Diagnostic challenge in a patient with nephropathic juvenile cystinosis: a case report

Satomi Higashi,Etsuro Tokuhiro,Shuichi Ito,Natsuki Matsunoshita,Kandai Nozu,Masako Otani

doi:10.1186/s12882-017-0721-4

Abstract

BackgroundCystinosis is a rare autosomal recessive lysosomal disorder characterized by the accumulation of cystine in lysosomes. Cystinosis is much rarer in Asian than Caucasian populations. There are only 14 patients have with cystinosis alive in Japan. Most cystinosis is the nephropathic infantile form, as indicated by its apparent and severe clinical manifestations, including renal and ocular symptoms. Patients with the nephropathic juvenile form account for 5% of those with cystinosis. Their diagnosis is frequently delayed and difficult because of slower progression to end-stage renal disease and fewer cystine crystals in the cornea. Molecular analysis and a cysteine-binding protein assay should be performed when patients with proximal tubulopathy of an unknown origin are encountered.Case presentationA 12-year-old boy had been suffering from Fanconi syndrome since he was 3 years old. He was only recently diagnosed despite repeated ophthalmological examinations. Corneal cystine crystals were found when he was 12 years old, and he was diagnosed with cystinosis by high free cystine content in granulocytes (6.36 nmol half-cystine/mg protein, normal: <0.15). Analysis of the CTNS gene showed two novel heterozygous single nucleotide substitutions of c.329G > C and c.329 + 2 T > C. Both were splicing site variants causing exon 6 skipping proven by transcript analysis, although the functional prediction site showed c.329G > C, p.(Gly110Ala) as a benign missense substitution. The patient’s estimated glomerular filtration rate was 66.8 mL/min/1.73 m2. He was immediately treated with cysteamine after diagnosis.ConclusionsEven if no ophthalmological abnormalities are present, nephropathic juvenile cystinosis should be suspected in children with Fanconi syndrome. Transcript analysis was useful to detect pathogenic splicing variants in this patient.

Highlights

Cystinosis is a rare autosomal recessive lysosomal disorder characterized by the accumulation of cystine in lysosomes
Even if no ophthalmological abnormalities are present, nephropathic juvenile cystinosis should be suspected in children with Fanconi syndrome
This results in various clinical manifestations, such as Fanconi syndrome, end-stage renal disease (ESRD), hypothyroidism, hypogonadism, insulin-dependent diabetes mellitus, muscle weakness, swallowing dysfunction, central nervous system complications, keratopathy, and pigmentary retinopathy [1,2,3]

Summary

Background

Cystinosis is an autosomal recessive lysosomal disorder characterized by the accumulation of cystine in lysosomes throughout the body. We describe a Japanese patient with juvenile nephropathic cystinosis with two novel splice-site mutations causing exon skipping proven by transcript analysis. Direct sequencing analysis of genomic DNA for the CTNS gene showed two novel heterozygous single nucleotide substitutions of c.329G > C and c.329 + 2 T > C The former is the last nucleotide of exon 6 and the latter is at the consensus sequence of the splicing donor site at intron 6 (Fig. 2a). The father’s genomic DNA analysis was not available because of the absence of consent, these results could suggest the patient had a compound heterozygous mutation in the CTNS gene The former variant (c.329G > C) might be a single nucleotide polymorphism of p.(Gly110Ala) because the two functional prediction sites of the amino acid variant (PolyPhen and SIFT) showed this as benign.

Discussion

Findings

Conclusion