X-linked hypophosphatemia: Management and treatment prospects.

X-linked hypophosphatemia (XLH), due to a PHEX gene mutation, is the most common genetic form of rickets and osteomalacia. Manifestations in children consist of rickets, lower-limb bone deformities, bone pain, failure to thrive, dental abscesses, and/or craniostenosis. Adults may present with persistent bone pain, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis. Regardless of whether the patient is an infant, child, adolescent or adult, an early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life. Treatment options include active vitamin D analogs and phosphate supplementation to correct the 1.25(OH)2 vitamin D deficiency and to compensate for the renal phosphate wasting, respectively. The recently introduced FGF23 antagonist burosumab is designed to restore renal phosphate reabsorption by the proximal tubule and to stimulate endogenous calcitriol production. In Europe, burosumab is licensed for use in pediatric patients older than 1 year who have XLH. This review discusses the diagnosis and treatment of XLH and describes the indications of the various available treatments.

Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications.

OBJECTIVE: Hereditary hypophosphatemias (HH) are rare monogenic conditions characterized by decreased renal tubular phosphate reabsorption. The aim of this study was to explore the prevalence, genotypes, phenotypic spectrum, treatment response, and complications of treatment in the Norwegian population of children with HH. DESIGN: Retrospective national cohort study. METHODS: Sanger sequencing and multiplex ligand-dependent probe amplification analysis of PHEX and Sanger sequencing of FGF23, DMP1, ENPP1KL, and FAM20C were performed to assess genotype in patients with HH with or without rickets in all pediatric hospital departments across Norway. Patients with hypercalcuria were screened for SLC34A3 mutations. In one family, exome sequencing was performed. Information from the patients' medical records was collected for the evaluation of phenotype. RESULTS: Twety-eight patients with HH (18 females and ten males) from 19 different families were identified. X-linked dominant hypophosphatemic rickets (XLHR) was confirmed in 21 children from 13 families. The total number of inhabitants in Norway aged 18 or below by 1st January 2010 was 1,109,156, giving an XLHR prevalence of ∼1 in 60,000 Norwegian children. FAM20C mutations were found in two brothers and SLC34A3 mutations in one patient. In XLHR, growth was compromised in spite of treatment with oral phosphate and active vitamin D compounds, with males tending to be more affected than females. Nephrocalcinosis tended to be slightly more common in patients starting treatment before 1 year of age, and was associated with higher average treatment doses of phosphate. However, none of these differences reached statistical significance. CONCLUSIONS: We present the first national cohort of HH in children. The prevalence of XLHR seems to be lower in Norwegian children than reported earlier.

Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant SPAK.

BACKGROUND: The WNK-dependent STE20/SPS1-related proline/alanine-rich kinase (SPAK) regulates the renal thiazide sensitive NaCl cotransporter (NCC) and the renal furosemide sensitive Na+, K+, 2Cl- cotransporter (NKCC2) and thus participates in the regulation of renal salt excretion, extracellular fluid volume and blood pressure. Inhibition of NCC leads to anticalciuria. Moreover, NCC is also expressed in osteoblasts where it is implicated in the regulation of bone mineralization. Osteoblasts further influence mineral metabolism by releasing the phosphaturic hormone FGF23. The present study explored, whether SPAK participates in the regulation of calcium-phosphate homeostasis. METHODS: FGF23 serum levels and phosphate homeostasis were analyzed in gene targeted mice expressing SPAK resistant to WNK-dependent activation (spak(tg/tg)) and in mice expressing wild type SPAK (spak(wt/wt)). RESULTS: Serum FGF23 level was significantly higher, urinary phosphate excretion significantly larger and serum phosphate concentration significantly lower in spak(tg/tg) mice than in spak(wt/wt) mice. Urinary calcium excretion was significantly decreased in spaktg/tg mice. Serum levels of calcitriol and PTH were not significantly different between the genotypes. Bone density was significantly increased in spak(tg/tg) mice compared to spak(wt/wt) mice. Treatment of spak(wt/wt) mice with HCT increased FGF23 serum levels, and led to phosphaturia and hypophosphatemia. CONCLUSIONS: SPAK is a strong regulator of FGF23 formation, bone mineralization and renal Ca2+ and phosphate excretion.

Incidence and prevalence of nutritional and hereditary rickets in southern Denmark.

