ESPE Abstracts

Background: Wolfram syndrome (WS) is a rare autosomal recessive genetic disorder. We present two sisters from non-consanguineous parents, who presented to our pediatric endocrinology clinic due to severe polyuria-polydipsia with inappropriately treated DM (HbA1c 8.2% and 10.1%) and untreated DI.

Methods: DNA was tested with PCR amplification and sequencing analysis (Sanger sequencing) of the entire coding region and all exon-intron splice junctions of the WFS1 gene (chromosome 4): reference sequence: NM_006005.3, with the A of the ATG start codon at position 1.

Results: A novel homozygous point missense c.2069G>A mutation in amino acid position 690 (p.C690Y) replacing Cysteine with Tyrosine in exon 8 was found in both sisters, the parents being heterozygous. The mutation causes amino acid change and is damaging with a score of 1.000 (Polyphen-2).

Cases: Sister-A, 19yrs old with a BMI<−2SDS, totally blind since 13 yrs, had primary amenorrhea and bladder incontinence; normal cranial nerve examination except oculomotion with roving eye movements; normal muscle strength and deep tendon reflexes 2/4; no extrapyramidal or ataxia signs; visual acuity ‘No Light Perception’ in both eyes; pupillary light reflex completely absent with mid-dilated pupils; normal anterior segment; intraocular pressure 12 mmHg bilaterally; complete optic nerve atrophy in dilated fundus examination; tympanogram type A, TOAEs ‘pass’ bilateral, as well as aABRs in Otologic and Audiologic testing; appropriate for age mental status with signs of severe depression. Sister-B, prepubertal 7yrs old had normal neurological examination; visual acuity 6/15 (0.40 LogMAR) and 6/19 (0.50 LogMAR) with +1.00 diopters sphere corrective lens in both eyes; symmetrically reduced pupillary light reflex with not relative afferent pupillary reflex; normal anterior segment; intraocular pressure 12mmHg and 11mmHg; moderate optic nerve atrophy; tympanogram type C, right side ‘pass’ and left ‘fail’ of TOAEs, with aABRs ‘pass’ bilateral. Both had normal electrolytes, severe neurogenic bladder and Grade III hydronephrosis. Both presented salt-wasting due to ANP elevation when treatment for DI was started, successfully treated with fludrocortisone along with frequent bladder catheterizations. Within six months, patient’s A BMI normalized, and she had menstrual onset. Persistence of hydronephrosis in patient B revealed a grade III bilateral vesicoureteral reflux treated with endoscopic injection of Deflux.

Conclusions: We present a novel detrimental homozygous WFS1 gene mutation in two sisters from non-consanguineous parents of Greek descent, both originated 5–6 generations before from Trapezund, an ancient Greek colony located in the former Greek Pontos, presently in Turkey, indicating a founder mutation effect.