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Phenotypic variability in patients with fanconi-bickel syndrome with identical mutations.

ABSTRACT: OBJECTIVE:To describe the phenotypic features of an ethnically homogenous group of patients with Fanconi-Bickel syndrome harboring the p.R310X mutation. METHODS:The study group consisted of eight patients from a single Bedouin family with clinically and molecularly diagnosed Fanconi-Bickel syndrome who had been followed at the same tertiary medical center for 8 years or more. All were homozygous for the p.R310X mutation. The medical files were reviewed for presenting signs and symptoms, laboratory and imaging findings, treatment regimens, and disease severity over time. RESULTS:Seven patients were diagnosed at our center before age 1 year, and one transferred from another center at age 16 years. Most patients presented with failure to thrive and/or hepatomegaly. All had short stature and doll-like facies. Most had biochemical abnormalities. Evaluation of the long-term findings revealed a wide spectrum of disease severity according to the following parameters: growth patterns, maximal electrolyte replacement therapy, skeletal and renal complications, frequency of follow-up visits, and hospitalizations for disease exacerbations. There was no apparent association of the clinical picture at presentation and later disease severity. CONCLUSION:Fanconi-Bickel syndrome has a broad phenotypic variability in patients harboring the same homozygous p.R301X mutation. This finding might be explained by genetic elements such as modifier genes and epigenetic factors, as well as the effects of still-undetermined environmental and nutritional factors.

SUBMITTER: Fridman E

PROVIDER: S-EPMC4270862 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Phenotypic variability in patients with fanconi-bickel syndrome with identical mutations.

Fridman Elena E Zeharia Avraham A Markus-Eidlitz Tal T Haimi Cohen Yishai Y

JIMD reports 20140410

<h4>Objective</h4>To describe the phenotypic features of an ethnically homogenous group of patients with Fanconi-Bickel syndrome harboring the p.R310X mutation.<h4>Methods</h4>The study group consisted of eight patients from a single Bedouin family with clinically and molecularly diagnosed Fanconi-Bickel syndrome who had been followed at the same tertiary medical center for 8 years or more. All were homozygous for the p.R310X mutation. The medical files were reviewed for presenting signs and sym ...[more]

PMID: 24718840

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Project description:BackgroundFanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction.MethodsClinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed.ResultsHepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3-) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3- and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from - 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient.ConclusionsEarly diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.

Dataset Information

Phenotypic variability in patients with fanconi-bickel syndrome with identical mutations.

Publications

Phenotypic variability in patients with fanconi-bickel syndrome with identical mutations.

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