A number sign (#) is used with this entry because of evidence that rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD) is caused by homozygous mutation in the RRM2B gene (604712) on chromosome 8q22.

See also autosomal recessive mitochondrial DNA depletion syndrome (612075), autosomal dominant progressive external ophthalmoplegia (adPEO) with mitochondrial DNA (mtDNA) deletions-5 (PEOA5; 613077), both caused by mutations in the RRM2B gene.

Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD) is characterized by onset of hearing impairment and reduced vision within the first 5 years of life. Renal dysfunction results in rickets-like skeletal changes, and death may occur in childhood or young adulthood due to renal failure (Beighton et al., 1993).

During a large-scale survey of persons with Usher syndrome (retinitis pigmentosa and sensorineural deafness; see 276900), Beighton et al. (1993) identified 14 children in 9 Afrikaner families in South Africa with a combination of progressive rod-cone dystrophy, sensorineural deafness, and renal dysfunction of the Fanconi type leading to rickets-like skeletal changes and renal failure. Eight of the 11 children had died between the ages of 3 and 20 years; in most patients, the cause of death was reported to be renal failure. Onset of auditory and visual dysfunction was usually before age 5 and invariably before age 10 years. Retinitis pigmentosa or Usher syndrome had initially been diagnosed in every child, and cataracts had been documented as a complicating factor in 4 of the children. Renal dysfunction usually presented with albuminuria during the first 5 years, and the skeletal complications of 'renal rickets' were generally evident during the first decade. A stunted stature and malalignment of the weightbearing bones were the major skeletal manifestations. None of the parents were affected. Although minor changes were found in the eyes of the father of 2 affected sibs, none of the parents were known to be consanguineous. However, Beighton et al. (1993) noted that the Afrikaner population, which numbered more than 3 million at the time of the report, is derived from a comparatively small number of founders.

Roberts et al. (2020) reported 6 patients from 5 unrelated Afrikaner families with rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction and mutation in the RRM2B gene, including 2 Afrikaner sisters (patients 30.3 and 30.4, family A) who were originally reported by Beighton et al. (1993) as patients 1 and 2. Both sisters died from renal failure in early adulthood. Of the 4 new probands, one was an 18-year-old male patient (1506.1, family B) who was in renal failure, had cochlear implants for hearing impairment, and was blind due to tunnel vision and bilateral pigmented retinopathy. Patient 1510.2 (family C) was a 13-year-old girl who had cochlear implants for sensorineural hearing loss that was diagnosed at 3 years of age, and also had 'renal rickets' and rod-cone dystrophy. Patient 38.1 was reported to have hearing loss and rod-cone dystrophy from birth, with advanced visual impairment by age 10. Ocular examination at age 15 showed optic atrophy with waxy pallor of discs, depigmented maculae, and minimal bone spicule pigment clumping; cataracts had been removed. The patient also had skeletal fractures and Fanconi-type renal disease. Patient 229.1 had retinitis pigmentosa with onset before 4 years of age, renal infections beginning at 5 years of age, profound hearing loss with cochlear implants by age 17, and Fanconi-type renal disease.

The transmission pattern of RCDFRD in the families reported by Beighton et al. (1993) was consistent with autosomal recessive inheritance.

In 2 deceased Afrikaner sisters (patients 30.3 and 30.4, family A) with rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction, who were originally reported by Beighton et al. (1993) as patients 1 and 2, Roberts et al. (2020) identified homozygosity for a missense mutation in the RRM2B gene (E262D; 604712.0016). Sanger sequencing demonstrated that their unaffected parents were heterozygous for the mutation, which was not found in 34 healthy Afrikaner controls or in public variant databases. Analysis of DNA samples from 2 more unrelated cases (patient 1506.1, family B, and patient 1510.2, family C) revealed homozygosity for the same E262D mutation in the RRM2B gene, with the expected segregation in both families. Sequencing the RRM2B gene in 46 patients with related phenotypes from the University of Cape Town inherited retinal disease repository identified homozygosity for the E262D variant in 2 additional unrelated probands (patients 38.1 and 229.1) with RCDFRD. Haplotype analysis suggested a probable founder effect in the Afrikaner population. Evaluation of a muscle biopsy from patient 1510.2 showed no evidence of mtDNA deletions or depletion, but microscopy was consistent with a mild mitochondrial abnormality.