SFEBES2016 Oral Communications Early Career Oral Communications (6 abstracts)
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.
07 Nov 2016 - 09 Nov 2016