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

Background: Mutations in the NNT (Nicotinamide Nucleotide Transhydrogenase) gene has been just recently shown to cause familial glucocorticoid deficiency (FGD), probably by decreasing the rate of reactive oxygen species (ROS) detoxification in adrenocortical cells. Affected individuals typically present within the first few months of life with isolated glucocorticoid deficiency. We report a novel mutation in NNT gene, in two Palestinian kindreds presenting uniquely with neonatal addisonian crisis (both mineralo and glucocorticoid deficiency) in 4 cases. Clinical data: Family A: A Palestinian male infant with normal male external genitalia born to consanguineous parents, presented in the neonatal period with addisonian crisis, Na: 118, and K:6. mmol/l, decreased basal and ACTH stimulated Cortisol and 17 hydroxyprogesterone (2.3- 2.32ug/dl and 1 - 1.2ng/ml respectively), normal infantile Testosterone at 0.72ng/ml, and elevated Plasma Renin Activity at >15ng/ml/hr. Two female cousins had similar manifestations. Family B: A female neonate from consanguineous kindred presented with a similar phenotype. Results: Whole exom sequencing in two affected cousins from family A revealed a G200S homozygous mutation in NNT gene in both individuals. The variant segregated with the disease in the family: the other affected cousin was homozygous, and in all three pairs of parents were heterozygous. In family B the affected patient was also homozygous G200S and her parents were heterozygotes. Haplotype analysis and expression studies studying the ROS detoxification capacity in fibroblasts are underway. Conclusion: The novel G200S mutation in the very recently described NNT gene causes a unique early infantile addisonian crisis with both mineralo and glucocorticoid deficiency. NNT mutations should be added to the differential diagnosis of neonatal addissonian crisis. Given the ubiquitous nature of this protein, further studies are required to elucidate the specific target organs for various NNT mutations. Over time, affected individuals may develop other organ pathologies related to impaired antioxidant defense and will therefore need careful monitoring.