Benign prenatal hypophosphatasia: a treatable disease not to be missed.

Prenatal bowing of the long bones is often associated with severe bone dysplasias. We report a child who presented marked bowing of the long bones at birth but showed a relatively benign postnatal course with spontaneous improvement of bowing. The fetal imaging showed normal skeletal mineralization and normal chest and abdominal circumferences despite the limb bowing and shortening. Decreased serum alkaline phosphatase activity and elevated urine phosphoethanolamine was biochemically evident, and compound heterozygous mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene were identified, which confirmed the diagnosis of a benign form of prenatal hypophosphatasia. Benign prenatal hypophosphatasia should be considered in the differential diagnosis of congenital bowing of the long bones.

Two novel PHEX mutations in Taiwanese patients with X-linked hypophosphatemic rickets.

BACKGROUND: X-linked hypophosphatemic rickets (XLH) is an X-linked dominant disease characterized by renal phosphate wasting, hypophosphatemia, aberrant vitamin D metabolism, and defective bone mineralization. The disease is caused by mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X-chromosome) located at Xp22.1. To date, a variety of PHEX mutations have been identified in these patients. METHODS: PCR and direct sequencing was performed for all exons and intron-exon boundaries of the PHEX gene in two XLH families. RESULTS: Two novel mutations, including a missense mutation (L206W) in exon 5 and a frameshift mutation (nucleotide 1826_1830delAAAAG, stop after codon 610) in exon 18 were discovered and the laboratory and radiographic findings for these patients analyzed. CONCLUSIONS: We found that PHEX gene mutations were responsible for XLH in these Taiwanese patients. Additional studies are needed to enhance understanding of the role of PHEX in XLH pathogenesis.

Surgical treatment of femoral bending deformity in a patient with vitamin D-resistant rickets.

Surgical treatment of patients with vitamin D-resistant rickets is reserved for management of severe deformities or pathological fractures of the lower limbs. This case report describes the operative management of a child with vitamin D-resistant rickets suffering from a pathological fracture and a bending deformity of the right femoral bone. A modified technique of fragmentation and realignment by intramedullary fixation was performed using an unreamed humerus nail. We corrected the anatomical proximal femoral shaft angle (aMPFA) from 68 degrees to 84 degrees and achieved three more centimetres of femoral length. The same procedure was performed on the left femur and corrected the aMPFA from 108 degrees to 89 degrees and gained 2.5 more centimetres of femoral length. Thus the legs were almost equal in length. We preferred the modified technique of multiple osteotomies and intramedullary fixation by nailing (originally described by Sofield and Millar) because the correction of angulation and rotation of the femoral shaft in one step appeared to be much easier than with plate fixation. Moreover, this method seems to reduce the number of refractures and enables the patients to approach the normal activities of growing children.

Vitamin D-dependent rickets type II in a cat.

A cat with clinical signs Indicating rickets was diagnosed as having a defect of vitamin D receptors. Clinical signs had been seen from four months of age. Treatment with calcium supplementation and various forms of vitamin D did not alter plasma calcium levels or reverse skeletal lesions of lateral antebrachial bowing, lumbar spinal lordosis and costochondral beading. Analgesics were effective for relieving skeletal pain during the bone growth phase and were withdrawn when the animal reached skeletal maturity. Therapy for hip osteoarthritis was given from five years of age until the cat was euthanased at nine years of age as a result of refractory hip pain.

Identification of fifteen novel PHEX gene mutations in Finnish patients with hypophosphatemic rickets.

We have carried out a mutation screening of the PHEX gene in Finnish patients with hypophosphatemia. A total of 100% (5/5) of the familial HYP patients (X-linked hypophosphatemia) and 93% (14/15) of the sporadic cases were found to carry a mutation in the PHEX gene. We identified 18 mutations, of which 15 were novel. We report also a new polymorphism 46bp upstream of exon 16. Two families were segregating the same nonsense mutation in exon 1 (R20X), but since this mutation has been previously reported in three independent studies, we consider it to be a mutational hotspot rather than a Finnish founder mutation. We did not find PHEX gene mutations in two additional hypophosphatemia families in which the mode of inheritance was other than X-linked dominant. Also, no mutation could be detected in a patient with suspected oncogenic osteomalacia (OHO).

Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets.

