Oral findings in patients with autosomal dominant hypophosphatemic bone disease and X-linked hypophosphatemia: further evidence that they are different diseases.

Oral examinations were performed on 5 patients with hypophosphatemic bone disease (HBD) (2 males and 3 females), 14 patients with X-linked hypophosphatemia (XLH), and 4 affected XLH relatives (6 males and 12 females). The control subjects were the unaffected siblings and parents of the patients and unrelated healthy, gender- and age-matched subjects. Serum phosphorus values were the same by disease type and gender in patients with HBD and XLH. They shared certain dental abnormalities, in particular pulpal necrosis and large pulp spaces. However, only patients with XLH had Class III malocclusions and mild enamel defects, and males with XLH had more severe occlusal and enamel defects than females with XLH. Different dental phenotypes are further evidence that XLH and HBD are different diseases. The dental abnormalities were not prevented by treatment, instituted early in life, which raised serum phosphorus to the near normal range.

Nephrocalcinosis and its relationship to treatment of hereditary rickets.

Renal ultrasonography was performed on 23 patients with X-linked hypophosphatemic rickets (XLH) and 11 patients with autosomal recessive vitamin D-dependent rickets (ARVDD). A pattern of increased echogenicity of the renal pyramids (ERP) was identified in 11/23 patients with XLH and 3/11 patients with ARVDD; this ultrasonographic finding has previously been associated with medullary nephrocalcinosis. Patients with XLH and ERP had significantly higher mean serum calcium and phosphate concentrations, more frequent episodes of hypercalcemia, and higher doses of oral vitamin D and phosphate during the first 3 years of therapy. Episodes of hypercalcemia were more frequent when patients received higher doses of vitamin D2 (greater than 4000 IU/kg/day) or 1,25-dihydroxycholecalciferol (greater than 40 ng/kg/day). Episodes of hypercalciuria were significantly increased at doses of greater than 20 ng/kg/day 1,25-dihydroxycholecalciferol. In patients with ARVDD, ERP was also correlated with vitamin D dose and frequency of hypercalcemia episodes. ERP was not associated with an elevation of serum creatinine or loss of urinary concentrating ability in either patient group.

Audiometric evidence for two forms of X-linked hypophosphatemia in humans, apparent counterparts of Hyp and Gy mutations in mouse.

Two forms of X-linked hypophosphatemia occur in the mouse. One form, caused by the Hyp gene, is a counterpart of human X-linked hypophosphatemic "vitamin D-resistant rickets". The other, recently characterized, is caused by a different gene (Gy) closely linked to Hyp on the mouse X-chromosome. The Gy mutation also impairs cochlear function in the mouse. We measured hearing in 22 patients with X-linked hypophosphatemia; five, including 2 mother-son pairs, had sensorineural hearing deficits due to cochlear dysfunction. We suggest the disease in these persons may be the human counterpart of the Gy phenotype in the mouse, which implies there are 2 forms of X-linked hypophosphatemia in humans.

The Hartnup phenotype: Mendelian transport disorder, multifactorial disease.

The Hartnup mutation affects an amino acid transport system of intestine and kidney used by a large group of neutral charge alpha-amino acids (six essential and several nonessential). We compared developmental outcomes and medical histories of 21 Hartnup subjects, identified through newborn screening, with those of 19 control sibs. We found no significant differences in means of growth percentiles and IQ scores between Hartnup and control groups (but all low academic performance scores were found in the Hartnup group, and various skin lesions occurred in five Hartnup subjects), no significant difference between means of the summed plasma values for amino acids affected by the Hartnup gene in Hartnup and control groups, two Hartnup subjects with clinical manifestations--impaired somatic growth and IQ in one, impaired growth and a "pellagrin" episode in the other--who had the lowest summed plasma amino acid values in the Hartnup group; the corresponding values for their sibs were the low outliers in the control group, and two tissue-specific forms of the Hartnup (transport) phenotype: renal and intestinal involvement (15 families) and renal involvement alone (one family), both forms having been inherited as autosomal recessives (the symptomatic probands had the usual form). Whereas deficient activity of the "Hartnup" transport system is monogenic, the associated plasma amino acid value (measured genotype) is polygenic. The latter describes the parameter of homeostasis and liability to disease. Cause of Hartnup disease is multifactorial.

Ontogeny modifies manifestations of cystinuria genes: implications for counseling.

