Alternative titles; symbols
SNOMEDCT: 237889002; ORPHA: 89937; DO: 0050948;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.32 | Hypophosphatemic rickets, autosomal dominant | 193100 | Autosomal dominant | 3 | FGF23 | 605380 |
A number sign (#) is used with this entry because autosomal dominant hypophosphatemic rickets (ADHR) is caused by heterozygous mutation in the FGF23 gene (605380), a member of the fibroblast growth factor family, on chromosome 12p13.
Autosomal dominant hypophosphatemic rickets (ADHR) is characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D3 (calcitriol) levels. Patients frequently present with bone pain, rickets, and tooth abscesses. In contrast to X-linked dominant hypophosphatemic rickets (XLH; 307800), ADHR shows incomplete penetrance, variable age at onset (childhood to adult), and resolution of the phosphate-wasting defect in rare cases (Econs et al., 1997).
See also hypophosphatemic bone disease (146350).
Genetic Heterogeneity of Hypophosphatemic Rickets
Other forms of hypophosphatemic rickets include autosomal recessive forms, i.e., ARHR1 (241520), caused by mutation in the DMP1 gene (600980) on chromosome 4q21, and ARHR2 (613312), caused by mutation in the ENPP1 gene (173335) on chromosome 6q23. An X-linked dominant form (XLHR; 307800) is caused by mutation in the PHEX gene (300550), and an X-linked recessive form (300554) is caused by mutation in the CLCN5 gene (300008).
Clinical Variability of Hypophosphatemic Rickets
Hypophosphatemic rickets can be caused by disorders of vitamin D metabolism or action (see VDDR1A, 264700). A form of hypophosphatemic rickets with hypercalciuria (HHRH; 241530) is caused by mutation in the SLC34A3 gene (609826), and there is evidence that a form of hypophosphatemic rickets with hyperparathyroidism (612089) may be caused by a translocation that results in an increase in alpha-klotho levels (KLOTHO; 604824).
Harrison et al. (1966) reported a brother and 2 sisters with hypophosphatemia, whose father had hypophosphatemia, severe osteomalacia, and stunting of growth and whose mother was normal (also see Bianchine et al., 1971). Follow-up on the family (Harrison and Harrison, 1979) stated the father had had hypophosphatemic rickets and osteomalacia as a child for which osteotomies were performed. As an adult, the father had active osteomalacia with severe pain in the hips, legs, and neck. Several automobile accidents and other trauma contributed to the damage to the skeleton. At age 50, he walked with the aid of canes, had limited motion in both hips, and fusion of articular facets of the cervical spine. He had 4 children of whom 2 daughters and a son were affected. The oldest daughter gave birth to an affected son. Serum alkaline phosphatase was elevated at 3 months of age and he subsequently developed hypophosphatemia and active rickets related to inadequate compliance with treatment.
Econs and McEnery (1997) reported a large kindred from southern Ohio in which 23 individuals had hypophosphatemic rickets inherited in an autosomal dominant pattern spanning 5 generations. Patients could be divided into 2 general groups: those who presented with renal phosphate wasting after puberty and those who presented with renal phosphate wasting and rickets as children. There were equal numbers of patients in each group. Nine patients, all female, presented from 14.5 to 45 years with bone pain, fatigue, and weakness. Although several patients had pseudofractures and/or stress fractures, none had a history of rickets or lower limb deformities. All had hypophosphatemia, and some of the women presented shortly after pregnancy. Vitamin D and phosphate therapy resulted in clinical improvement in many patients. Among the 9 patients who presented between ages 1 to 3 years, all showed rickets and hypophosphatemia. Two of these patients, both male, later lost the renal phosphate-wasting defect in their mid-to-late teens. Additional studies of all patients showed inappropriately normal serum 1,25-dihydroxyvitamin D3. Econs and McEnery (1997) noted that ADHR is similar clinically to X-linked hypophosphatemia, with the additional unique features of incomplete penetrance, delayed onset, and occasional resolution of the phosphate-wasting defect.
Wilson et al. (1965) reported a family study initiated from a female proband with typical vitamin D-resistant rickets. Only the proband was clinically affected but, although the parents had normal blood phosphorus, many more remote relatives had hypophosphatemia. Father-to-son transmission of hypophosphatemia was observed. Although the normal parents and their relationship as second cousins suggested autosomal recessive inheritance, the authors favored autosomal dominance with reduced penetrance.
In their literature review, Winters et al. (1958) noted a report of male-to-male transmission of 'vitamin D resistant rickets,' which may have been an instance of hypophosphatemic bone disease (146350). Pak et al. (1972) also reported a presumably autosomal dominant form of vitamin D-resistant rickets.
In both ADHR and XLH, Brickman et al. (1973) found that treatment with 1,25-dihydroxycholecalciferol alone was ineffective.
Econs and McEnery (1997) reported successful treatment of ADHR with phosphate and high doses of vitamin D.
