SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency.

This is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Clinical Endocrinology & Metabolism following peer review. The version of record Settas, N., et al. (2018). "SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency." The Journal of Clinical Endocrinology & Metabolism: jc.2018-02238-jc.02018-02238. is available online at: https://doi.org/10.1210/jc.2018-02238Context 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. Objective To understand if SGPL1 mutations are involved in the pathogenesis of PAI in patients who do not exhibit NS. Methods Sequencing of the SGPL1 gene in 21 patients with familial glucocorticoid disease or triple A syndrome. Results 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. Conclusions 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.Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (project number Z1A HD008920)National Institute of Child Health and Human Development http://dx.doi.org/10.13039/100000071, Z1A HD008920, Constantine A. Strataki

X-linked acrogigantism syndrome : Clinical Profile and Therapeutic responses

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors.We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27months), patients had a median height and weight standard deviation scores (SDS) of > +3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despitemoderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in allfive cases where it was employed. X-LAGis anewinfant-onset gigantismsyndrome thathas a severe clinical phenotype leading to challenging disease management