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.

Diagnosis of phosphaturic mesenchymal tumor (mixed connective tissue type) by cytopathology.

Oncogenic osteomalacia (OO) is a rare paraneoplastic condition in which a bone or soft tissue tumor induces biochemical and clinical signs and symptoms of osteomalacia (or rickets) most often by the production of the phosphaturic protein, fibroblast growth factor-23. Phosphaturic mesenchymal tumor, mixed connective tissue type (PMTMCT) is a rare, histologically distinct tumor that represents the most common cause of OO. As the clinical diagnosis of OO is typically suspected on the basis of clinical and biochemical features and the presence of a bone or soft tissue tumor, cytologic examination might potentially provide the necessary pathologic confirmation of OO. In this case of a 46-year-old female with clinical stigmata of OO and a right distal humeral mass, we report that the fine-needle aspiration findings of short, cytologically bland spindled cells embedded in a fine, fibrillary stromal-rich matrix and the presence of osteoclast-type giant cells associated with the stromal matrix provide strong pathological evidence for PMTMCT and assist in pathologically confirming the clinical impression of OO, thus alleviating the need for a more invasive diagnostic surgical procedure.

Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.

An autosomal recessive form of hypophosphatemia (ARHP) was recently shown to be caused by homozygous mutations in DMP1, the gene encoding dentin matrix protein-1 (DMP-1), a non-collagenous bone matrix protein with an important role in the development and mineralization of bone and teeth. Here, we describe a previously not reported consanguineous ARHP kindred in which the three affected individuals carry a novel homozygous DMP-1 mutation. The index case presented at the age of 3 years with bowing of his legs and showed hypophosphatemia due to insufficient renal phosphate retention. Serum alkaline phosphatase activity was elevated, with initially normal PTH. FGF23 was inappropriately normal at an older age while being treated with oral phosphate and 1,25(OH)(2)D. Similar clinical and biochemical findings, except for elevated FGF23 levels, were present in his 16-month-old brother and his 12.5-year-old female cousin; the parents of the three affected children are first-degree cousins. Nucleotide sequence analysis was performed on PCR-amplified exons encoding DMP-1 and flanking intronic regions. A novel homozygous frame-shift mutation (c.485Tdel; p.Glu163ArgfsX53) in exon 6 resulting in a premature stop codon was identified in all effected individuals. The parents and available unaffected siblings were heterozygous for c.485Tdel. Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent and deciduous teeth displayed enlarged pulp chambers. The identified genetic mutation underscores the importance of DMP-1 mutations in the pathogenesis of ARHP. Furthermore, DMP-1 mutations appear to contribute, through yet unknown mechanisms, to tooth development.

[X-ray features of vitamin D-deficiency and vitamin D-resistant rickets].

To study the age-related features of growth areas and to detect the x-ray background of recurrent deformities in patients with rickets-like diseases, the investigators analyzed knee arthrograms in 74 patients aged 4 to 16 years (28 and 46 patients with vitamin D-deficiency or vitamin D-resistant rickets (phosphate diabetes), respectively) prior to treatment and in the late period.

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.

Hypophosphatemic rickets: the role of hemiepiphysiodesis.

Despite early medical intervention, children with hypophosphatemic rickets often have progressive deformities in the lower extremities. With the forces imparted by gravity and weight bearing, varus or valgus deformities that might otherwise have been physiological are likely to progress, causing gait disturbance and pain. Proper medical management is important and may theoretically slow or prevent the progression of varus or valgus, but is ineffective at correcting deformity once established. We have reviewed the literature and gathered a series of 10 patients, most of whom underwent hemiepiphysiodesis. We are presenting the rationale for, and the results of, that surgery, in an effort to define the role of this minimally invasive procedure.

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.

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.

Growth and metabolic control during puberty in girls with X-linked hypophosphataemic rickets.

OBJECTIVE: X-linked hypophosphataemic rickets (XLH) results in defective bone mineralization and impaired growth. Treatment with oral phosphate (Pi) and calcitriol improves but does not normalize growth. This study assessed whether pubertal growth and metabolic control contribute to the height deficit. METHODS: Study included patients with XLH who were treated with Pi-calcitriol from diagnosis to adult height; their hospital records, biochemistry and radiographs were reviewed. RESULTS: Six females with XLH were included. Their mean peak height velocity and total height gain during puberty were nearly normal despite deteriorating metabolic control. CONCLUSIONS: In treated girls with XLH, the pubertal growth is nearly normal despite suboptimal metabolic control. The major height loss occurs prior to puberty and is not recovered during the pubertal growth spurt.

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.

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.

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.

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.

Lumbar and radial bone mineral density in children and adolescents with X-linked hypophosphatemia: evaluation with dual X-ray absorptiometry.

OBJECTIVE: To evaluate the bone mineral status of children being treated for X-linked hypophosphatemia, including potential differences between cortical bone in the radial diaphysis and combined cortical and trabecular bone in the lumbar spine. DESIGN AND PATIENTS: Forty-four bone mineral evaluations were performed in 11 children and adolescents with X-linked hypophosphatemia. Bone mineral density (BMD) of the lumbar spine and the radial diaphysis were measured by dual X-ray absorptiometry (DXA), second metacarpal cortical thickness was measured on hand radiographs, and these results were expressed as Z-scores (standard deviations from the mean). RESULTS: For the 11 initial examinations, Z-scores (mean+/-SD) were: radial BMD, -2.73+/-1.15, lumbar BMD, +1.28+/-1.53; and cortical thickness, -2.21+/-0.95. Lumbar BMD Z-scores were significantly greater than those for radial BMD and cortical thickness. On follow-up examinations there was a mild increase in radial BMD and decrease in lumbar BMD. Although these changes were statistically significant, they were quite small and the discordance between radial and lumbar BMD was not corrected. CONCLUSIONS: Children and adolescents who are being treated for X-linked hypophosphatemia manifest a bone mineral disorder characterized by decreased BMD in the appendicular skeleton and increased BMD in the lumbar spine. Although current therapy is successful in its anti-rachitic effects, it does not correct this bone mineral disorder and additional therapeutic trials should be considered.

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).