By genomewide search in a large family with autosomal dominant hypophosphatemic rickets, Econs et al. (1997) identified a candidate disease locus, termed ADHR, on chromosome 12p. Two-point lod scores using an affecteds-only analysis for selected markers were 5.65 at theta = 0.0 for VWF (613160) in 12p13.3 and 3.73 at theta = 0.0 for CD4 (186940). Multipoint linkage analysis delineated an 18-cM interval between markers D12S100 and D12S397 (maximum multipoint lod score of 8.13). Moreover, there was no evidence of linkage between ADHR and regions of the genome that contain the 2 known sodium-dependent inorganic phosphate cotransporters: 5q35, the location of the SLC34A1 gene (182309); and 6p, the location of the SLC17A1 gene (182308).
Holm et al. (1997) observed a female patient with apparently sporadic hypophosphatemia and an apparently balanced, de novo 9;13 translocation. The breakpoints were at 9q22 and 13q14. See 612089.
In affected members of 4 unrelated families with ADHR, the ADHR Consortium (2000) identified 3 different missense mutations in the FGF23 gene (see, e.g., 605380.0001-605380.0002). Three of the families had been reported by Econs and McEnery (1997), Bianchine et al. (1971), and Rowe et al. (1992). These mutations represented the first mutations found in a human FGF gene.
Associations Pending Confirmation
For discussion of a possible association between autosomal dominant hypophosphatemic rickets (see, e.g., 193100) and mutation in the SGK3 gene, see 607591.0001.
ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nature Genet. 26: 345-348, 2000. [PubMed: 11062477] [Full Text: https://doi.org/10.1038/81664]
Bianchine, J. W., Stambler, A. A., Harrison, H. E. Familial hypophosphatemic rickets showing autosomal dominant inheritance. Birth Defects Orig. Art. Ser. VII(6): 287-294, 1971. [PubMed: 5173181]
Brickman, A. S., Coburn, J. W., Kurokawa, K., Bethune, J. E., Harrison, H. E., Norman, A. W. Actions of 1,25 dihydroxycholecalciferol in patients with hypophosphatemic, vitamin-D-resistant rickets. New Eng. J. Med. 289: 495-498, 1973. [PubMed: 4353218] [Full Text: https://doi.org/10.1056/NEJM197309062891002]
Deluca, H. F. Vitamin D. New Eng. J. Med. 281: 1103-1104, 1969. [PubMed: 4309963] [Full Text: https://doi.org/10.1056/NEJM196911132812006]
Econs, M. J., McEnery, P. T., Lennon, F., Speer, M. C. Autosomal dominant hypophosphatemic rickets is linked to chromosome 12p13. J. Clin. Invest. 100: 2653-2657, 1997. [PubMed: 9389727] [Full Text: https://doi.org/10.1172/JCI119809]
Econs, M. J., McEnery, P. T. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J. Clin. Endocr. Metab. 82: 674-681, 1997. [PubMed: 9024275] [Full Text: https://doi.org/10.1210/jcem.82.2.3765]
Harrison, H. E., Harrison, H. C., Lifshitz, F., Johnson, A. D. Growth disturbance in hereditary hypophosphatemia. Am. J. Dis. Child. 112: 290-297, 1966. [PubMed: 5925614] [Full Text: https://doi.org/10.1001/archpedi.1966.02090130064005]
Harrison, H. E., Harrison, H. C. Disorders of Calcium and Phosphate Metabolism in Childhood and Adolescence. Philadelphia: W. B. Saunders (pub.) 1979. Pp. 230-238.
Holm, I. A., Huang, X., Kunkel, L. M. Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets. Am. J. Hum. Genet. 60: 790-797, 1997. [PubMed: 9106524]
Pak, C. Y. C., Deluca, H. F., Bartter, F. C., Henneman, D. H., Frame, B., Simopoulos, A. P., Delea, C. S. Treatment of vitamin D-resistant rickets with 25-hydroxycholecalciferol. Arch. Intern. Med. 129: 894-899, 1972. [PubMed: 4338211]
Rowe, P. S. N., Read, A. P., Mountford, R., Benham, F., Kruse, T. A., Camerino, G., Davies, K. E., O'Riordan, J. L. H. Three DNA markers for hypophosphataemic rickets. Hum. Genet. 89: 539-542, 1992. [PubMed: 1353055] [Full Text: https://doi.org/10.1007/BF00219180]
Wilson, D. R., York, S. E., Jaworski, Z. F., Yendt, E. R. Studies in hypophosphatemic vitamin D-refractory osteomalacia in adults: oral phosphate supplements as an adjunct to therapy. Medicine 44: 99-134, 1965. [PubMed: 14272750] [Full Text: https://doi.org/10.1097/00005792-196503000-00001]
Winters, R. W., Graham, J. B., Williams, T. F., McFalls, V. W., Burnett, C. H. A genetic study of familial hypophosphatemia and vitamin D-resistant rickets with a review of the literature. Medicine 37: 97-142, 1958. [PubMed: 13565132] [Full Text: https://doi.org/10.1097/00005792-195805000-00001]