Alternative titles; symbols
SNOMEDCT: 723999009; ORPHA: 140976;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q22.1 | ?RHYNS syndrome | 602152 | Autosomal recessive | 3 | TMEM67 | 609884 |
A number sign (#) is used with this entry because of evidence that RHYNS syndrome is caused by compound heterozygous mutation in the TMEM67 gene (609884) on chromosome 8q22. One such patient has been reported.
RHYNS syndrome is characterized by gaze palsy, retinitis pigmentosa, sensorineural hearing loss, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (Di Rocco et al., 1997).
Di Rocco et al. (1997) reported a 17.5-year-old boy who at birth was noted to have right-sided ptosis and right exotropia, and left esotropia (Brancati et al., 2018). At age 4 years, short stature prompted endocrine evaluation that revealed poor response to stimulation for both growth hormone (GH1; 139250) and thyroid-stimulating hormone (TSH; see 188540). He also had severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. At age 10, left-sided 'transmissive' deafness was diagnosed, and at age 11 he was found to have retinitis pigmentosa (RP), with completely extinguished electroretinograms (ERGs) bilaterally. At 12 years of age, the proband developed progressive renal failure, and renal biopsy at age 16 was consistent with nephronophthisis. The authors noted that a similarly affected child had been described by Bianchi et al. (1988); that patient, who had ptosis, RP, juvenile nephronophthisis, hypopituitarism, skeletal anomalies, and liver disease, died at age 10 from renal failure. Di Rocco et al. (1997) designated the syndrome 'RHYNS,' for retinitis pigmentosa, hypopituitarism, nephronophthisis, and skeletal dysplasia.
Hedera and Gorski (2001) described 2 brothers, ages 14 years and 10 years, who had early onset RP, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. One brother also exhibited bilateral ptosis and esotropia of the left eye. Neither brother showed signs of renal disease. The authors suggested that the phenotype was consistent with RHYNS syndrome.
Brancati et al. (2018) restudied the Italian patient with RHYNS syndrome who was originally reported by Di Rocco et al. (1997). At age 38 years, he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. There was diffuse reduction of the bone density with thinning of the diaphyseal cortex, particularly in the hands. He had undergone successful renal transplantation at age 34. Audiometry revealed pantonal left-sided moderate-to-severe sensorineural hearing loss, and ophthalmologic examination confirmed no residual visual acuity with completely extinguished ERGs bilaterally. Neuropsychologic evaluation showed no functional deficits, and brain imaging was normal.
The presence of RHYNS syndrome in 2 brothers described by Hedera and Gorski (2001) supported an autosomal recessive mode of inheritance; however, the authors noted that all 4 reported cases were male, and thus an X-linked mode of inheritance could not be excluded.
By whole-exome sequencing in a 38-year-old Italian man with RHYNS syndrome, originally reported by Di Rocco et al. (1997), Brancati et al. (2018) identified compound heterozygosity for mutations in the TMEM67 gene: a nonsense mutation (R208X; 609884.0011) and a missense mutation (D430G; 609884.0026). His unaffected father and 2 unaffected brothers were heterozygous for the nonsense mutation, and his unaffected mother was heterozygous for the missense mutation.
Bianchi, C., Barera, G., Picciotti, M., Barbiano di Belgioioso, G., Bellini, F. Juvenile nephronophthisis associated with new skeletal abnormalities, tapetoretinal degeneration and liver fibrosis. Helv. Paediat. Acta 43: 449-455, 1988. [PubMed: 2745140]
Brancati, F., Camerota, L., Colao, E., Vega-Warner, V., Zhao, X., Zhang, R., Bottillo, I., Castori, M., Caglioti, A., Sangiuolo, F., Novelli, G., Perrotti, N., and 16 others. Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome. Europ. J. Hum. Genet. 26: 1266-1271, 2018. [PubMed: 29891882] [Full Text: https://doi.org/10.1038/s41431-018-0183-6]
Di Rocco, M., Picco, P., Arslanian, A., Restagno, G., Perfumo, F., Buoncompagni, A., Gattorno, M., Borrone, C. Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome? Am. J. Med. Genet. 73: 1-4, 1997. [PubMed: 9375913] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19971128)73:1<1::aid-ajmg1>3.0.co;2-y]
Hedera, P., Gorski, J. L. Retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia in two brothers: possible familial RHYNS syndrome. Am. J. Med. Genet. 101: 142-145, 2001. [PubMed: 11391657] [Full Text: https://doi.org/10.1002/ajmg.1338]