ESPE Abstracts (2014) 82 P-D-1-2-4

Mineralo and Glucocorticoid Deficiency in Early Infancy are Caused by a Founder Novel Mutation in the Nicotinamide Nucleotide Transhydrogenase Gene

Abdulsalam Abu-Libdeha, Ariella Weinberg-Shukronb,c, Sharon Zeligsonb, Fouad Zhadehd, Liran Carmelb, Paul Renbaumb,c, Ephrat Levy-Lahadb,c & David Zangena

aDivision of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel; bMedical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel; cHadassah Medical School, Hebrew University, Jerusalem, Israel; dEdmond J. Safra Campus, Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel

Background: Nicotinamide nucleotide transhydrogenase (NNT) gene mutations have been recently shown to cause familial glucocorticoid deficiency (FGD), by decreasing reactive oxygen species (ROS) detoxification in adrenocortical cells. Affected infants present within the first few months with isolated glucocorticoid deficiency.

Objective and Hypotheses: To study the genetic etiology of four cases presenting uniquely with neonatal addisonian crisis (both mineralo and glucocorticoid deficiency).

Clinical presentation and method: Palestinian male infant with normal external genitalia born to consanguineous parents, presented neonatally with Na: 118, K: 6 mmol/l, decreased basal and ACTH stimulated cortisol and 17-hydroxyprogesterone, normal infantile testosterone, and elevated plasma renin activity (>15 ng/ml per h). Two female cousins and another unrelated female neonate presented with similar manifestations. Whole exom next generation sequencing was performed on two affected cousins from the first kindred. Functional assessment of ROS detoxification capacity by was performed on skin biopsy derived cultured fibroblasts using the ’7’2dichlorodihydroflourescein (DCF) method.

Results: Whole exom sequencing revealed a G200S homozygous mutation in NNT gene. The homozygous variant found segregated with the disease in both unrelated families, and all four pairs of parents were heterozygous. Haplotype analysis revealed a founder effect while the mutation was not found in 100 alleles from ethnically matched controls. Expression studies of the ROS detoxification capacity in fibroblasts revealed an increase in ROS production in the fibroblasts derived from affected patients when compared to controls.

Conclusion: The founder and novel G200S mutation in the very recently described NNT gene causes uniquely early-infantile-severe mineralo and glucocorticoid deficiency. NNT mutations should be added to the differential diagnosis of neonatal addissonian crisis. ROS detoxification capacity is reduced in patients with the G200S NNT mutation. Given the ubiquitous nature of NNT, further studies of various mutations are required to elucidate the specific target organs prone to develop pathologies in relation to their impaired antioxidant defense.

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