Thomas F. Roe

Changes in Vertebral Bone Density in Black Girls and White Girls during Childhood and Puberty

BACKGROUND The prevalence of osteoporosis and the incidence of vertebral fractures are lower in black women than in white women, findings generally attributed to racial differences in adult bone mass. Little is known, however, about the factors that contribute to racial variations in bone mass or the time of life when such differences become manifest. This study was done to characterize the changes in vertebral bone density at various stages of sexual development in black and white females. METHODS We measured cancellous vertebral bone density by quantitative computed tomography in 75 black female subjects between 2 and 20 years old and 75 whites matched for age and stage of sexual development. RESULTS The vertebral bone density did not differ between black girls and white girls before puberty. Bone density increased during puberty in each racial group, but the magnitude of the increase from prepubertal values was substantially greater in black than in white subjects (34 percent vs. 11 percent). CONCLUSIONS The marked difference between black and white females in cancellous vertebral bone density occurs during a relatively brief period late in puberty. Metabolic and hormonal events related to the achievement of sexual maturity during adolescence may be important determinants of racial differences in bone mass in women.

VITAMIN D-RECEPTOR GENE POLYMORPHISMS AND BONE DENSITY IN PREPUBERTAL AMERICAN GIRLS OF MEXICAN DESCENT

BACKGROUND Bone mass is under strong genetic control, and recent studies in adults have suggested that allelic differences in the gene for the vitamin D receptor may account for inherited variability in bone mass. We studied the relations of the vitamin D-receptor genotype to skeletal development and variation in the size, volume, and density of bone in children. METHODS We identified three allelic variants of the vitamin D-receptor gene using the polymerase chain reaction and three restriction enzymes (ApaI, BsmI, and TaqI) in 100 normal prepubertal American girls of Mexican descent. We then determined the relations of the different vitamin D-receptor genotypes (AA, Aa, aa, BB, Bb, bb, TT, Tt, and tt) to the cross-sectional area, cortical area, and cortical bone density of the femoral shaft and the cross-sectional area and density of the lumbar vertebrae. RESULTS The vitamin D-receptor genotype was associated with femoral and vertebral bone density. Girls with aa and bb genotypes had 2 to 3 percent higher femoral bone density (P=0.008 and P=0.04, respectively) and 8 to 10 percent higher vertebral bone density (P=0.01 and P=0.03, respectively) than girls with AA and BB genotypes. There was no association between the cross-sectional area of the vertebrae or the cross-sectional or cortical area of the femur and the vitamin D-receptor genotype. The chronologic age, bone age, height, weight, body-surface area, and body-mass index did not differ significantly among girls with different vitamin D-receptor genotypes. CONCLUSIONS Vitamin D-receptor gene alleles predict the density of femoral and vertebral bone in prepubertal American girls of Mexican descent.

