Martin Tieder

SLC34A3 Mutations in Patients with Hereditary Hypophosphatemic Rickets with Hypercalciuria Predict a Key Role for the Sodium-Phosphate Cotransporter NaPi-IIc in Maintaining Phosphate Homeostasis

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10 patients who received the diagnosis of HHRH. The disease mapped to a 1.6-Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaP(i)-IIc. Nucleotide sequence analysis revealed a homozygous single-nucleotide deletion (c.228delC) in this candidate gene in all individuals affected by HHRH. This mutation is predicted to truncate the NaP(i)-IIc protein in the first membrane-spanning domain and thus likely results in a complete loss of function of this protein in individuals homozygous for c.228delC. In addition, compound heterozygous missense and deletion mutations were found in three additional unrelated HHRH kindreds, which supports the conclusion that this disease is caused by SLC34A3 mutations affecting both alleles. Individuals of the investigated kindreds who were heterozygous for a SLC34A3 mutation frequently showed hypercalciuria, often in association with mild hypophosphatemia and/or elevations in 1,25-dihydroxyvitamin D levels. We conclude that NaP(i)-IIc has a key role in the regulation of phosphate homeostasis.

Hereditary Hypophosphatemic Rickets with Hypercalciuria

We studied a new hereditary syndrome of hypophosphatemic rickets and hypercalciuria in six affected members of one kindred. In all patients, the manifestations of disease began in early childhood. The characteristic features are rickets, short stature, increased renal phosphate clearance (the ratio between the maximal tubular reabsorption rate for phosphorus and the glomerular filtration rate [TmP/GFR] is 2 to 4 S.D. below the age-related mean), hypercalciuria (8.6 mg of urinary calcium per kilogram of body weight per 24 hours vs. the upper normal value of 4.0), normal serum calcium levels, increased gastrointestinal absorption of calcium and phosphorus, an elevated serum concentration of 1,25-dihydroxyvitamin D (390 +/- 99 pg per milliliter vs. the upper normal value of 110), and suppressed parathyroid function (an immunoreactive parathyroid hormone level of 0.33 +/- 0.1 ng per milliliter and a cyclic AMP level of 1.39 +/- 0.12 nmol per deciliter of glomerular filtrate vs. the lower normal values of 0.3 and 1.5, respectively). Long-term phosphate supplementation as the sole therapy resulted in reversal of all clinical and biochemical abnormalities except the decreased TmP/GFR. We propose that the pivotal defect in this syndrome is a renal phosphate leak resulting in hypophosphatemia with an appropriate elevation of 1,25-dihydroxyvitamin D levels, which causes increased calcium absorption, parathyroid suppression, and hypercalciuria. This syndrome may represent one end of a spectrum of hereditary absorptive hypercalciuria. Our observations support the importance of phosphate as a mediator in controlling 1,25-dihydroxyvitamin D production in human beings.

A Loss-of-Function Mutation in NaPi-IIa and Renal Fanconi's Syndrome

We describe two siblings from a consanguineous family with autosomal recessive Fanconis syndrome and hypophosphatemic rickets. Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa, as the causative mutation. Functional studies in Xenopus laevis oocytes and in opossum kidney cells indicated complete loss of function of the mutant NaPi-IIa, resulting from failure of the transporter to reach the plasma membrane. These findings show that disruption of the human NaPi-IIa profoundly impairs overall renal phosphate reabsorption and proximal-tubule function and provide evidence of the critical role of NaPi-IIa in human renal phosphate handling.

Direct Measurement of TP/GFR: A Simple and Reliable Parameter of Renal Phosphate Handling

As the Walton-Bijvoet nomogram for estimating renal phosphate (P) threshold (TmP/GFR) is not applicable to children of all ages, we sought an alternative method for measuring renal handling of P. Recognizing that the nomogram represents an indirect correlation between TmP/GFR and TP/GFR under fasting conditions, we examined this directly in 26 children. An excellent correlation was found, expressed as TmP/GFR = (fasting TP/GFR X 1.1) -0.3 (r = 0.95). The regression line in adults, expressed as TmP/GFR = (fasting TP/GFR X 1.4) -0.9 (calculated from published studies) is markedly different at the higher values typical for children. Since no advantage could be seen in the use of a mathematically derived TmP, we investigated the direct use of measured TP/GFR (tubular P reabsorption per 100 ml glomerular filtrate) as a measure of renal P handling in clinical practice. No differences were found between morning fasting and nonfasting values. Measurements in 151 healthy subjects aged 3 days to 53 years established normal values in relation to age. The use of this parameter in patients is shown to accurately reflect defects and changes in renal P handling. We believe it to be the preferred parameter because it represents a directly measured physiologic function applicable to all age-groups.

