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A technique of oblique tibial osteotomy is described which is effective in correcting varus and medial rotational deformities in young children. The oblique cut in one plane corrects both elements of the deformity at the same time. We have used the method on both legs in four children and satisfactory results were obtained.
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.
Three polymorphic markers have been used to improve the genetic map of the region Xp22.1-p22.2, which contains the HYP (hypophosphataemic rickets) locus. DXS365 gave no recombinants with HYP, with a peak Lod score of 5.4 at theta = 0.0. A microsatellite marker mPA274 was derived for the DXS274 locus; it detects five alleles with a polymorphism information content of 0.55. Combining information from this microsatellite and the original DXS274 marker, probe CRI-L1391, the peak Lod score for DXS274 against HYP was 9.6 at theta = 0.02. A microsatellite associated with the DXS207 locus (mPA207) gave a peak lod score against HYP of 4.7 at theta = 0.14. A consideration of key recombinants and multilocus analysis suggests the gene order. Xpter-DXS207-DXS43-DXS197-(DXS365,HYP)- DXS274-DXS41-Xcen.
We have screened fourteen kindreds with X-linked hypophosphataemic rickets with four microsatellite markers, viz AFM163yh2, DXS999 (AFM234yf12), DXS443 and DXS365, in order to refine the genetic map flanking the gene, and to define a close flanking interval for the construction of a yeast artificial chromosome (YAC) and cosmid contig. The genetic data were enhanced after the isolation of a large 1.2-megabase YAC derived from AFM163yh2, in which marker DXS274 was present but not DXS365 or DXS443. Against HYP, DXS365, AFM163yh2 and DXS443 showed no recombinants (Zmax = 18.1, Zmax = 9.9, and Zmax = 16.0 respectively). DXS999 gave Zmax = 9.6 at 4% recombination and lies distal to HYP but proximal to DXS197 and DXS43. The disease gene and markers AFM163yh2 and DXS365 are flanked by DXS443 and DXS274. Combining the genetic and physical data, we are able to propose the following gene marker order: Xptel-DXS43-DXS197-DXS999-DXS443-[(DXS3 65-AFM163yh2), HYP]-DXS274-DXS41-Xcen.
Growth failure with disproportionate short stature is the major clinical feature of patients with X-linked hypophosphatemic rickets (HYP). We studied the pattern of linear growth and body proportion in an untreated normally growing HYP child also affected by Klinefelter's syndrome. Auxologic data were compared with those of a HYP half-brother who showed growth failure despite long-term treatment either with vitamin D or with vitamin-D-analog plus phosphate salt supplementation. The degree of body disproportion changed from negative values to positive values in the proband, whereas it was reduced in the half-brother. We conclude that, in the proband, the normal pattern of growth and the lack of the typical body disproportion as seen in HYP patients are attributable to the concomitant presence of Klinefelter's syndrome.
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X-linked hypophosphataemic vitamin D-resistant rickets is a rare cause of spinal canal stenosis. Two brothers with this condition presented in adulthood with thoracic myelopathy due to spinal canal stenosis. Both were treated by laminectomy using diamond-tipped burrs, with symptomatic improvement.
We have studied gluconeogenesis and intracellular pH levels in normal (+/Y) and X-linked hypophosphatemic (Hyp/Y) mice. Compared with +/Y littermates, Hyp/Y mouse osteoblasts showed a higher rate of glucose production from fructose (10-fold), glutamine, and malate, but no significant difference when alpha-ketoglutarate was used as substrate. The activities of the pentose cycle enzymes, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase, were not different in the two osteoblast preparations. Examination of intracellular pH (pHi) using the double excitation of the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM) revealed a significantly lower pHi in Hyp/Y mouse osteoblasts compared with +/Y mouse osteoblasts (7.01 +/- 0.03 n = 10 versus 7.15 +/- 0.04 n = 8, respectively; P < 0.05). These results show for the first time that osteoblasts are capable of glucose production and that glucose production is altered in the Hyp/Y mouse osteoblast. As altered gluconeogenesis has been associated with reduced intracellular pH in other systems, a similar mechanism may be operative in the Hyp/Y mouse osteoblast. The observed defects may be intrinsic to the Hyp phenotype as the alterations in intracellular pH and gluconeogenesis persisted in vitro, or they may represent impressed memory from the in vivo state and the presumed circulating factor that influences phosphate transport.
Vitamin D resistant hypophosphataemic rickets is a rare cause of spinal cord compression. The compression is caused by a combination of thickening of the laminae and calcification of the ligamentum flavum. Modern imaging techniques including CT and MRI provide excellent detail of both the level and degree of compression. MRI is particularly useful for examining the rest of the spinal cord for areas of impending compression and for postoperative follow-up. With careful surgical decompression a full neurological recovery can be achieved.
