Intrafamilial phenotypic variability in pediatric Wolfram syndrome associated with a homozygous WFS1 p.(Tyr669Ter) variant: a Palestinian family case series

Abstract

Wolfram syndrome is a rare, progressive multisystem disorder most commonly caused by biallelic pathogenic variants in WFS1 . It is classically characterized by early-onset diabetes mellitus and optic atrophy, with variable auditory, urinary, renal, endocrine, and neurological involvement. Manifestations may differ among relatives carrying the same pathogenic variant, creating diagnostic and surveillance challenges. We report four related Palestinian girls from two nuclear families connected through a double-sibship marriage pattern. Neither parental couple reported known consanguinity. All four children were homozygous for the pathogenic nonsense WFS1 variant NM_006005.3:c.2007T > G; p.(Tyr669Ter), developed diabetes mellitus between 11 months and 2 years of age, and required insulin treatment. Their currently documented extra-pancreatic manifestations differed. Case 1 had optic-disc pallor suggestive of optic atrophy, severe neurogenic bladder with bilateral hydronephrosis, chronic kidney disease, sensorineural hearing loss, growth impairment, and delayed or slowly progressing puberty with elevated gonadotropins raising concern for gonadal dysfunction. Polyuria, polydipsia, and low urine specific gravity raised concern for arginine vasopressin deficiency, but formal confirmation was not completed. Case 2 had neurogenic bladder with bilateral hydronephrosis, mild conductive hearing loss of uncertain relationship to Wolfram syndrome, and co-occurring congenital heart disease. Case 3 had mild optic-disc atrophy documented on formal ophthalmologic assessment, with mildly decreased visual acuity in the right eye and 6/6 in the left eye; audiological assessment was normal, and renal ultrasonography showed no hydronephrosis. Case 4 had infantile-onset diabetes mellitus and moderate optic-disc atrophy, with severely decreased visual acuity in both eyes and retinal nerve fiber layer thinning on optical coherence tomography. She also had co-occurring unilateral cleft lip and palate and tetralogy of Fallot requiring surgical and catheter-based interventions, with repeat cardiac catheterization and pulmonary dilatation planned. All four parents were heterozygous carriers of the familial variant. These cases demonstrate intrafamilial variability in the pattern and severity of currently documented manifestations among children carrying the same homozygous WFS1 variant. Differences in age, surveillance timing, and completeness of assessment limit conclusions regarding lifetime disease severity. The findings support genetic evaluation, family screening, and individualized multidisciplinary surveillance in children with early-onset diabetes mellitus, particularly when available islet-autoantibody tests are negative, family clustering is present, or extra-pancreatic manifestations emerge. The cardiac and craniofacial abnormalities should remain regarded as co-occurring findings of uncertain relationship to WFS1 .

The authors' abstract, as published at the source. BMC Pediatrics, 2026 · DOI ↗