A New Kindred with Hereditary Hypophosphatemic Rickets with Hypercalciuria: Implications for Correct Diagnosis and Treatment

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a new autosomal form of hypophosphatemic rickets, recently described. This disease is characterized, and differs from other forms of hereditary hypophosphatemic rickets and/or osteomalacia by increased serum levels of 1,25-dihydroxyvitamin D, hypercalciuria and complete remission of the disease on phosphate therapy alone. However, only another probable Israeli kindred, and seemingly a few sporadic cases from Europe, North America and Japan have been reported in the literature. We describe here a new kindred of Jewish Yemenite origin (unrelated to other Israeli families) with typical HHRH. Two additional members of this family suffer from a milder asymptomatic form of the disease, which presents as absorptive hypercalciuria without signs or symptoms of bone disease. It seems to us that HHRH is underdiagnosed, due to its similarity to other hypophosphatemic syndromes in clinical, radiological and most biochemical parameters. Therefore, it is recommended that urinary calcium excretion and serum 1,25-dihydroxyvitamin D concentrations be measured in every patient with hypophosphatemic rickets/and or osteomalacia before the initiation of any therapy. The correct diagnosis of HHRN is of immense therapeutic implications. Phosphate therapy alone could cause a complete remission in HHRH, while the addition of active vitamin D metabolites, as is recommended in hypophosphatemic vitamin D resistant rickets, could cause deterioration in the patients condition.

Elevated Serum 1,25-Dihydroxyvitamin D Concentrations in Siblings with Primary Fanconi's Syndrome

THE de Toni–Debre–Fanconi syndrome,1 2 3 or Fanconis syndrome, is characterized by multiple abnormalities in renal tubular function. Defective handling of phosphate, glucose, and amino acids is th...

Maffucci's syndrome—The result of neural abnormalities? Evidence of mitogenic neurotransmitters present in enchondromas and soft tissue hemangiomas

Background. Maffuccis syndrome (MS) is distinguished by the enigmatic association of benign cartilaginous bone tumors and soft tissue hemangiomas.

Hyperoxaluria Is Not a Cause of Nephrocalcinosis in Phosphate-Treated Patients with Hereditary Hypophosphatemic Rickets

The treatment of X-linked hypophosphatemia (XLH) consists of phosphate and vitamin D3 derivatives. Transient hypercalciuria and hypercalcemia are well-known signs of vitamin D intoxication. Despite urinary calcium excretion control, the danger of nephrocalcinosis in treated patients has been emphasized. It has recently been suggested that hyperoxaluria might be a causative factor of nephrocalcinosis other than calcium in phosphate-treated XLH patients. We measured urinary oxalate and phosphate excretion in 12 patients with the syndrome of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) receiving only oral phosphates and in 5 XLH patients receiving both oral phosphates and vitamin D. No correlation was found between the dosage of phosphate supplements or urinary phosphate excretion and urinary oxalate excretion, in either group of patients. Nephrocalcinosis, presenting as hyperechogenicity of the medullary pyramids, was found in 2 of the 5 XLH patients and only in 2 HHRH patients who had been treated with excessive doses of vitamin D2 and calcium, prior to the true diagnosis being established. We conclude: (1) hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets; (2) prolonged phosphate treatment alone does not induce nephrocalcinosis in HHRH patients, and (3) we believe that in XLH patients, nephrocalcinosis is essentially due to vitamin D overdosage at some stage, or noncompliance in phosphate intake, leading to repeated undetected hypercalciuric periods.

Detection and incidence of anomalies associated with hypospadias

Hypospadias has been associated with synchronous congenital anomalies, especially in the urogenital system, and routine screening of patients with hypospadias has been advocated. In recent years, ultrasound (US) has replaced intravenous pyelography (IVP) as the primary screening test for urological deformities, yet there has never been a study of the relative diagnostic efficacy of the two tests in these patients. In this study, we assessed the incidence of urogenital and extraurogenital congenital anomalies in our hypospadias patients that were noted during physical examination and/or laboratory and imaging screening, and evaluated the efficacy of our changing routine screening protocols. We conducted a retrospective analysis of the charts of all hypospadias patients seen at Assaf Harofeh Medical Center. One hundred and sixty-three hypospadias patients fulfilled the documentation criteria we set for this study. We found a high incidence of urogenital and extraurogenital anomalies associated with hypospadias and noted a previously unreported increased incidence of various forms of facial dysmorphism. Additionally, we noted that the accepted concept that US or IVP alone were satisfactory screening tools for asymptomatic low-grade hypospadias patients is probably incorrect. Based on our findings, we recommend that initial screening of all asymptomatic hypospadias patients include US, cystogram, urinalysis, and urine culture.

Hereditary Hypophosphatemic Rickets with Hypercalciuria: Report of a New Kindred

We report a new kindred of hereditary hypophosphatemic rickets with hypercalciuria. The symptomatic child and several relatives had increased renal phosphate clearance leading to hypophosphatemia, hyperabsorptive hypercalciuria, low PTH and increased 1,25-(OH)2D serum level. However, association with vitamin D deficiency and normal urinary excretion of cyclic AMP might suggest another tubular defect in phosphate transport.