Alternative titles; symbols
SNOMEDCT: 726080006, 90505000; ORPHA: 289176; DO: 0050949;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q22.1 | Hypophosphatemic rickets, AR | 241520 | Autosomal recessive | 3 | DMP1 | 600980 |
A number sign (#) is used with this entry because of evidence that autosomal recessive hypophosphatemic rickets-1 (ARHR1) is caused by homozygous mutation in the DMP1 gene (600980) on chromosome 4q22.
For a general phenotypic description and a discussion of genetic heterogeneity of hypophosphatemic rickets, see 193100.
Lorenz-Depiereux et al. (2006) investigated 3 multiplex families in which the affected individuals showed clinical, biochemical, and histomorphometric parameters very similar to those observed in X-linked (see 307800) and autosomal dominant hypophosphatemic rickets (193100). However, inspection of the pedigrees suggested autosomal recessive inheritance. In the first family, the diagnosis of hypophosphatemic rickets was made in the 3 affected sibs between the age of 8 and 14 years, after the family moved from Turkey to Germany. At the time of diagnosis, the oldest patient in the sibship, the sister, had coxa vara, genu vara, and rachitic rosary. Despite treatment with vitamin D and phosphate supplementations, bowing of the legs did not improve and she required repeated osteotomies. In the brothers from the second family, of Spanish origin, the diagnosis of hypophosphatemic rickets was made at the age of 14 and 18 months. X-rays of the lower extremities showed typical signs of rickets with bowing of the legs and widening of the metaphyses. Bowing of the legs improved to nearly normal after treatment with phosphate and vitamin D substitution. One of the brothers had dentin defects and multiple dental caries at age 5 years, whereas the other had normal dental status. At the age of 8 years, an x-ray of the skull of the older brother showed osteosclerotic appearance especially at the base of the skull and the calvarial bones. In both brothers intact plasma levels of the phosphaturic protein fibroblast growth factor-23 (FGF23; 605380) were clearly elevated. In the third family, of Lebanese origin, the index case and his affected sister were diagnosed with hypophosphatemia and osteosclerosis at age 32 and 30 years, respectively, although both reportedly had clinical problems with their legs during childhood. On the other hand, their nephew was diagnosed with hypophosphatemic rickets at almost 2 years of age. Skeletal radiographs of the 2 older patients demonstrated severe osteosclerosis combined with coarse and thickened calvaria, broad and undermodelled ribs and clavicles, and enthesopathies. Consistent with these findings, the index case in this family presented with severe, incapacitating back pain and joint stiffness.
Feng et al. (2006) studied 2 families, both of Lebanese origin. All 4 affected individuals manifested rickets and osteomalacia with isolated renal phosphate wasting associated with elevated FGF23 levels and normocalciuria.
The transmission pattern of ARHR1 in the families reported by Lorenz-Depiereux et al. (2006) was consistent with autosomal recessive inheritance.
Lorenz-Depiereux et al. (2006) performed a genomewide linkage analysis in 3 families with ARHP using SNP array genotyping. Assuming that the disease alleles could be identical by descent in each family, they analyzed the data by homozygosity mapping and identified a 4.6-Mb candidate region on chromosome 4q21.
Lorenz-Depiereux et al. (2006) found that the candidate region for ARHP contained a cluster of genes encoding a class of tooth and bone noncollagenous matrix proteins that are referred to as SIBLING proteins (small integrin-binding ligand, N-linked glycoproteins). By direct sequencing, Lorenz-Depiereux et al. (2006) searched for mutations in the exons and relevant flanking intronic regions of these genes. In the affected members of all 3 investigated families, they identified different homozygous, presumably loss-of-function mutations in DMP1 (600980.0001-600980.0003). Each of the unaffected parents was heterozygous for the respective mutation.
In all 4 affected individuals from 2 families with ARHP, both of Lebanese origin, Feng et al. (2006) identified homozygous mutations in the DMP1 gene.
Stamp and Baker (1976) reported a brother and sister, children of a first-cousin marriage, who presented with severe rickets in infancy and were followed to adulthood. Their disease showed continued activity, marked resistance to vitamin D, early fusion of cranial sutures, greatly increased bone density, nerve deafness, and lifelong hypophosphatemia unaffected by treatment. Both parents and a third sib were normal clinically and biochemically. Blood grouping by Dr. Ruth Sanger supported paternity and consanguinity. Subsequent HLA typing and genetic fingerprinting likewise supported paternity (Baker and Stamp, 1989). This is 1 example of the multiple mendelian forms of renal hypophosphatemia (Scriver and Reade, 1987).
Weir (1977) reported 2 pairs of sibs with autosomal recessive hypophosphatemic rickets. All of the patients had bilateral marked narrowing of the internal auditory canals, and 3 had some degree of sensorineural hearing loss.
Baker, L. R. I., Stamp, T. C. B. Autosomal recessive hypophosphataemia. (Letter) Arch. Dis. Child. 64: 1209 only, 1989. [PubMed: 2782942] [Full Text: https://doi.org/10.1136/adc.64.8.1209-a]
Feng, J. Q., Ward, L. M., Liu, S., Lu, Y., Xie, Y., Yuan, B., Yu, X., Rauch, F., Davis, S. I., Zhang, S., Rios, H., Drezner, M. K., Quarles, L. D., Bonewald, L. F., White, K. E. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nature Genet. 38: 1310-1315, 2006. [PubMed: 17033621] [Full Text: https://doi.org/10.1038/ng1905]
Lorenz-Depiereux, B., Bastepe, M., Benet-Pages, A., Amyere, M., Wagenstaller, J., Muller-Barth, U., Badenhoop, K., Kaiser, S. M., Rittmaster, R. S., Shlossberg, A. H., Olivares, J. L., Loris, C., Ramos, F. J., Glorieux, F., Vikkula, M., Juppner, H., Strom, T. M. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nature Genet. 38: 1248-1250, 2006. [PubMed: 17033625] [Full Text: https://doi.org/10.1038/ng1868]
Scriver, C. R., Reade, T. M. Renal hypophosphataemia has several mendelian forms. (Letter) Lancet 330: 918 only, 1987. Note: Originally Volume II. [PubMed: 2889114] [Full Text: https://doi.org/10.1016/s0140-6736(87)91407-3]
Stamp, T. C. B., Baker, L. R. I. Recessive hypophosphataemic rickets, and possible aetiology of the 'vitamin D-resistant' syndrome. Arch. Dis. Child. 51: 360-365, 1976. [PubMed: 180907] [Full Text: https://doi.org/10.1136/adc.51.5.360]
Weir, N. Sensorineural deafness associated with recessive hypophosphataemic rickets. J. Laryngol. Otol. 91: 717-722, 1977. [PubMed: 894124] [Full Text: https://doi.org/10.1017/s0022215100084255]