ESPE Abstracts

Sphingosine 1-phosphate lyase insufficiency syndrome (SPLIS) was described in 2017 as a novel condition affecting sphingolipid metabolism, with bi-allelic loss of function mutations in SGPL1. There is a multisystemic phenotype including steroid resistant nephrotic syndrome and primary adrenal insufficiency (PAI) and to a lesser extent ichthyosis, neurological disease and lymphopenia. Hypogonadism is described amongst some affected patients. To interrogate the steroid hormone related-presentation we reviewed clinical data within our patient cohort with SPLIS and the wider literature. 46 patients have been diagnosed with SPLIS with significant associated mortality (n = 23/46, 51%; 4 of these in utero). A significant proportion (n = 28/46, 60%) presented with glucocorticoid deficiency, some of whom had additional mineralocorticoid deficiency (n = 7/28, 25%). The vast majority of those with PAI also had nephrotic syndrome (n = 24/28, 86%). However, amongst 3 kindreds, 3 patients presented with PAI alone, and 1 patient with PAI and neurological disease, interestingly with the same SGPL1 mutation, c.665 G>A; p.Arg222Gln. Nonetheless, 6 other patients with this mutation manifested both PAI and nephrotic syndrome. Five further patients had adrenal calcifications though biochemistry was not undertaken. Most patients presented with PAI in the first 2 years of life (n = 21/28), with the oldest presenting at 11 years. Adrenal calcifications were commonly described in those with documented imaging (n = 13/15, 87%). Primary gonadal failure was reported in 8 male cases, all with concomitant PAI. Presenting features included microphallus (n = 7/8) and cryptorchidism (n = 8/8), indicating reduced in utero androgen exposure. Hypospadias was not reported. All who had biochemical evaluation demonstrated raised basal LH and FSH/exaggerated response to LHRH stimulation, a lack of testosterone response to HCG stimulation and low antimullerian hormone (AMH) levels. To date there are no reports of pubertal delay in female patients, and they have normal ovarian reserve as evidenced by AMH levels (n = 2). SPLIS is unique amongst sphingolipid disorders in presenting with significant endocrinopathy. Early manifestations suggest an impact on in utero adrenal and gonadal development with late disease implying an effect on acute steroidogenesis. The pathological mechanism associated with this sphingolipid pathway disruption needs to be further explored. Investigation for SGPL1 mutations is warranted in PAI with nephrotic syndrome, but it should also be considered in the differential of PAI and 46XY DSD. Timely diagnosis allows for initiation of appropriate screening and therapeutics in the syndrome, with significant impact on morbidity and mortality.