in the wider literature up to January 2022. Glucocorticoid insufficiency in early childhood is the most common endocrine manifestation affecting 64% of the 50 patients reported with SPLIS, a third of these individuals have additional mineralocorticoid deficiency. Whilst most individuals also have nephrotic syndrome, SGPL1 variants also account for isolated adrenal insufficiency at presentation. Primary gonadal insufficiency, manifesting with microphallus and cryptorchidism, is reported in less than one third of affected boys, all with concomitant adrenal disease. Mild primary hypothyroidism affects approximately a third of patients. There is paucity of data on the impact of SGPL1 deficiency on growth, and pubertal development, limited by the early and high mortality rate (approximately 50%). There is no clear genotype-phenotype correlation overall in the syndrome, with variable disease penetrance within individual kindreds. However, with regards to endocrine phenotype the most prevalent disease variant p.R222Q (affecting 22%) is most consistently associated with isolated glucocorticoid deficiency. We conclude that SPLIS is associated with significant multiple endocrine disorders. Whilst endocrinopathy in the syndrome generally presents in infancy, late onset disease also occurs. Screening for these is therefore warranted both at diagnosis and through follow-up.

Combined novel homozygous variants in both SGPL1 and STAT1 presenting with severe combined immune deficiency: case report and literature review

“…Children presenting early in life had a more severe clinical presentation with primary adrenal insufficiency or steroidresistant nephrotic syndrome being seen in the early postnatal period. Overall mortality rate is high, approaching 47% (17).…”

Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome: A Retrospective Cross-Sectional Study of 76 Patients

“…The rst reports of the monogenic cause of this condition in 2017 focused on two of the most common clinical features, namely steroid-resistant nephrotic syndrome (often associated with focal segmental glomerulosclerosis pathology), and primary adrenal insu ciency [5 6]. Adrenal insu ciency may include low glucocorticoids with or without low mineralocorticoids, and in boys may also include low testosterone levels leading to gonadal dysgenesis [7]. Other effects observed in SPLIS patients include peripheral neuropathy, central nervous system involvement, immune dysfunction, hypercholesterolemia, and ichthyosis or acanthosis [5 6 8 9].…”

Addison’s Disease: Diagnosis and Management Strategies

“…54 However, Maharaj et al found 50 cases and identified a 64% prevalence of AD. 68 Novel SGPL1 mutation has been reported in relationship with pediatric presentation without hyperpigmentation. 69 More than 200 NR0B1 mutations have been recorded so far.…”