ESPE Abstracts (2016) 86 FC15.2

aCentre for Endocrinology, Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK; bKULeuven, LIPIT, Leuven, Belgium; cDepartment of Genetics and Genomic Medicine, University College London Institute of Child Health, London, UK; dServicio de Nefrologia, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; eCentro de Investigaciones Endocrinológicas (CEDIE, Dr. Cesar Bergadá; CONICET- FEI – Division de Endocrinologia, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; fDepartment of Paediatric Endocrinology, Alder Hey Children’s Hospital, Liverpool, UK; gDepartment of Paediatric Endocrinology, Birmingham Children’s Hospital, Birmingham, UK; hBristol Children’s Renal Unit, Bristol Royal Hospital for Children, Bristol, UK; iDepartment of Pediatric Endocrinology and Diabetes, Health Sciences University, Suleymaniye Maternity and Children’s Training and Research Hospital, Istanbul, Turkey; jDepartment of Pediatric Endocrinology and Diabetes, Gulhane Military Medical School, Ankara, Turkey; kDepartment of Pediatric Endocrinology and Diabetes, Marmara University, Pendik Education and Research Hospital, Istanbul, Turkey; lSection of Endocrinology, Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan

Background: Primary adrenal insufficiency (PAI) is most commonly congenital in children. PAI is genetically heterogeneous with some gene defects causing syndromic disease. A third of patients have no genetic diagnosis meaning their prognosis is uncertain. We recently investigated families with a novel combination of PAI and steroid resistant nephrotic syndrome.

Objective and hypotheses: To discover the genetic defect underlying this syndrome.

Method: Whole exome sequencing (WES) was performed in two families with Sanger sequencing of SGPL1 to confirm segregation and screen further families.

Results: By WES and Sanger sequencing three different mutations in SGPL1 were identified in four families. All mutations were homozygous in affected individuals and heterozygous in their asymptomatic parents. Kindred 1, three patients had a novel missense mutation [c.665G>A; p.R222Q], the index case presented with PAI (8 m), developed focal segmental glomerulosclerosis (FSGS) at 2.5y and received a kidney transplant aged 5y. A younger sibling with similar clinical history (not sequenced) died (4y) whilst an older sibling (8y) and a cousin (3y) have only PAI. Kindred 2, a child presenting with PAI had the p.R222Q mutation and at age 3.7y has no renal phenotype. Kindred 3, a female baby presenting with PAI (6 m) had a novel in-frame deletion, [c.1633_1635delTTC; p.F545del] and developed FSGS (5y) on follow-up, additional features included ichthyosis and neurological symptoms. Kindred 4, two affected siblings manifesting PAI and nephrotic syndrome (<1yr) had a canonical splice site change, [c.261+1G>A; p.?], the male sibling additionally presented with micropenis, unilateral cryptorchidism, ichthyosis and developed neurological symptoms.

Conclusion: We have identified a novel, potentially progressive, disorder incorporating PAI and nephrotic syndrome amongst other features. This novel syndrome highlights the importance of the sphingolipid metabolic pathway in adrenal function. A genetic diagnosis for patients with this form of PAI is important for correct treatment, genetic counselling and screening for co-morbidities.

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