X-Linked hypophosphatemic rickets (XLH) is characterized by hypophosphatemia, rickets, and impaired growth. Despite oral phosphate and 1,25-dihydroxyvitamin D(3) treatment, many patients have suboptimal growth and bone healing. The aim of this study was to assess whether age at treatment onset impacts the outcome. Growth data, biochemistry, and radiographs of 19 well-controlled patients with XLH were analyzed retrospectively. Patients were divided into two groups based on the age at treatment onset (group 1, <1.0 yr; group 2, >or=1.0 yr). The median height z-score was higher in group 1 (n = 8) than in group 2 (n = 11) at treatment onset [-0.4 SD score (SDS) vs. -1.7 SDS; P = 0.001], at the end of the first treatment year (-0.7 SDS vs. -1.8 SDS; P = 0.009), throughout childhood (P > 0.05) and until predicted adult height (-0.2 SDS vs. -1.2 SDS; P = 0.06). The degree of hypophosphatemia was similar in both groups, but serum alkaline phosphatase remained higher in group 2 throughout childhood. Radiographic signs of rickets were more marked in group 2, but even patients with early treatment developed significant skeletal changes of rickets. These data suggest that treatment commenced in early infancy results in improved outcome in patients with XLH, but does not completely normalize skeletal development.

Long-term therapy of viramin D-resistant richets with 25-hydroxycholecalciferol.

The long-term effects of the vitamin D metabolite, 25-hydroxycholecalciferol (25-HCC), were evaluated in 2 children with hypophosphatemic vitamin D-resistant rickets. Serial total balance studies demonstrated an apparent lack of correlation between the effects of the vitamin on intestinal absorption of calcium and phosphorus and both the onset of healing in 1 of the 2 patients treated with 5,000 to 7,500 u of the metabolite and the absence of demonstrable radiologic improvement in another patient in whom the final dosage was 20,000 u. per day. At first, the metabolite induced a positive calcium balance in both patients resulting largely from a reduction in intestinal calcium excretion. Despite a continued positive calcium balance, 1 of the 2 patients did not demonstrate further healing, while in the other patient healing was noted even when total calcium balance was negative. Serum phosphate levels did not return to normal in either patient, nor was phosphate excretion altered by 25-HCC. Serum alkaline phosphatase remained elevated in both. Serum immunoassayable parathyroid hormone levels were consistently normal to high-normal in the 2 patients throughout more than 24 months of observation. No instances of hypercalcemia and only occasional hypercalciuric episodes were noted.

X-linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography, and absorptiometry.

PURPOSE AND PATIENTS AND METHODS: X-linked hypophosphatemia (XLH) is the most common inherited form of rickets, yet its influence on skeletal mass in adulthood is controversial and incompletely characterized. Accordingly, we measured bone mass at several skeletal sites using histomorphometric and radiographic techniques in 19 adults (four men) with XLH (age range 20 to 66 years). Most subjects had not received medical therapy for XLH since puberty. RESULTS: Eight of 14 subjects who underwent transiliac bone biopsy had an elevated cancellous bone volume (osteoid and calcified bone), and the group's mean value was supranormal (p less than 0.01). Mineralized bone volume, however, was above normal in only three subjects (NS). Another measure of trabecular bone density, vertebral mineral density by computed tomography, was elevated in three of 13 subjects, and the mean value of the group was increased (p = 0.05). Integral spine bone mineral density (BMD) assessed by dual photon absorptiometry (DPA) was elevated in six of 16 subjects, and the mean was also above normal (p less than 0.01). However, total body calcium, total body BMD (both by DPA), and forearm bone mineral content assessed by single photon absorptiometry (predominantly cortical bone) were normal in almost all subjects, as were the group means for these parameters. Mean regional BMD (by DPA) was below normal in the upper and lower limbs (p less than 0.001) and above normal in the spine (p less than 0.005) and ribs (p less than 0.01). There was no relationship between these indices of bone mass and either biochemical or clinical parameters of disease severity, although men tended to have higher z-scores for axial bone density than premenopausal women whose values, in turn, tended to be higher than those in postmenopausal women (NS). CONCLUSION: We conclude that axial bone mass tends to be increased in adults with XLH, sometimes dramatically so, and this is only partially attributable to hyperosteoidosis. Peripheral bone mass, however, tends to be diminished. Despite these group trends, most adults with untreated XLH have normal indices of bone mass as assessed by a variety of techniques at the commonly used measurement sites. These findings suggest that "osteoporotic" fractures are unlikely to develop as a late complication of XLH in adults.

Tumor-induced osteomalacia and rickets.

Tumor-induced osteomalacia is a clinicopathological entity in which vitamin D-resistant osteomalacia or rickets occurs in association with a tumor. A total of 72 cases (three current, 69 from review of literature) has been reported to date. Men and women are equally affected. The majority are adults over 30 years old who exhibit progressive lower leg and back pain. Forty bone and 31 soft-tissue tumors were responsible for this syndrome; two-thirds occurred in the extremities. Chemical findings are typical: low serum phosphorus, normal serum calcium, and elevated alkaline phosphatase. Serum levels of 1,25-dihydroxyvitamin D were low or undetectable. Histologically, more than a third were classified as vascular tumors, and half of these cases were hemangiopericytomas that were distributed equally between bone and soft tissues. Other common diagnoses included nonossifying fibromas, "mesenchymal" and giant-cell tumor variants. Features common to all tumors were prominent vascularity, and giant and primitive stromal cells. Only 10 were histologically malignant. Ultrastructural studies have not shown any secretory granules suggestive of a hormone-secreting tumor. It is clear, however, that the tumor is responsible for the osteomalacia because the complete removal generally results in a dramatic reversal of all symptoms and signs.

