Neonatal Wolfram Syndrome: Novel De-novo Dominant Mutation Presenting as an Unusual Clinical Phenotype

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 596-623-Case Reports: Pediatric Endocrinology & Metabolism
Clinical
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-612
David Zangen*1, Abdulsalam Abulibdeh2, Ranit Jaron3, Tom Walsh4, mary-Claire King5 and Efrat Levy-Lahad3
1Hadassah Hebrew Univ Med Ctr, Jerusalem, Israel, 2Hadassah Hebrew University Medical Center, Jerusalem, Israel, 3Shaare Zedek Medical Center, Jerusalem, Israel, 4University of.Washington, Seattle, WA, 5University of Washington, Seattle, WA
Background: Wolfram, known also as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) syndrome (WS) is a rare neurodegenerative disorder resulting usually from biallelic WFS1 gene mutations. Diabetes mellitus usually its first symptom, rarely presents prior to 1y of age.

Clinical and molecular studies: Exome sequencing was performed on a 5.9 years old boy from a consanguineous Palestinian family. He presented neonatally at 40d of age with persistent neonatal diabetes, bilateral cataracts, congenital (prelingual) deafness and left hydronephrosis.  During follow up he developed failure to thrive, microcephaly, severe psychomotor retardation, seizures, severe scoliosis and bilateral lower limbs contractures. Laboratory investigations revealed normal serum electrolytes, lipase and thyroid function tests, normal urine osmolality, low serum insulin levels, negative anti insulin antibodies,  normal pancreas by sonogram, 46,XY karyotype, and normal  sequencing of the KiR6.2  gene. Whole exome sequencing revealed a heterozygous, c.923 C>T (p. S308F) novel, de-novo, missense mutation in an evolutionary conserved amino acid of WFS1; that  was defined damaging by predicting softwares. Although wolframin 1’s function has not been established its known formation as an oligomer suggests, that a dominant negative effect may cause the severe phenotype

Conclusion: A novel de-novo heterozygous WFS1 mutation causes a unique and severe WS with cataracts, deafness and diabetes mellitus presenting neonatally. The clinical application of next-generation sequencing technology enhanced the diagnosis of a rare genetic disorder in a patient with atypical presentation and may have a role in defining new clinical manifestations of rare syndromes, such as WS.

Nothing to Disclose: DZ, AA, RJ, TW, MCK, EL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm