Sang Whay Kooh

Pathogenesis of Hereditary Vitamin-D-Dependent Rickets

Abstract Requirements of vitamin D2, vitamin D3, 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3 were studied in five patients with vitamin-D-dependent rickets, a recessively inherited form of v...

Constitutively Activated Receptors for Parathyroid Hormone and Parathyroid Hormone–Related Peptide in Jansen's Metaphyseal Chondrodysplasia

BACKGROUND An activating mutation of the receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) was recently found in a patient with Jansenss metaphyseal chondrodysplasia, a rare form of short-limbed dwarfism associated with hypercalcemia and normal or low serum concentrations of the two hormones. To investigate this and other activating mutations and to refine the classification of this unusual disorder, we analyzed genomic DNA from six additional patients with Jansens disease. METHODS Exons encoding the PTH-PTHrP receptor were amplified by the polymerase chain reaction (PCR), and the products were analyzed by gel electrophoresis or direct nucleotide-sequence analysis. Nucleotide changes were confirmed by restriction-enzyme digestion of genomic DNA or the PCR products. RESULTS The previously reported mutation, which changes a histidine at position 223 to arginine (H223R), was found in genomic DNA from three of the six patients but not in DNA from their healthy relatives or 45 unrelated normal subjects. A novel missense mutation that changes a threonine in the receptors sixth membrane-spanning region to proline (T410P) was identified in another patient but not in 62 normal subjects. In two patients with radiologic evidence of Jansens metaphyseal chondrodysplasia but less severe hypercalcemia, no receptor mutations were detected. In COS-7 cels expressing PTH-PTHrP receptors with the T410P or H223R mutation, basal cyclic AMP accumulation was four to six times higher than in cells expressing wild-type receptors. CONCLUSIONS The expression of constitutively active PTH-PTHrp receptors in kidney, bone, and growth-plate chondrocytes provides a plausible genetic explanation for mineral-ion abnormalities and metaphyseal changes in patients with Jansens disease.

Treatment of Hypoparathyroidism and Pseudohypoparathyroidism with Metabolites of Vitamin D: Evidence for Impaired Conversion of 25-Hydroxyvitamin D to 1α,25-Dihydroxyvitamin D

In hypoparathyroidism and pseudohypoparathyroidism, pharmacologic doses of vitamin D correct hypocalcemia, but the mechanism is unknown. In two children with hypoparathyroidism and one with pseudohypoparathyroidism we tested the hypothesis that in these conditions there is a defect in synthesis of 1 alpha,25-dihydroxyvitamin D3, the principal active metabolite of vitamin D. In both conditions, minute doses of the metabolite (0.04 to 0.08 mug per kilogram of body weight per day) quickly corrected hypocalcemia and increased intestinal calcium absorption. On the other hand, the effective dose of 25-hydroxyvitamin D3 to maintain normocalcemia was 3 to 4 mug per kilogram per day in the two conditions. Thus, the dosage ratio of 25-hydroxyvitamin D3 to 1 alpha,25-dihydroxyvitamin D3 approximated 100:1. By contrast this ratio was approximately 3:1 in two infants with vitamin D deficiency, a condition in which optimal metabolism of vitamin D would be expected. These findings suggest an impaired conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D in both hypoparathyroidism and pseudohypoparathyroidism.

Rickets due to calcium deficiency

The importance of an adequate intake of calcium for normal skeletal growth and mineralization is well known. However, the dietary requirement for calcium is hard to define,1 2 3 4 5 6 and whether a...

Bone mass and soft tissue composition in adolescents with anorexia nervosa

The relationship between bone mass and compartments of soft tissue was studied in 22 adolescent women with anorexia nervosa (mean, 17 years). Results were compared to data on age- and gender-matched controls. Bone mass of the lumbar vertebrae and femoral neck, fat and lean tissue was measured by dual energy X-ray absorptiometry (DXA). Bone mass in the central third of the skeleton, by neutron activation analysis (NAA), and body protein, by prompt gamma ray analysis (PGA), was measured on patients, but not controls. The patients had significantly lower values than controls in total weight (26%), lean tissue (16%), fat (60%), bone mass of lumbar spine (14%), and femoral neck (15%). The mean calcium bone index (CaBI), the central skeletal calcium normalized for body size based on height, was significantly lower than the value for external controls, (0.86 +/- 0.10 vs. 0.97 +/- 0.10). The nitrogen index (NI), body protein normalized for height, showed a similar reduction from external controls (0.84 +/- 0.10 vs. 1.0 +/- 0.10). Bone mass (both DXA and NAA data) was strongly correlated to lean tissue and to protein; the correlations to fat were weaker. Follow-up studies after 7-26 months in 12 patients showed a modest increase in weight (mean, 4.9 kg) which was due, primarily, to an increase in fat with only insignificant increase in lean tissue and in protein. In bone mass, there was either no change or further loss. Only four restored body weight to normal (BMI > 20) and they achieved normal menstruation, but even these four responders showed no increase in bone mass. Our studies confirm that adolescent females with anorexia nervosa suffer losses not only in all compartments of body composition, but also demonstrate that the restoration of bone mass lags behind improvement in soft tissue compartments. These results were independent of methods used for the measurements.

Persistent Systemic Hypertension in Infants and Children

Formerly considered an interesting rarity, persistent hypertension in infants and children has become more easily detectable through improved methods of investigation and better amenable to control by diet, medication, and surgery. Normal blood pressure in children, its range and how to take it, definition of hypertensive levels, causes and presenting features in children, treatment, and prevention are explored.

Pathogenesis of rickets in chronic hepatobiliary disease in children

To investigate whether hepatobiliary rickets is caused by defective intestinal absorption of vitamin D or by impaired hepatic hydroxylation of the vitamin, we studied three children who developed severe rickets, hypocalcemia, and hypophosphatemia, two despite having received 400 to 800 IU vitamin D per day by mouth, and one despite prolonged treatment with 10,000 IU daily. On oral vitamin D therapy, plasma vitamin D and 25-hydroxyvitamin D levels were low. When two children were treated with weekly intravenous doses of 3,000 IU vitamin D to approximate the recommended prophylactic allowance, their plasma calcium and phosphate values improved promptly, the radiographic lesions healed, and the plasma concentrations of vitamin D and 25-hydroxyvitamin D became normal. Our studies indicate that the primary cause of hepatobiliary rickets is intestinal malabsorption of vitamin D, not impairment of the hepatic metabolism of the vitamin.

Observer reliability in grading nephrocalcinosis on ultrasound examinations in children

Background. Nephrocalcinosis is often associated with a variety of hypercalcemic conditions. Diagnostic ultrasound is often used for assessing nephrocalcinosis in children, but its reliability has not been proven. Objective. To determine the reliability of expert interpretation of sonographic films with a grading scale of severity for nephrocalcinosis. Materials and methods. Fifty-eight ultrasonographic films of 30 children with Williams syndrome and other conditions know to be associated with nephrocalcinosis were assessed. We used a blinded randomized design to assess intra- and interobserver reliability. Results. Grades I, II, and III nephrocalcinosis were noted in 13 %, 19 %, and 27 % of the examinations, respectively. The weighted kappa coefficient was 0.80 (standard error 0.12; 95 % confidence interval 0.68–0.92) for intraobserver agreement and 0.76 (standard error 0.13; 95 % confidence interval 0.63 to 0.89) for interobserver agreement. Reliability in assessing change from one examination to the next, with independently graded films, was fair with an unweighted kappa coefficient of 0.68 (95 % confidence interval 0.38–0.96) and 0.51 (95 % confidence interval 0.21–0.80) for intra- and interobserver reliability, respectively. Conclusion. The severity of nephrocalcinosis can be reliably interpreted with an ultrasonography grading scale.

Renal tubular acidosis and osteopetrosis with carbonic anhydrase II deficiency : pathogenesis of impaired acidification

Abstract. Renal tubular acidosis with osteopetrosis is an autosomal recessive disorder due to deficiency of carbonic anhydrase II (CAII). A 3.5-year-old Egyptian boy with osteopetrosis and cerebral calcification had a persistent normal anion gap type of metabolic acidosis (plasma pH 7.26) and a mild degree of hypokalemia. A baseline urine pH was 7.0; ammonium (NH4+) excretion was low at 11 μmol/min per 1.73 m2; fractional excretion of bicarbonate HCO3 (FEHCO3) was high at 9%, when plasma HCO3 was 20 mmol/l; citrate excretion rate was high for the degree of acidosis at 0.35 mmol/mmol creatinine. Intravenous administration of sodium bicarbonate led to a urine pH of 7.6, a FEHCO3 of 14%, a urine-blood PCO2 difference of 7 mmHg, NH4+ excretion fell to close to nil, and citrate excretion remained at 0.38 mmol/mmol creatinine. Intravenous administration of arginine hydrochloride caused the urine pH to fall to 5.8, the FEHCO3 to fall to 0, the NH4+ excretion rate to rise to 43 μmol/min per 1.73 m2, and citrate excretion to fall to <0.01 mmol/mmol creatinine. These results show that our patient had a low rate of NH4+ excretion, a low urine minus blood PCO2 difference in alkaline urine, and a low urinary citrate excretion, but only when he was severely acidotic. He failed to achieve a maximally low urine pH. These findings indicate that his renal acidification mechanisms were impaired in both the proximal and distal tubule, the result of his CAII deficiency.

Prolonged high-dose phosphate treatment: a risk factor for tertiary hyperparathyroidism in X-linked hypophosphatemic rickets

objective X‐linked hypophosphatemic rickets is characterized by renal phosphate wasting, hypophosphatemia and defective bone mineralization. Treatment with oral phosphate (Pi) and calcitriol improves skeletal changes but associates with secondary hyperparathyroidism and nephrocalcinosis. Tertiary hyperparathyroidism is a rare complication of the treatment. The aim of the present study was to identify treatment‐related factors that might be associated with the transition of secondary hyperparathyroidism to tertiary hyperparathyroidism in patients with X‐linked hypophosphatemic rickets.