Glycogen Storage Disease in Adults

Table 1 The glycogen storage diseases (GSD) include more than ten separate genetic defects that impair glycogen breakdown, primarily in liver or muscle or both. Even the types most frequently encountered (GSD-Ia and GSD-III) are uncommon, each with an incidence of approximately 1 in 100 000 births. Thus, no single institution has followed and reported on a large series of patients. The importance of several major complications was recognized only recently because only single cases were initially reported. Our study represents the largest number of adults with GSD-Ia and GSD-Ib to be included in one investigation and is the first to focus on clinical and social outcomes. Although two groups of investigators recently described the clinical course of patients with GSD in Europe and Israel, most of the patients studied were children [1, 2]. Relatively little information is available about adults with these diseases. We collected information on adults with GSD-Ia, GSD-Ib, and GSD-III in the United States and Canada in order to identify long-term complications that may be amenable to prevention and to determine the effect of the disease on education, employment, and family life. Table 1. SI Units Glycogen Storage Disease Types Ia, Ib, and III Glycogen storage disease type Ia results from deficient glucose-6-phosphatase activity in liver, kidney, and intestine [3]. Glucose-6-phosphatase is a single 35-kd protein [4]. When glucose-6-phosphatase activity is deficient, the liver is unable to hydrolyze glucose from glucose-6-phosphate that has been derived either from the metabolism of stored glycogen or from gluconeogenesis. Patients must depend on dietary carbohydrate to maintain euglycemia; during a fast of more than a few hours, the serum glucose concentration may decrease profoundly, and seizures are common in children. Mental retardation is uncommon, however, because the brain is protected by its ability to metabolize lactate that is present at high concentrations in the serum. Chronic hypoglycemia causes a sustained increase of counter-regulatory hormones, such as cortisol. In childhood, GSD-Ia typically results in poor growth and delayed puberty. Hyperuricemia occurs probably because ATP synthesis from ADP is driven by deamination of the AMP product to inosine that is subsequently metabolized to uric acid. Renal excretion of uric acid may also be decreased because lactate competes for the renal anion transporter. Fatty liver and hyperlipidemia result from the large influx of adipose-derived fatty acids into the liver in response to low insulin and high glucagon and cortisol concentrations. Anemia that is refractory to iron supplementation is believed to occur because of chronic disease. In untreated adults with GSD-Ia, the blood glucose decreases only to about 2.8 mmol/L (50 mg/dL) after an overnight fast. Symptomatic hypoglycemia is uncommon in untreated adults, but increases of counter-regulatory hormones probably persist. Adults with GSD-Ia have a high incidence of hepatic adenomas and focal segmental glomerulosclerosis [3, 5, 6]. The continuing abnormalities in counter-regulatory hormones, together with the hyperuricemia and hyperlipidemia, may be responsible for many of the complications observed in adult patients. Glycogen storage disease type Ib results from a deficiency of the glucose-6-phosphate translocase that transports glucose-6-phosphate into the lumen of the endoplasmic reticulum where it is hydrolyzed by glucose-6-phosphatase [3]. The translocase has not been purified. Without the translocase, glucose-6-phosphate cannot reach the hydrolytic enzyme; thus, patients with GSD-Ib are also unable to maintain euglycemia. The resulting metabolic consequences are identical in both forms of GSD-I. Because patients with GSD-Ib also have neutropenia and recurrent bacterial infections [3, 7], it seems likely that the glucose-6-phosphate translocase plays a role in normal neutrophil function. In GSD-III, glycogen debranching enzyme is deficient [3]. This enzyme is a 165-kd protein that contains two catalytic sites that are required for activity. The enzyme has been cloned and sequenced [8]. Normally, successive glucose residues are released from glycogen by glycogen phosphorylase until the glycogen chains are within four glucose residues of a branch point. The first catalytic activity of the debranching enzyme (oligo-1,4,-1,4-glucantransferase) transfers three of the remaining glucose residues to the terminus of another glucose chain. The second catalytic activity (amylo-1,6-glucosidase) then hydrolyzes the branch-point glucose residue. Three molecular subgroups of GSD-III have been well defined [9]; each is associated with enzyme deficiency in the liver and with childhood hypoglycemia. In adults with GSD-III, hypoglycemia is uncommon. As in GSD-I, poor growth may be prominent, but the growth rate increases before puberty, and adult height is normal [10]. Additionally, increases in transaminase levels provide evidence of hepatocellular damage, and liver biopsies show periportal fibrosis [10], perhaps