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.

Primary infantile hypomagnesaemia: outcome after 21 years and treatment with continuous nocturnal nasogastric magnesium infusion.

UNLABELLED: Primary infantile hypomagnesaemia is an infrequent cause of neonatal hypocalcaemic seizures but one that responds well to magnesium supplementation. We describe a 22-year-old male, first reported at 4 months of age, who is currently free of neurological deficit but has suffered from intermittent hypomagnesaemic tetany and chronic diarrhoea due to large oral magnesium supplements. Hypothesizing that modest hypercalcaemia might prevent the tetany, we conducted a trial of 5 microg/day 1,25(OH)2D3 over 5 days. Despite the resultant increase in calcium, he developed tetany with the reduction of magnesium intake and decline of serum magnesium from 0.63 to 0.39 mmol/l (normal >0.65 mmol/l). After 1,25(OH)2D3 was stopped and the parenteral magnesium injections suspended, 33% of his usual oral supplement was given instead by continuous nasogastric infusion and serum magnesium rose to 0.60 mmol/l. This regimen was better tolerated because of decreased gastrointestinal side-effects and freedom from parenteral injections. We observed that 1,25(OH)2D3 supplements do not promote magnesium retention nor does the resultant hypercalcaemia prevent hypomagnesaemic tetany. CONCLUSION: Continuous nocturnal nasogastric infusion may be considered in lieu of parenteral therapy in primary infantile hypomagnesaemia.

Growth hormone deficiency in autoimmune polyglandular disease type 1.

This is a case report of 2 patients who were diagnosed to have autoimmune polyglandular disease type 1. Both developed mucocutaneous candidiasis, hypoparathyroidism, vitiligo, and adrenocortical insufficiency. Both were noticed to have subnormal linear growth velocity and delayed bone age. Both showed subnormal stimulated serum growth hormone values indicating growth hormone deficiency. The first case showed favorable response to growth hormone therapy.

A trial of growth hormone therapy in well-controlled hypophosphataemic rickets.

OBJECTIVE: Conventional therapy of hypophosphataemic rickets (HR) with oral phosphate and calcitriol does not always result in normal linear growth. Recombinant human growth hormone (rhGH) offers theoretical advantages as an adjunctive therapy. We aimed to determine the effects of adjunctive rhGH therapy in children with well-controlled HR. PATIENTS: In this report, 5 prepubertal children (aged 3.5-10.9 years) with well-controlled HR on conventional therapy were given adjunctive standard dose rhGH therapy for one year. DESIGN AND MEASUREMENTS: Height, growth velocity, metabolic markers of calcium and phosphate metabolism, body composition, bone mineral density, wrist and knee X-rays, and renal sonography were assessed at regular intervals. Height and growth velocities were also calculated 12 months after ceasing rhGH therapy. RESULTS: After 12 months therapy with rhGH, no significant biochemical or radiological benefits were observed. A significant increase in height SD score was observed (P = 0.023), but this was not associated with any increase in the growth velocity SD score and appears to have been due to catch-up growth caused by conventional therapy alone. When rhGH therapy was ceased, no significant decreases in mean height SD or growth velocity SD scores were observed. CONCLUSIONS: In well-controlled hypophosphataemic rickets patients receiving conventional therapy, adjunctive therapy with standard dose rhGH offers no benefits in linear growth or rachitic disease markers.

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.

Asymmetric medullary nephrocalcinosis in two children.

Medullary nephrocalcinosis (MNC) is usually a bilateral process with symmetric involvement of both kidneys. Asymmetric medullary nephrocalcinosis has been previously reported in the literature, but has not been well illustrated or explained. We report the sonographic findings in two pediatric patients with hypercalcemia. In both patients an unrelated unilateral renal abnormality, (renal vein thrombosis in one and obstructive hydronephrosis in the other) prevented the development of MNC in the affected kidney, probably by decreasing the glomerular filtration rate and/or altering the renal tubular function.

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

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 has 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 mumol/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 mumol/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.

A new classification for renal defects in net acid excretion.

The traditional classification of the group of disorders called renal tubular acidosis (RTA) into proximal and distal subclasses is based on which nephron segment is thought to have an abnormal function. Nevertheless, such a distinction may not be correct and also does not characterize the pathophysiology of the renal acidosis in each patient. In this article, we propose an alternative classification, one that is based on the component of net acid excretion that is abnormal. We also suggest expanding the definition of net acid excretion to include a term that describes the renal handling of metabolizable organic anions because their loss in the urine represents the loss of "potential bicarbonate." Because a low rate of excretion of ammonium (NH4+) is present in patients with both distal and isolated proximal RTA, our initial clinical step in patients with hyperchloremic metabolic acidosis (HCMA) is to evaluate the rate of excretion of NH4+. The basis for a low rate of excretion of NH4+ is shown by examining the urine pH. If the urine pH is low, further studies are performed to determine why the availability of NH3 is low; if the urine pH is high, further investigations are initiated to examine if the defect in H+ secretion involves the proximal or the distal nephron. Conversely, if the rate of excretion of NH4+ is high in a patient with HCMA, a component of the degree of acidosis could be attributable to a high rate of excretion of metabolizable organic anions. Case examples are provided to illustrate the approach and its implications for future molecular studies.

Primary hyperparathyroidism in a paediatric hospital.

We retrospectively reviewed the presentation and management of children with primary hyperparathyroidism (PHPT) from 1973 to 1995 at a paediatric tertiary-care centre. There were 11 patients (6 females), aged 12.3-17.7 years at presentation, with sporadic PHPT confirmed by histopathology (single adenoma). Presentation consisted of renal colic, or non-specific gastrointestinal, musculoskeletal or neurological symptoms. Misdiagnosis was common until hypercalcaemia was identified, 0.5-24 months after onset of symptoms (mean 7.7 months). All patients had hypercalcaemia and low-normal serum phosphate. The parathyroid hormone (PTH) radioimmunoassay used before 1986 was elevated in 1/4 patients; the intact PTH assay used after 1986 was elevated in 7/7 patients. At presentation, six had end-organ damage: band keratopathy, renal lesions, and/or bone disease. Preoperative localization was accurate in 0/4 patients diagnosed before 1986, but 5/7 patients diagnosed after 1986: three by ultrasound or sestamibi scan alone, and two by ultrasound and technetium scan. Surgical outcome was not dependent upon the accuracy of pre-operative localization. PHPT is rare in children but usually associated with end-organ damage, presumably due to delayed diagnosis. It should be considered in the differential diagnosis of unexplained non-specific complaints. The intact PTH assay greatly assists pre-operative diagnosis. The usefulness of pre-operative localization requires further research.

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 Jansens's 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 Jansen's 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 receptor's 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 Jansen's 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 Jansen's disease.

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.

Persistence of Vitamin D-deficiency rickets in Toronto in the 1990s.

To assess the current picture of vitamin D deficiency, we reviewed all 17 cases of vitamin D-deficiency rikets seen in the referral clinic of a children's hospital in Toronto between 1988 and 1993. The diagnosis was made at 7 to 33 months of age. All the children were symptomatic all had biochemical and radiographic abnormalities, two suffered hypocalcemic seizures, and all had bowing of the extremities. Twelve of the children were born to parents who were recent immigrants to Canada. All were of Asian or African origin with dark skin. All the children had been exclusively breastfed with no vitamin D supplementation, and had had little or no sunlight exposure. All the patients responded to vitamin D therapy. We conclude that vitamin D-deficiency rickets remains an environmental/nutritional deficiency disease in this city and that efforts at prevention should target children with pigmented skin from families who are recent immigrants.

Normal parathyroid hormone responsiveness of bone-derived cells from a patient with pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is characterized by a lack of response to parathyroid hormone (PTH); however, normal skeletal responsiveness to PTH in some patients with PHP type Ia was previously suggested on the basis of clinical observations. To test this hypothesis, we measured cyclic adenosine monophosphate (cAMP) production in response to various agonists in bone-derived osteoblast-like (OBL) cells from trabecular explants obtained from an iliac crest biopsy of a 25-year-old woman with PHP. The patient was proved to have PHP type Ia on the basis of Albright's hereditary osteodystrophy and decreased activity of stimulatory guanine nucleotide-binding protein (Gs) in erythrocytes. Responsiveness of the patient's OBL cells was compared with OBL cells from eight subjects aged 18-39 years who had no evidence of metabolic bone disease. OBL cells from the patient responded to the following agonists (expressed in multiples of elevation of cAMP, stimulated/basal, mean +/- SE, n = 3): PTH, 3.8 +/- 0.3; forskolin, 8.2 +/- 0.2; and cholera toxin, 56.8 +/- 10.0. These responses were not significantly different from those of control OBL cells: PTH, 4.5 +/- 1.1 (range 2.4-7.5); forskolin, 7.7 +/- 1.4; and cholera toxin, 57.9 +/- 16.2. The normal cholera toxin response indicated the presence of functional Gs. Bone cells from patients with PHP type Ia may exhibit a normal PTH receptor-coupled adenylyl cyclase system in vitro despite clinical evidence of impaired hormone-responsive adenylyl cyclase in other tissues, including the kidney. Skeletal responsiveness to PTH may explain the long periods of spontaneous normocalcemia observed in this patient.

Bone mass in children with congenital hypothyroidism treated with thyroxine since birth.

To determine whether the large doses of thyroxine treatment early in life adversely affect bone mass, we measured bone mass of 20 congenital hypothyroid (CH) patients (8.4 +/- 2.2 years) who were diagnosed and treated since birth. Starting thyroxine dose and current dose were 8.5 +/- 1.9 micrograms/kg/day and 3.1 + 1.2 micrograms/kg/day respectively. Thyroid function and serum biochemical tests for calcium homeostasis were normal at the time of study. Bone mass was measured by dual energy X-ray absorptiometry. Nine siblings served as controls. The patients' bone mineral density was within the normal range of population controls, and was not different from the sibling controls. The patients also had height-adjusted bone mineral content equal to the expected height-adjusted values in the siblings. Our studies indicate that the large doses of thyroxine therapy for CH do not cause osteopenia in childhood.

Hypoparathyroidism associated with systemic lupus erythematosus.

We describe a 15-year-old girl with systemic lupus erythematosus (SLE) who presented with hypocalcemia and a generalized seizure in the setting of an intercurrent illness and active central nervous system lupus. She was subsequently found to have idiopathic hypoparathyroidism. The association of SLE with hypoparathyroidism is extremely rare and this case represents the first pediatric report of this rare association. We suggest there may be a common underlying pathophysiological process linking these diseases.

Nephrocalcinosis and nephrolithiasis due to subcutaneous fat necrosis with hypercalcemia in two full-term asphyxiated neonates: sonographic findings.

Subcutaneous fat necrosis leading to hypercalcemia is rare but well documented in asphyxiated neonates. This paper presents two such neonates in whom sonography revealed the development of nephrocalcinosis and nephrolithiasis. The kidneys had initially been shown to be normal sonographically. In one infant, nephrocalcinosis developed as increasing echogenicity of the medullary pyramids. In the other, increased echogenicity of the renal cortex of uncertain cause developed together with nephrolithiasis. These sonographic appearances have not been described previously in this entity.

The value and limitation of dual-energy X-ray absorptiometry.

In population studies, in which patients and controls are of comparable size, bone mineral area density (BMD) gives reliable results for mean bone mass data although, with sequential data, BMD may under-estimate the degree of change in bone mass. In children BMD data should be reliable, provided that patients and controls, matched for age and sex, are also of the same size. With disease children may be small for their age so that low bone mass by BMD may be due to small body size and not necessarily to osteopoenia. In these situations the bone mineral content (BMC) index may be more reliable than BMD. To assess bone mass status in individuals, BMC index, as well as BMD, should be used, particularly with adults at the extremes of body size (the very small or very tall).

Comparisons between oral and intraperitoneal 1,25-dihydroxyvitamin D3 therapy in children treated with peritoneal dialysis.

Recent studies in adults have suggested that parenteral 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) may have advantages over oral therapy in the management of renal osteodystrophy. The purpose of this study was to determine whether there were clear differences between oral and IP 1,25(OH)2D3 treatments in children who did not pose a treatment problem. Seven children (5 males, 2 females, aged 1.8 to 16 years, median 4.8 years) undergoing peritoneal dialysis were initially treated with oral 1,25(OH)2D3 for a one month equilibration period They were randomly assigned to 3 months of either oral or intraperitoneal (IP) therapy with 1,25(OH)2D3 followed by 3-months-treatment using the alternative route. No significant differences in serum creatinine, phosphate, or parathyroid hormone concentrations were found between the different routes of administration in the patients. No significant differences in height standard deviation scores or renal osteodystrophy scores were found over the six-month study. Paired oral and IP pharmacokinetic studies were performed on these 7 patients and 2 other children who had been treated for at least 2 months using either oral or IP 1,25(OH)2D3. Serum was taken prior to one of the usual 1,25(OH)2D3 doses and 0.5, 1.5, 3, 6, and 24 h afterward. The highest measured concentrations of 1,25(OH)2D3 were found at 1.5 h for both oral and IP treatments (mean Cmax [SD]: oral 116 [23] pmol/l, IP 121 [24] pmol/l, p > 0.05). The AUC's for oral and IP therapy were similar (1701 [276] and 1645 [301] pmol/h/l, respectively). In the paired pharmacokinetic studies no significant differences were found between oral and IP treatments for the serum half life (27.4 [11.6] h and 19.2 [8.1] h, respectively) and total body clearance (15.3 [2.1] h and 18.4 [3.3] h, respectively) of 1,25(OH)2D3. In children who respond appropriately to oral 1,25(OH)2D3 there is no biological advantage to the use of IP 1,25(OH)2D3.