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Autosomal dominant hypophosphatemic rickets
Autosomal dominant hypophosphatemic rickets (ADHR) is a hereditary renal phosphate-wasting disorder characterized by hypophosphatemia, rickets and/or osteomalacia.
- Autosomal dominant hypophosphatemia
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant
- Age of onset: All ages
- ICD-10: E83.3
- OMIM: 193100
- UMLS: C0342642
- MeSH: -
- GARD: -
- MedDRA: -
Less than 100 cases have been described. Clinical manifestations depend on the age of onset (childhood, adolescence, even adulthood) and on the severity of hypophosphatemia.
During childhood, the disease manifests with short stature, rickets affecting primarily lower extremity deformities. When the disease manifests during adulthood, clinical findings include bone pain (hips, legs, neck), fatigue, muscle weakness, and repeated bone fractures. Some patients are asymptomatic throughout life, some patients alternate between affected and unaffected.
The disease is caused by "activating" mutations in the FGF23 gene (12p13) encoding fibroblast growth factor 23, a phosphate-regulating hormone (phosphatonin). These mutations render FGF23 resistant to cleavage and thus cause an increase in circulating levels, which leads to reduced renal phosphate reabsorption and bone demineralization. ADHR is transmitted as an autosomal dominant trait with incomplete penetrance.
Diagnosis is based on clinical findings, and biochemical and X-ray examination. Biochemical findings can include significant hypophosphatemia, hyperphosphaturia (that can disappear with age), elevated circulating levels of fibroblast growth factor 23 (FGF23) associated with normal serum levels of calcium, increased plasma levels of alkaline phosphatase and inappropriately normal or low serum levels of calcitriol (1,25-dihydroxyvitamin D). Recent data suggest that low serum iron levels are associated with more severe hypophosphatemia due to a further increase in FGF23 levels. Radiological findings include typical rickets/osteomalacia/osteoporosis signs. In children they include fraying and cupping of metaphyseal regions and in adults, pseudofractures. Phosphate excretion can be evaluated by measuring the maximum tubular reabsorption per glomerular filtration rate. Molecular genetic testing confirms the diagnosis.
Differential diagnosis includes X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia (ARHP), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), fibrous dysplasia of bones, renal Fanconi syndrome (see these terms), vitamin D deficiency, and tumor-induced osteomalacia.
Management and treatment
Treatment aims at improving growth, bone or joint pain, enhancing mineralization of bones, and preventing skeletal deformities caused by rickets. It consists of daily oral administration of phosphate and calcitriol and is associated with frequent monitoring of height, calcium, alkaline phosphatase, parathyroid hormone, and phosphate serum concentrations, as well as urinary calcium and creatinine. Calcitriol is given to prevent secondary hyperparathyroidism that can be caused by phosphate administration. Corrective surgery of skeletal deformities may be required in some cases. Sometimes, nephrocalcinosis and hyperparathyroidism can be observed as complications of the therapy; frequent follow-up is therefore necessary. Several forms of adjuvant therapy are being tested to prevent/reduce complications of the current therapy.
With treatment, prognosis is very good: growth is normalized and skeletal deformities can be corrected.