Introduction:
Fanconi renotubular syndrome type 5 (FRTS5; MIM #618913) is an ultrarare autosomal recessive disorder caused by pathogenic variants in the NDUFAF6 gene, which encodes NADH: ubiquinone oxidoreductase complex assembly factor 6 and leads to aberrant splicing of NDUFAF6 mRNA and loss of the mitochondria-located NDUFAF6 isoform, resulting in mitochondrial respiratory chain complex I deficiency. FRTS5 characterized by generalized proximal renal tubular dysfunction, manifesting in childhood and progressing to ESKD in middle adulthood, and pulmonary fibrosis. FRTS5 have been reported only in individuals of Acadian descent. The aim of the study was to present a case with FRTS5 due to previously reported in Acadian cohort intronic variant in the NDUFAF6 gene in a child from Russia.
Methods:
Results:
The boy was born from non-consanguineous parents with birth weight 3050 g and height 50 cm. Family history of kidney disease was negative. The child presented with failure to thrive, bone deformities, attacks of weakness, lethargy, vomiting from the age of 3 years. Glycosuria, low molecular weight (LMW) proteinuria (increased β-2 microglobulin) and aminoaciduria were revealed at the age of 4 years. At the first admission at the age of 5 years the boy had short stature (height <3P and weight <10P), genu valgum and full-blown Fanconi syndrome (FS) including polyuria (2.2 l/m2/d), metabolic acidosis (pH 7.3, HCO3- 17 mmol/l), phosphaturia with decreased TRP (54.9%) and TmP/eGFR (0.63 mmol/mmol) and hypophosphatemia (1.14 mmol/l), glycosuria (6.4 mmol/d), LMW proteinuria (urinary β-2 microglobulin level 20112 µg/l), aminoaciduria and rickets (X-ray: widening of the distal femoral and proximal tibial growth plates, RSS=9). He had high alkaline phosphatase (APL) level (162 U/L) and decreased eGFR (CKID U25 54 ml/min/1.73 m2). Kidney ultrasound showed medullary nephrocalcinosis grade 2. NGS revealed previously reported as a pathogenic homozygous variant c.298-768T>C in intron 2 in NDUFAF6 gene. Sanger sequencing and family segregation analysis are pending. The boy has been treated with L-сarnitine, phosphate supplements, calcitriol and sodium bicarbonate for 2 years. At the age of 7 years the boy had normal growth and weight (height 25P, weight 25P), there were no X-ray signs of activity of rickets (RSS=0), however genu valgum and full-blown FS were persisted, eGFR decreased to 50.6 ml/min/1.73 m2. Pulmonary function tests did not reveal any pathological abnormalities.
Conclusions:
We presented the first report of a patient with FRTS5 outside the Acadian cohort. Ongoing therapy was resulted to normalization of growth rates and a reduction in rickets symptoms despite the persistence of FS. The absence of pulmonary complication may be related to the child's age and may appear in adulthood. We recommend to perform testing of NDUFAF6 variants in all patients with FS even those who are not of Acadian descent and in the absence of kidney failure and pulmonary involvement.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.