OBJECTIVE: To estimate the incidence of nutritional rickets and the incidence and prevalence of hereditary rickets. DESIGN: Population-based retrospective cohort study based on a review of medical records. METHODS: Patients aged 0-14.9 years referred to or discharged from hospitals in southern Denmark from 1985 to 2005 with a diagnosis of rickets were identified by register search, and their medical records were retrieved. Patients fulfilling the diagnostic criteria of primary rickets were included. RESULTS: We identified 112 patients with nutritional rickets of whom 74% were immigrants. From 1995 to 2005, the average incidence of nutritional rickets in children aged 0-14.9 and 0-2.9 years was 2.9 and 5.8 per 100,000 per year respectively. Among immigrant children born in Denmark, the average incidence was 60 (0-14.9 years) per 100,000 per year. Ethnic Danish children were only diagnosed in early childhood and the average incidence in the age group 0-2.9 years declined from 5.0 to 2.0 per 100,000 per year during 1985-1994 to 1995-2005. Sixteen cases of hereditary rickets were diagnosed during the study period giving an average incidence of 4.3 per 100,000 (0-0.9 years) per year. The prevalence of hypophosphatemic rickets and vitamin D-dependent rickets type 1 was 4.8 and 0.4 per 100,000 (0-14.9 years) respectively. CONCLUSIONS: Nutritional rickets is rare in southern Denmark and largely restricted to immigrants, but the incidence among ethnic Danish children was unexpectedly high. Hereditary rickets is the most common cause of rickets in ethnic Danish children, but nutritional rickets is most frequent among all young children.

Evaluation of bone mineral density and bone metabolism in children with multiple bone fractures.

BACKGROUND: The aim of the study was to carry out a comprehensive analysis of determinants of multiple bone fractures in children with regard to densitometric indices and markers of bone metabolism. MATERIAL AND METHODS: The study involved 112 children aged 5-18 years, including 81 patients with a history of at least 3 bone fractures and 31 healthy patients in a control group. Total body and spinal DXA densitometry of the skeleton (DPX-L apparatus, Lunar) was carried out in all children. Laboratory assays comprised the determination of calcium, phosphorus, magnesium (in the serum and 24-hour urine collection), parathormone, liver metabolite of vitamin D, osteocalcin, bone alkaline phosphatase, and N-terminal cross-linked telopeptide of collagen type I (NTx). RESULTS: Mean values of DXA Z-score, both in total body and in spinal scans, were significantly lower in children with multiple fractures as compared to controls. In children with multiple fractures, there was a higher prevalence of hypercalciuria, hypermagnesuria and hyperphosphaturia. Decreased levels of the liver metabolite of vitamin D were observed in 20/81 (24.7%) patients in this group and in 6/31 controls. Other findings included a higher level of NTx in 38/75 (50.7%) patients with fractures, an increased activity of bone alkaline phosphatase in 29, and of osteocalcin in 12 patients. In this group, there was a significant negative correlation between biochemical bone turnover markers and low bone mass. Also, lower DXA Z-scores were found in children with higher urinary calcium excretion. CONCLUSIONS: 1. Decreased bone mineral density was the most frequent risk factor for bone fractures in children; it was found in about 2/3 of the patients with multiple bone fractures. 2. Accelerated bone turnover, and, particularly, increased bone resorption, indicates a derangement of bone metabolism in children with multiple fractures. 3. Repeated fractures during the body growth period are an indication for a quantitative evaluation of bone mass, calcium-phosphate metabolism and bone turnover markers.

The enigma of hyperparathyroidism in hypophosphatemic rickets.

Familial hypophosphatemic rickets (XLH) is caused by inactivating mutations of the cell surface metalloproteinase PHEX. It is characterized by low-normal serum levels of 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], normocalcemia, and hypophosphatemia. Hyperparathyroidism is regularly seen in patients treated with phosphate supplements, although circulating serum phosphate levels do not reach the normal range. The mechanism is unknown. Decreased serum concentrations of ionized calcium following phosphate supplements might contribute to the development of hyperparathyroidism. Secondary and even tertiary hyperparathyroidism can, however, be observed in patients who have never received phosphate treatment. This points to an abnormal regulation of production and/or degradation of parathyroid hormone (PTH). Recently, the expression of the PHEX gene in hypertrophied parathyroid glands of a patient with XLH has been reported. It is unclear whether the mutant PHEX gene can induce hyperparathyroidism by abnormal regulation of peptidases.

Impact of demographic distribution and population growth rate on haplotypic diversity linked to a disease gene and their consequences for the estimation of recombination rate: example of a French Canadian population.

A disease gene introduced into a rapidly growing population by a single individual remains in strong linkage disequilibrium with the surrounding molecular markers. Mapping strategies taking advantage of this phenomenon allow increased mapping resolution as compared to pedigree analysis. Demographic models underlying these strategies usually assume the population exponential growth approximated by Poisson distribution of the number of children per individual. Knowing the real demographic distribution in the studied French-Canadian population, we analyzed the validity of the Poisson approximation. We adapted the existing model of the Poisson branching process to the case of a rapidly growing population and to non-Poisson distributions. In consequence, we were able to apply maximum-likelihood methods to estimate the recombination rate under various demographic scenarios. Our analysis shows that the growth rate has a higher impact on the estimation of recombination rate than the shape of the demographic distribution. The choice of the demographic model (Poisson vs. non-Poisson) has little effect on the estimation of the recombination rate but affects the expected distribution of haplotype frequencies. This distribution, however, depends much more on the population growth rate. Finally, we also demonstrate the usefulness of the Luria-Delbrück method, which gives a correct estimation of the recombination rate in a growing population, provided the sampling error is taken into account in the confidence intervals.

