SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency.

Multiple autosomal recessive genes have been etiologically linked to Primary Adrenal Insufficiency (PAI). Recently, SGPL1 gene mutations were recognized as causes of steroid-resistant nephrotic syndrome type 14 (NPHS14), a sphingolipidosis with multisystemic manifestations including PAI. Interestingly, this is the only monogenetic form of nephrotic syndrome (NS) and the sole sphingolipidosis causing adrenal disease.

To understand if SGPL1 mutations are involved in the pathogenesis of PAI in patients who do not exhibit NS.

Sequencing of the SGPL1 gene in 21 patients with familial glucocorticoid disease or triple A syndrome.

We identified two missense SGPL1 variants in four patients, two being first-cousins. We describe in detail the proband, a boy born to Saudi Arabian consanguineous parents with a homozygous c.665G>A, p.R222Q SGPL1 variant. The patient presented with hypoglycemia and seizures at age two years and was ultimately diagnosed with PAI (isolated glucocorticoid deficiency). A brain MRI showed abnormalities in the basal ganglia consistent with a degenerative process albeit the patient had no neurological symptoms.

New genetic causes of PAI continue to be identified. We suggest that screening for SGPL1 mutations should not be reserved only for patients with nephrotic syndrome but may also include patients with PAI that lack other clinical manifestations of NPHS14 since, in certain cases, kidney disease and accompanying features might develop later on. Timely diagnosis of this specific sphingolipidosis, while the kidneys still function normally, can lead to prompt initiation of therapy and improve outcome especially, if a targeted NPHS14-treatment is available in the future.

The Journal of clinical endocrinology and metabolism. 2018 Dec 03 [Epub ahead of print]

Nikolaos Settas, Rebecca Persky, Fabio R Faucz, Nicole Sheanon, Antonis Voutetakis, Maya Lodish, Louise A Metherell, Constantine A Stratakis

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics & Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Division of Pediatric Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio., Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom.