Nancy E. Friedman

Calcification of Entheses Associated with X-Linked Hypophosphatemic Osteomalacia

We undertook a retrospective analysis of 26 patients with X-linked hypophosphatemic osteomalacia (or rickets), whose ages ranged from 1 to 62 years and who were from 11 different kindreds, to determine the prevalence and clinical characteristics of a unique disorder of the entheses (tendons, ligaments, and joint capsules). We found a generalized involvement of the entheses, with exuberant calcification of tendon and ligament insertions and of joint capsules, in 69 per cent of the subjects. The prevalence and extent of disease increased with age but were not correlated with sex. Commonly affected sites included the hand and sacroiliac joints. Histologic evaluation in a selected patient revealed intratendinous lamellar bone but no inflammatory cells. Our observations indicate that this disorder is an integral part of X-linked hypophosphatemic osteomalacia and exhibits clinical, radiographic, and histologic characteristics that differentiate it from degenerative disorders of these tissues and seronegative spondyloarthropathies.

Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol.

Although conventional therapy (pharmacologic doses of vitamin D and phosphorus supplementation) is usually successful in healing the rachitic bone lesion in patients with X-linked hypophosphatemic rickets, it does not heal the coexistent osteomalacia. Because serum 1,25-dihydroxyvitamin D levels are inappropriately low in these patients and high calcitriol concentrations may be required to heal the osteomalacia, we chose to treat five affected subjects with high doses of calcitriol (68.2 +/- 10.0 ng/kg total body weight/d) and supplemental phosphorus (1-2 g/d) performing metabolic studies and bone biopsies before and after 5-8 mo of this therapy in each individual. Of these five patients, three (aged 13, 13, and 19 yr) were receiving conventional treatment at the inception of the study and therefore showed base-line serum phosphorus concentrations within the normal range. The remaining two untreated patients (aged 2 and 37 yr) displayed characteristic hypophosphatemia before calcitriol therapy. All five patients demonstrated serum calcitriol levels in the low normal range (22.5 +/- 3.2 pg/ml), impaired renal phosphorus conservation (tubular maximum for the reabsorption of phosphate per deciliter of glomerular filtrate, 2.13 +/- 0.20 mg/dl), and osteomalacia on bone biopsy (relative osteoid volume, 14.4 +/- 1.7%; mean osteoid seam width, 27.7 +/- 3.7 micron; mineral apposition rate, 0.46 +/- 0.12 micron/d). On high doses of calcitriol, serum 1,25-dihydroxyvitamin D levels rose into the supraphysiologic range (74.1 +/- 3.8 pg/ml) with an associated increment in the serum phosphorus concentration (2.82 +/- 0.19 to 3.78 +/- 0.32 mg/dl) and improvement of the renal tubular maximum for phosphate reabsorption (3.17 +/- 0.22 mg/dl). The serum calcium rose in each patient while the immunoactive parathyroid hormone concentration measured by three different assays remained within the normal range. Most importantly, repeat bone biopsies showed that high doses of calcitriol and phosphorus supplements had reversed the mineralization defect in all patients (mineral apposition rate, 0.88 +/- 0.04 micron/d) and consequently reduced parameters of bone osteoid content to normal (relative osteoid volume, 4.1 +/- 0.7%; mean osteoid seam width, 11.0 +/- 1.0 micron). Complications (hypercalcemia and hypercalciuria) ensued in four of these five patients within 1-17 mo of documented bone healing, necessitating reduction of calcitriol doses to a mean of 1.6 +/- 0.2 micrograms/d (28 +/- 4 ng/kg ideal body weight per day). At follow-up bone biopsy, these four subjects continued to manifest normal bone mineralization dynamics (mineral apposition rate, 0.88 +/-0.10 micrometer/d) on reduced doses of 1.25-dihydroxyvitamin D with phosphorus supplements (2 g/d) for a mean of 21.3 +/- 1.3 mo after bone healing was first documented. Static histomorphometric parameters also remained normal (relative osteoid volume, 1.5 +/- 0.4%; mean osteoid seam width, 13.5 +/- 0.8 micrometer). These data indicate that administration of supraphysiologic amounts of calcitriol, in conjunction with oral phosphorus, results in complete healing of vitamin D resistant osteomalacia in patients with X-linked hypophosphatemic rickets. Although complications predictably require calcitriol dose reductions once healing is achieved, continued bone healing can be maintained for up to 1 yr with lower doses of 1,25-dihydroxyvitamin D and continued phosphorus supplementation.

Echocardiographic evidence for impaired myocardial performance in children with type I diabetes mellitus

Thirty-three children with type I diabetes mellitus and 51 normal children underwent M-mode echocardiography. Abnormalities of myocardial performance were present in many of the diabetic children. The mean end-systolic volume of the left ventricle was greater in diabetics compared to control subjects. Mean ejection fraction, minor axis shortening, and velocity of circumferential fiber shortening were decreased in the diabetics. There was no evidence of increased myocardial mass in these diabetic children. There was no correlation between myocardial dysfunction, clinical assessment of control, or glycohemoglobin in the diabetic children.

Methylphenidate in Neuropsychological Sequelae of Radiotherapy and Chemotherapy of Childhood Brain Tumors and Leukemia

or chemotherapy-induced encephalopathy. We report 12 children with brain tumor or acute lymphocytic leukemia who had an adequate trial of methylphenidate. Ten had sustained benefit, with improvement in attention, academic achievement, language skills, memory, and behavior. Children with previous radiotherapy to brain, with or without additional chemotherapy, were considered for a trial of methylphenidate therapy if they had experienced a decline in academic performance, attentional difficulties, behavioral lability, or other decreases in mental ability. They represent a complex series of patients, with diverse intracranial tumors (which by themselves may affect behavior and mentation) and complex treatments, including surgery, high-dose limited-field or whole-brain radiotherapy, and often, chemotherapy with multiple agents. Four were considered hyperactive and/or learning disabled before the diagnosis of a neoplasm; whether this was an early manifestation of the tumor is unknown. Results were assessed from the reports of parents and teachers and from direct observation, after at least 6

X-LINKED HYPOPHOSPHATEMIC RICKETS WITHOUT RICKETS

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.

1121 ECHOCARDIOGRAPHIC EVIDENCE FOR IMPAIRED MYOCARDIAL PERFORMANCE IN CHILDREN WITH TYPE I DIABETES MELLITUS

Myocardial performance was assessed by M-mode echocardiography in 33 children (6 8/12-19 3/12 yr) with Type I diabetes mellitus and in 51 normal children (6 2/12-18 8/12). Left ventricular end systolic dimension (LVESD), and left ventricular end systolic volume/M2 (LVESV/M2) were greater in diabetics than controls. Left ventricular ejection fraction (LVEF), minor axis shortening (MAS), and velocity of circumferential fiber shortening (VCF) were less in diabetics than controls.Hgb A1 levels in children with diabetes (15.5±0.6%, range 10.1-22.2%, normal 5.9-8.7%) correlated with clinical assessment of control (p<.01). Age, Hgb A1, duration of diabetes, and clinical assessment did not predict myocardial function. We conclude that there is impaired myocardial contractility in some children with insulin-dependent diabetes not correlated with duration of diabetes, age, clinical assessment of control, or Hgb A1. The long-term significance of this finding and the effect of improved control remain to be assessed.