Clinical course of hypophosphatemic rickets in 23 adults.

Twenty-three adult patients (19 females, 4 males) with x-linked hypophosphatemic rickets (HPR) underwent a retrospective evaluation of the clinical course and a clinical examination by a nephrologist, orthopedic surgeon and dentist. Blood and urine analysis, bone density measurements with QCT and DEXA, ultrasonic examination of the kidneys were performed and the patients were asked to fill in a standardized questionnaire on pain and psychosocial rehabilitation. Mean final height was 152.4 cm +/- 8.5 SD in females and 157.3 cm +/- 8.9 SD in males. Decreased joint mobility was seen in all patients, deviations of the normal leg axis in 18/23 patients in spite of 69 correcting osteotomies in the past. Dental (n = 14) and psychosocial problems were associated with inability to work (n = 8). There was a trend that patients with a very low Tp/GFR had a more severe course of the disease. Early therapy with vitamin D metabolites and phosphate had a beneficial effect on growth, bone density and deformations. Eight patients had nephrocalcinosis due to vitamin D and phosphate therapy and had normal kidney function. Four patients had urinary tract abnormalities. We conclude that patients with HPR should receive continuous interdisciplinary care given by nephrologists, orthopedic surgeons, physiotherapists and dentists not only during childhood but also as adults.

Adult-onset idiopathic phosphate diabetes. II. Time-course of clinical, laboratory test, and bone mineral density abnormalities under combined phosphate and calcitriol therapy.

STUDY OBJECTIVE: to investigate the time-course of clinical, laboratory test, and bone mineral density abnormalities in patients with mild phosphate diabetes treated for at least one year with calcitriol, 0.5 to 1.5 micrograms, and oral phosphate, 788 to 2300 mg per day, in three divided doses. PATIENTS AND METHODS: we studied eight patients with mild phosphate diabetes defined as a rate for tubular reabsorption of phosphate of less than 18% with a maximal rate for tubular reabsorption of phosphate (Tm) of less than 0.77 in the absence of any detectable cause of secondary tubular disease. Treatment efficacy was evaluated on the basis of pain severity, pain-related functional disability, serum phosphate and calcium levels, maximal rate for tubular reabsorption of phosphate, and dual-photon absorptiometry-measured bone mineral density. RESULTS: three patients experienced complete relief of pain and fatigue and were able to resume their normal activities. Partial relief was seen in two other patients. The three remaining patients had no response to treatment. Renal colic occurred in one patient. None of the patients developed hypercalcemia.

X-linked hypophosphatemic rickets without "rickets".

Wrist and knee radiographs from children with X-linked hypophosphatemic rickets were analyzed and compared with those from normal children and children with established rickets to assess whether radiographically apparent rickets is a consistent abnormality in X-linked hypophosphatemia. The absence or presence of rickets was correctly identified in 94.8% of wrist and knee films from normal and positive controls. In contrast, patients with X-linked hypophosphatemia exhibited rachitic abnormalities in only 5 of 11 wrist and 13 of 15 knee radiographs. As a result, 4 patients within this study group had rickets at the knee and not at the wrist, whereas 5 displayed classic defects at both sites. Perhaps more important, 2 patients, aged 3.8 and 5.2 years, displayed no evidence of rickets in either wrist or knee films, although relatives exhibited demonstrable rachitic abnormalities. Our data indicate that radiographically detectable rickets is a variable abnormality of X-linked hypophosphatemia and does not provide an unambiguous index for the diagnosis of this disease.

Familial hypophosphataemic rickets: experience with 24 children from Kuwait.

Between 1982 and 1988, familial hypophosphataemic rickets (FHR) was diagnosed in 24 children, in nine during screening of the families of index patients. The average annual incidence was 0.2/1000 live births. There were 16 boys and 8 girls in 10 families, of which nine had more than one affected child. Their ages at the onset of the disease ranged between 10 months and 14 years (mean 6.9 yrs). Growth retardation and bowing of the legs were the most prominent features, observed in all index patients and in four of the patients diagnosed by screening. Treatment with 1 alpha-hydroxyvitamin D3 and phosphates was associated with acceleration of growth in all children, healing of rickets in 21, and normalization of the serum phosphate in 22. Two children with late diagnosis are now older than 16 years with a final height below the 3rd centile. Three more pubertal children are also shorter than the 3rd centile. In areas where nutritional rickets is common, FHR is likely to be missed and the treatment delayed with grave consequences; in particular, growth retardation and bone deformity.