Among 339,868 newborn infants screened at 3 weeks of age (91% compliance rate), 730 had elevated rates of excretion of cystine and the dibasic amino acids lysine, ornithine, and arginine; 191 infants had persistent "infantile cystinuria" on follow-up screening (100% compliance). Apparent incidence of the phenotype was 562 per million infants; this rate is seven times higher than for classic cystinuria in the adult segment of the Quebec population. We studied longitudinally 26 probands 2 to 4 months of age. Initially, each excreted cystine and dibasic amino acids at much higher levels than did normal infants or either parent. From parental phenotypes (heterozygous or homozygous normal) and urine amino acid excretion values at 6 months of age in probands, the infants were classified as either heterozygous for the various classic cystinuria genotypes--type I ("silent"), eight infants; type II (high excretor), three; type III (moderate excretor), nine--or homozygous (and genetic compound), six. Urine amino acid excretion diminished steadily with age, to reach the variant parental value in heterozygous infants but not in homozygotes. Cystinuria heterozygotes, with the possible exception of some type I individuals, could not be distinguished reliably from homozygotes in early infancy, although homozygotes had significantly higher excretion values as a group. We deduce that renal ontogeny amplifies phenotypic expression of cystinuria alleles, thus influencing correct classification of genotype (heterozygote vs homozygote, and type of allele). These findings have implications for counseling and the need for follow-up of infantile cystinuria.

Serum osteocalcin in the treatment of inherited rickets with 1,25-dihydroxyvitamin D3.

Osteocalcin is a vitamin K-dependent protein, synthesized in bone, which can be detected in serum. We have measured circulating osteocalcin levels in 10 patients with x-linked hypophosphatemia (XLH) and in 6 patients with autosomal recessive vitamin D dependence (ARVDD) who started 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] therapy. Patients with XLH were studied before and after 7-12 months of therapy that included 1,25-(OH)2D3 (10-72 ng/kg x day) and oral phosphate. Serum osteocalcin rose from 28 +/- 12 to 52 +/- 12 ng/ml (mean +/- SE; P less than 0.01) in concert with improvements in biochemical status and bone mineralization. Vitamin D therapy was withdrawn for 2 weeks from patients with ARVDD. The vitamin D-deplete status was evidenced by low 1,25-(OH)2D3 levels (12 +/- 2 pg/ml; n = 6). After 1 week of therapy with 1,25-(OH)2D3, serum calcium rose from 9.03 +/- 0.21 to 9.67 +/- 0.25 mg/dl (P less than 0.002), while serum phosphorus and alkaline phosphatase remained unchanged. Serum osteocalcin rose from 35 +/- 7 to 83 +/- 32 ng/ml (P less than 0.05). At 3 weeks, serum calcium remained elevated (9.63 +/- 0.18 ng/dl) over control levels (P less than 0.01); phosphorus and alkaline phosphatase were still unchanged. Serum osteocalcin rose to 114 +/- 42 ng/ml, significantly greater than values at 1 week (P less than 0.05). Thus, serum osteocalcin increases after 1,25-(OH)2D3 therapy in both ARVDD and XLH.

Panostotic fibrous dysplasia: a congenital disorder of bone with unusual facial appearance, bone fragility, hyperphosphatasemia, and hypophosphatemia.

We report a boy with unusual facial appearance, melanotic patches ("coast-of-Maine" type), myelofibrosis, recurrent femoral fractures, and widespread fibrous dysplasia of bone. Biochemical findings included raised serum alkaline phosphatase (bone isozyme) and 1,25-(OH)2 vitamin D, and low serum phosphorus levels. Elevated urinary excretion rates of total hydroxyproline, glycylproline, and gamma-carboxyglutamic acid indicated increased turnover of bone matrix. Transiliac bone biopsy showed a dearth of marrow elements, greatly increased bone turnover, and absence of normal trabecular organization. Serial radiographs showed progressive cortical thinning and loss of bony trabeculae. Calcitonin and etidronate treatments had no lasting effect on the progressive bone disease. The term "panostotic fibrous dysplasia" is suggested for this condition.

Outcome of early and long-term management of classical maple syrup urine disease.

The outcome of 8,400 treatment days in the lives of four patients with classical maple syrup urine disease (MSUD) (present ages: 1 3/12, 5 7/12, and 8 11/12 years) are described. Each diagnosis was made by clinical signs rather than by newborn screening. Acute-phase treatment beginning on the 11th day of life comprised peritoneal dialysis, intravenous lipid, and early intestinal alimentation. Mean age at discharge from hospital was 29 days. There were 16 readmissions to the hospital for the group (89 days, 1.05% treatment days) without any serious neurologic symptoms. The mean level of plasma leucine for the group (for levels below 1 mM) during treatment was 0.42 mM (normal for age range, 0.077 +/- 0.021 mM [mean +/- SD]). Plasma leucine exceeded 1 mM during 1.02% of treatment days (representing 8.6% of 1,042 measurements. Mean levels of plasma valine and isoleucine were 60% and 70% of the plasma leucine value for the group. Tolerance for dietary leucine did not exceed 620 mg/day in any patient. Somatic growth was normal and the mean current IQ/development quotient (DQ) score is 101 (range 89 to 117); the three oldest patients attend regular schools. A characteristic EEG pattern resembling the teeth of a comb was observed in three patients during the acute phase in the newborn period but not during long-term treatment. These results were obtained in an ambulatory program with home visiting.

X-linked hypophosphatemia: effect of calcitriol on renal handling of phosphate, serum phosphate, and bone mineralization.

Eleven patients with the Mendelian phenotype of x-linked hypophosphatemia (XLH) were treated with calcitriol [1,25-(OH)2D3] and phosphate. Ten patients had received prior treatment with ergocalciferol and phosphate. Five subjects were prepubertal and six were postpubertal. Response to calcitriol was measured under nonfasting and overnight fasting protocols. Bone biopsies were obtained before and after treatment. Calcitriol (mean dose, 30 ng/kg. day) 1) raised serum phosphorus uniformly in prepubertal patients but in only two of six postpubertal subjects; 2) did not change the theoretical renal phosphate threshold in the total patient group and thus had no effect on the primary transport defect in XLH; 3) improved trabecular bone mineralization in the total patient group, as determined by bone histomorphometry. The beneficial effect on extracellular phosphorus homeostasis was attributed to improved intestinal absorption of phosphorus; improvement in bone mineralization may reflect an additional effect of 1,25-(OH)2D3 on bone itself in XLH. Mild transient hypercalcemia occurred during 0.6% of 3545 treatment days and was readily controlled by adjusting the dosage of 1,25-(OH)2D3.

Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease.

The serum concentration of 1,25-dihydroxylvitamin D (1,25-[OH]2D) in normal children and in children with inherited diseases of bone was compared by use of a competitive binding assay. Observed values were: in 12 normal children and adolescents, 37.1 +/- 1.9 pg per milliliter (mean +/- S.D.); in 14 patients with X-linked hypophosphatemic rickets treated with vitamin D2 and phosphate supplements, 15.6 +/- 7.8 (P less than 0.01 versus control); in six patients with autosomal recessive vitamin D dependency treated with vitamin D2, 9.5 +/- 2.9 (P less than 0.01 versus control); and in four untreated patients with autosomal dominant hypophosphatemic (non-rachitic) bone disease, 30.2 +/- 6.3 (not significantly different from the controls). The difference in bone disease between X-linked hypophosphatemia (severe) and hypophosphatemic bone disease (mild) at comparable low serum levels of phosphate implies that 1,25-(OH)2D and phosphate may have independent roles in the pathogenesis of defective bone mineralization.

Response to crystalline 1alpha-hydroxyvitamin D3 in vitamin D dependency.

The therapeutic response to chemically synthesized 1alpha-hydroxycholecalciferol (1alpha-OH-D3) was studied in three patients with autosomal recessive vitamin D dependency (ARVDD). The daily maintenance dose for vitamin D2, to prevent signs of vitamin D deficiency in these patients, was 40-54.4 mug/kg, or about 100 times normal (Table 1). Withdrawal of maintenance therapy with vitamin D2 resulted in the ultimate reappearance of the vitamin D depletion syndrome in patients 1 and 2 (Figs. 1 and 2). The third patient presented with the deficiency syndrome despite adequate vitamin D nutrition and was recognized to have ARVDD. Treatment with 1alpha-OH-D3 by mouth in all three patients at dose levels of 1-3 mug/24 hr (80-100 ng/kg) corrected hypocalcemia and suppressed parathyroid hormone-dependent renal loss of amino acids (Figs. 1, 2, and 4). Rickets healed in 7-9 weeks on 1alpha-OH-D3 alone (Fig. 3). The therapeutic response was rapid. It was usually seen first in the rise of serum calcium (Figs. 5 and 6). Withdrawal of 1alpha-OH-D3 was followed first by a fall of serum phosphorus, then by a fall in serum calcium; the latter occurred within about 2 weeks of withdrawal. Because the synthesis of 1alpha-OH-D3 is simpler than for 1alpha,25-dihydroxycholecalciferol and because the former is an effective therapeutic analog of vitamin D hormone, we believe these studies in ARVDD reveal 1alpha-OH-D3 to be the agent of choice for treatment of this and analogous diseases.