Hypophosphatemic vitamin D-resistant rickets: metabolic balance studies in a child receiving 1,25 dihydroxyvitamin D3, phosphate, and ascorbic acid.

A child with hypophosphatemic vitamin D-resistant rickets was treated for three years with the conventional vitamin D-inorganic phosphate supplementation followed by a new therapeutic regimen consisting of 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3) and half of the previous phosphate supplementation. The effectiveness of the two treatment regimens was compared by calcium, phosphate, and magnesium balance techniques and by serial radiological examinations as well as careful height measurements. In addition, the lowering of the urinary pH with ascorbic acid supplementation seems to be associated with improvement in the renal tubular reabsorption of phosphate, but its distinct effect, separate from the rest of the treatment modalities, was not tested in this study. The conventional treatment did not correct the hypophosphatemia and alkaline phosphatase elevation, whereas the 1,25 (OH)2 D3-inorganic phosphate regimen is well tolerated and effective in achieving a sustained normalization of these variables. In addition, the improved growth and healing of rickets further attest to the efficacy of the new treatment.

Increased bone mineral content in young adults with familial hypophosphatemic vitamin D refractory rickets.

Seven adults with familial hypophosphatemia have been investigated by histologic and radiographic examination of bone, and estimates of bone mineral status by in vivo neutron activation analysis (IVNAA). Histological examination showed severe osteomalacia and osteosclerosis in all cases. Radiography showed skeletal deformities and other sequelae of severe rickets of childhood in five of the seven cases, with, in addition, thickened well-mineralized bones; the other two showed normal radiographs. IVNAA measurements showed that the first five had greater than normal bone calcium and that the other two had normal values. Thus, in all cases there is a greater than normal total bone tissue (osteoid and mineralized bone together). The quantitative body calcium measurements show clearly that osteosclerosis occurs in familial hypophosphatemia, confirming the opinions based on histological and radiological data. Although there has been occasional reference to this sclerosis in the literature, up to the present it has received little attention.

Axial osteomalacia with sacroiliitis and moderate phosphate diabetes: report of a case.

We report a new case of axial osteomalacia diagnosed in a 51-year-old white Caucasian male, made particular by its association with sacroiliitis, positive HLA-B27 antigen, and also moderate phosphate diabetes responsible for a decreased appendicular bone mass. The diagnosis was suspected when X-ray evaluation showed increased density and coarse trabeculation mainly involving the pelvis and spine. Dual energy X-ray absorptiometry confirmed the elevated bone density at the lumbar spine (T score: +1.92) contrasting with a decreased bone mass at the femoral neck (T score: -2.33). The diagnosis was confirmed by histomorphometry of the iliac crest showing marked thickening of the cortices (2190 microns +/- 0.574, N = 780 +/- 40) and an increased trabecular bone volume (33.24%, N = 14 +/- 3). Osteoid parameters were also markedly increased with an osteoid volume of 2.1% (N = 1.2 +/- 0.5) and a mean osteoid thickness of 28.7 microns (N = 13 +/- 2.5), with a normal bone fluoride content (0.082%, N < 0.10). Bone resorption as assessed on bone biopsy and by the measurement of markers of bone remodeling (serum procollagen type I C-terminal telopeptide and 24 hr urinary cross-laps to creatinine ratio) was increased. This latter finding was not necessarily due to axial osteomalacia and could be the consequence of moderate phosphate diabetes. The patient was treated with calcitriol which was promptly discontinued due to gastrointestinal symptoms and replaced by calcidiol without any significant effect on the low back pain.

Adult-onset vitamin D-resistant hypophosphatemic osteomalacia. A possible variant of vitamin D-resistant rickets.

A family of 133 members showing unusual manifestations of vitamin D-resistant hypophosphatemic osteomalacia was studied. The hypophosphatemic children did not have rickets or clinical femoral bowing: the hypophosphatemic young adults had minimum clinically evident femoral bowing; and the older adults (age forty and older) were progressively disabled by severe bowing. The disorder appears to be an X-linked dominant, with almost complete penetrance of the hypophosphatemic trait. The etiology of this disorder could not be determined.

Linear sebaceous naevus syndrome and resistant rickets.

