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Endocrine Abstracts (2016) 44 OC1.1 | DOI: 10.1530/endoabs.44.OC1.1

1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK; 2KULeuven, LIPIT, Leuven, Belgium; 3UCL Institute of Child Health, London, UK; 4Centro de Investigaciones, CONICET – FEI – División de Endocrinología Endocrinológicas “Dr. César Bergadá” (CEDIE), Hospital de Niños R. Gutierrez, Buenos Aires, Argentina; 5Unidad de Nefrología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; 6Department of Paediatric Endocrinology, Alder Hey Children’s Hospital, Liverpool, UK; 7Department of Paediatric Endocrinology, Birmingham Children’s Hospital, Birmingham, UK; 8Bristol Children’s Renal Unit, Bristol Royal Hospital for Children, Bristol, UK; 9Department of Pediatric Endocrinology and Diabetes, Health Sciences University, Suleymaniye Maternity and Children’s Training and Research Hospital, Istanbul, Turkey; 10Department of Pediatric Endocrinology and Diabetes, Gulhane Military Medical School, Ankara, Turkey; 11Department of Pediatric Endocrinology and Diabetes, Marmara University, Pendik Education and Research Hospital, Istanbul, Turkey; 12Section for Endocrinology, Aga Khan University, 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 rendering their prognosis uncertain. We 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 2.5 y, requiring a kidney transplant aged 5 y. A younger sibling with similar clinical history (not sequenced) died (4 y) whilst an older sibling (8 y) and cousin (3 y) have only PAI. Kindred 2, a child presenting with PAI had the p.R222Q mutation and has no renal phenotype at 3.7 y. Kindred 3, a female baby presenting with PAI (6 m) had a novel in-frame deletion, (c.1633_1635delTTC; p.F545del) and developed FSGS (5 y) on follow-up, additional features included ichthyosis and neurological symptoms. Kindred 4, two affected siblings manifesting PAI and nephrotic syndrome (<1 yr) had a canonical splice site change, (c.261+1G>A; p.?), the male sibling additionally has micropenis, unilateral cryptorchidism, ichthyosis and 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.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

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