Human hypophophatemic vitamin D-resistant rickets (X-linked hypophosphatemia-XLH) is characterized by hypophosphatemia, a decreased tubular reabsorption of phosphate (P(i)) and defective skeleton mineralization. Utilizing a mouse model (Hyp) of XLH, which demonstrates biological abnormalities and skeletal defects of XLH, we analyzed sodium-dependent phosphate transport in isolated osteoblasts derived from the calvaria of normophosphatemic and hypophosphatemic mice. Initial rates of phosphate uptake by normal and Hyp osteoblasts showed similar slopes. Osteoblasts from both normal and Hyp mice exhibited saturable, sodium-dependent phosphate transport with apparent Vmax and Km values not significantly different (normal mice, Vmax = 24.30 +/- 3.45 nmol/mg prot. 10 min, Km = 349.49 +/- 95.20 mumol/liter; Hyp mice, Vmax = 23.03 +/- 3.41 nmol/mg prot. 10 min, Km = 453.64 +/- 106.93 mumol/liter, n = 24). No differences were found in the ability of normal and Hyp osteoblasts to respond to P(i) transport after 5 hours of P(i) deprivation. Both cell types exhibited a similar increase in cAMP in response to PTH. The accumulated results demonstrate that P(i) uptake and transport in normal and Hyp mouse osteoblasts is a sodium-dependent saturable process. As osteoblast P(i) uptake and transport is apparently normal in the Hyp mouse model of XLH, the "osteoblastic failure" described for the Hyp mouse should be attributed to other mechanism(s).
Ten symptomatic patients with skeletal abnormalities of varying etiology at the craniovertebral junction were studied with gas or metrizamide myelography. The type of compressive pathology was accurately delineated by these techniques. The surgical approach was determined by the findings on the myelograms.
Vitamin D-dependent rickets type II (VDDR II) is a rare syndrome resulting in severe rickets and is resistant to treatment with vitamin D and its derivatives. Patient with this disease, who are frequently the children of consanguinous marriages, present with elevated circulating concentrations of 1,25-dihydroxy vitamin D, the active metabolite of vitamin D, and in vitro studies have indicated a failure of intracellular binding of the hormone. Alopecia has been noted in many of these patients and it has been suggested that this feature may indicate a more marked resistance to treatment. However we describe a 3-year-old boy with this disease who, although having normal hair growth, displayed extreme resistance to treatment with active vitamin D metabolites. In vitro studies of skin fibroblasts disclosed not only an absence of hormone binding or 1,25(OH)2D3-induced 24-hydroxylase activity but reduced metabolism of 1,25(OH)2D3 itself. In this child, treatment with exogenous 1,25-dihydroxy vitamin D3 at doses of up to 24 micrograms/day, which increased the circulating concentration of the metabolite to greater than 100 times the normal adult mean, failed to alleviate his condition and he died at the age of 39 months. This would therefore suggest that absence of alopecia, in this condition, cannot be regarded as a constant predictive sign of a lesser resistance and of responsiveness to Vitamin D treatment.
In 1974, a 2-year-old boy was diagnosed as having X-linked hypophosphataemic rickets (XLH) because of severe rickets and hypophosphataemia. The vitamin D metabolite concentrations, blood and urine chemistry and renal 25-hydroxyvitamin D3 (25OHD3)-1 alpha-hydroxylase were measured in 1982 (about 2 weeks after withdrawal of medication). 1 alpha-hydroxylase was 392 pg/mg tissue/20 min in the patient, which was high compared with aged-matched controls (69.7 +/- 28.5 pg/mg tissue/20 min, mean +/- SD, n = 7). Our present studies showed that the 1 alpha-hydroxylase activity in the patient with XLH was elevated. Therefore, the normal or low 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) concentrations in XLH patients could be due to accelerated catabolism of 1,25-(OH)2D3 or abnormally regulated 25OHD3-1 alpha-hydroxylase in response to hypophosphataemia, although significantly elevated above that in normal controls.
A child is described with rickets and alopecia who did not respond to high doses of vitamin D3 but who responded to a small dose of 1-alpha-hydroxyvitamin D3. Treatment was continued for 2 years and then stopped. She has not shown any signs of relapse 1 year after stopping treatment. Her alopecia, however, has remained unchanged. One year after stopping treatment, her serum 25-hydroxycholecalciferol and parathormone levels were within normal limits but serum 1,25-dihydroxycholecalciferol was elevated.
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X-linked hypophosphatemia is characterized by low serum phosphorus, relative vitamin D deficiency and rickets. Despite adequate metabolic control with oral phosphate and vitamin D therapy, patients with X-linked hypophosphatemia have short stature. Whether growth hormone (GH) deficiency plays a role in short stature in patients with X-linked hypophosphatemia is not known. The purpose of this report was to investigate the response of GH to sequential paired pharmacological stimulation in patients with X-linked hypophosphatemia. Basal GH was 3.8 +/- 0.7 ng/ml, insulin-like growth factor-I (IGF-I) was 225 +/- 38 ng/ml and IGF binding protein-3 was 3.0 +/- 0.2 mg/l in 16 children studied with X-linked hypophosphatemia. In response to L-dopa and arginine hydrochloride stimulation, serum GH rose to above 7 mg/ml in all patients. Thus, the short stature in patients with X-linked hypophosphatemia is not due to a GH/IGF-I secretory defect.
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