The association between vitamin-D-resistant rickets and linear sebaceous naevus syndrome is extremely rare. Only eight cases have been described in the English literature and in none were the skeletal aspects addressed. We present three new cases and describe the musculoskeletal features. The details and outcome of surgery for correction of the deformities are discussed. The disturbances of metabolism of vitamin D and the effects of pharmacological treatment are also described.

Adult hypophosphatemic osteomalacia: report of two cases.

Two cases of late hypophosphatemic osteomalacia are described: a male aged 30 who had the disease since he was 22 and a woman of 23 who had the disease since she was 14. Both presented with myopathy and bone pain, and showed hypophosphatemia, hyperglycinuria, reduced tubular phosphate reabsorption (TPR), increased hydroxyprolinuria and normal iPTH and iCT values. Radiologically the male had no Looser's zones and the woman did. Bone biopsy confirmed hypophosphatemic osteomalacia. Both cases were treated with vitamin D and oral phosphate and no improvement was observed. When treatment with 25(OH)D3 was initiated, no improvement was seen and afterwards this was combined with treatment using 1.25(OH)2D3 and from this time on a clinical improvement of the myopathy became evident in both patients. In the woman, healing of the bone lesions occurred at the same time as that of the myopathy, whereas in the male the bone lesions became worse. Healing of the myopathy was only obtained when treatment with 1.25(OH)2D3 was begun. Both patients had reduced values of 2.3 erythrocytic DPG and low level of serum phosphorus when the myopathy was cured, which suggests a lack of effect of 2.3 DPG or serum phosphorus as a cause of the myopathy. Although this had been attributed to a deficiency in the function of 25(OH)D3, the response to 1.25(OH)2D3 and due to the effects of this metabolite on calcium transport in muscle, suggests that the myopathy which occurs in late hypophosphatemic osteomalacia is a result of deficiency or resistance to the muscular effect of this metabolite. We cannot explain the lack of bone healing in the man and further therapeutic studies are required.

Prenatal diagnosis of congenital hypophosphatasia in a consanguineous Bedouin couple. A case report.

BACKGROUND: Hypophosphatasia is a rare autosomal recessive metabolic disorder characterized by low serum and tissue alkaline phosphatase activity, increased urinary excretion of phosphoethanolamine and ricketslike changes in the bone. CASE: We present a case of prenatal diagnosis of congenital hypophosphatasia in a consanguineous Bedouin couple. The case was diagnosed at 24.5 weeks of gestation. Sonographic evaluation revealed a fetus with short and deformed bones and a hypoechogenic skull. Based on the sonographic findings and the obstetric history of the couple, hypophosphatasia was diagnosed. The parents opted for pregnancy termination. Feticide was accomplished uneventfully. Laboratory findings confirmed the diagnosis. CONCLUSION: This couple was prone to this metabolic disorder due to their consanguineous marriage and previous affected fetus. Early-first-trimester prenatal diagnosis by first-trimester chorionic villus sampling or second-trimester measuring of alkaline phosphatase activity in the amniotic fluid is required to exclude this lethal disease in subsequent pregnancies.

Hypophosphatemic osteomalacia demonstrated by Tc-99m MDP bone scan: a case report.

Hypophosphatemic osteomalacia, a familial or rarely acquired disorder, is characterized biochemically by hypophosphatemia, decreased renal tubular reabsorption of phosphate, decreased intestinal absorption of calcium, and normal serum calcium. This report concerns a rare case of hypophosphatemic osteomalacia of unknown cause that was shown on Tc-99m MDP bone scanning.

[Familial hypophosphoremic rickets: pathogenic considerations based on two cases (author's transl)]. / Raquitismo hipofosforémico familiar: consideraciones patogénicas a propósito de dos observaciones.

Familial hypophosphoremic rickets, although exceptional, is a frequent form of presentation in communities where nutritional rachitism has been eradicated. Hypophosphoremia is the biochemical defect which led to an insuffieient osseous mineralization. The real pathogenic mechanism of the disease is still unknown. Two patients, mother and son, who presented anamnesic, biochemical and roentgenographic characteristics suggesting a familial hypophosphoremic rachitism are reported. Clinical, biochemical and roentgenologic data of a secondary reactive hyperparathyroidism were absent in both cases. The present knowledge on the metabolic pathway of vitamin D and its metabolites led us to consider that the basic pathogenic defect appears as a consequence of an intestinal malabsorption of phosphates due to an altered synthesis of 1,25-dihydroxycholecalciferol or its precursor 25-hydroxycholecalciferol.

X-linked hypophosphatemic rickets--a report of 2 cases and review of literature.

We report two cases of x-linked dominant hypophosphatemic rickets involving a man and his daughter. The family tree consists of 44 members with 13 of them having short stature and bowing of the lower limbs. The study of this family tree strongly suggests an x-linked dominant inheritance.