related to the abnormal short-branched glycogen structure. In patients with subtype GSD-IIIb, enzyme activity and immunoreactive material are absent in liver but are present in muscle; these patients do not have a myopathy. Patients with GSD-IIIa (78% of cases) lack enzyme activity and lack immunoreactive material in liver and muscle. Patients with GSD-IIId (7% of cases) lack only the transferase activity but have normal immunoreactive material in liver and muscle. In patients with GSD-IIIa and IIId, muscle weakness may occur either in childhood or after the third decade. Cardiomyopathy is apparent only after age 30 years [9]. Treatment of Glycogen Storage Disease For only the past 10 to 15 years, children with GSD-Ia and GSD-Ib were treated with either intermittent uncooked cornstarch or a nocturnal glucose infusion given by intragastric tube. When euglycemia is maintained in this manner, growth and pubertal development are normal, and it is hoped that the late complications of GSD-I will be prevented. A high-protein diet was recommended for patients with GSD-III. Diet supplementation can increase the growth rate in children with GSD-III [11], but beneficial results on the myopathy have been less well documented. In this retrospective study of adults with GSD types Ia, Ib, and III, we found, in addition to complications frequently recognized, a high incidence of osteopenia and fractures and of nephrocalcinosis, kidney stones, and pyelonephritis. We describe the long-term outlook for adult patients with GSD who have not had optimal lifelong dietary glucose therapy. Methods Information on patients 18 years of age or older was obtained by contacting specialists in pediatric metabolism, endocrinology, gastroenterology, and genetics throughout the United States and Canada and by advertising through the Association for Glycogen Storage Diseases and The New England Journal of Medicine. No registries of patients with GSD are available. Information was included on living adult patients with GSD and patients who had died since 1967. Diagnosis of GSD had been confirmed by enzyme assay of each patient or of an affected sibling. Fifty-six physicians were individually contacted. Nineteen stated that they were not treating any adult patients with GSD. Thirteen physicians in private practice or at 1 of 12 medical centers filled out a detailed questionnaire or sent copies of clinic and hospital records that were reviewed by two of us. To obtain an estimate of how many patients might be missed by this survey, we reviewed records from a reference laboratory (Washington University) of 21 patients with GSD-Ia and of 21 patients with GSD-III who were diagnosed between 1955 and 1972. If still alive, these patients would now range in age from 18 to 64 years. Our study includes only 5 of these patients with GSD-I and 1 with GSD-III. Thus, this report incompletely represents North American patients with GSD who are currently older than 18 years of age. Clinical, radiographic, and laboratory findings at the latest visit were obtained, but data were not universally available for every item on the questionnaire. In analyzing each response, information was considered to be available only if specifically recorded; omission of information was not recorded as either a negative or a positive response. The presence of liver adenomas, nephrocalcinosis, or kidney stones was based on data from ultrasound or radiographic studies. The diagnosis of osteopenia was based on data from radiographic studies. The normal values for height were taken from the National Center for Health Statistics [12]. Normal values for serum chemistry tests [13] were used. Results Glycogen Storage Disease Type Ia Case Report Patient 1, a 43-year-old divorced father of one child, is a poultry farmer. A liver biopsy and enzymatic assay were obtained at 4 years of age because of poor growth, hypoglycemia without seizures, hepatomegaly, and frequent nosebleeds. Despite frequent meals, growth continued to be poor, puberty was delayed, and the final adult height of 168 cm was achieved after 20 years of age. Allopurinol was taken inconsistently after one of many gouty attacks beginning from 18 years of age. The patient did not complete high school. As an adult, he has smoked 2 to 4 packs of cigarettes per day. After divorcing in his 20s, he frequently skipped breakfast and failed to follow a recommended diet. Instead, his diet was high in fat and consisted primarily of foods that required little preparation, such as candy and sandwiches. He has always denied symptomatic hypoglycemia, although his serum glucose concentration after an overnight fast is about 2.8 mmol/L (50 mg/dL). Beginning in his mid-20s, he had recurrent episodes of flank pain and hematuria that were treated with antibiotics, and he passed kidney stones. At age 24, an intravenous pyelogram showed punctate calcificati

Osteoporosis after cranial irradiation for acute lymphoblastic leukemia

A prospective study was conducted to investigate the possibility of osteoporosis after treatment for childhood acute lymphoblastic leukemia (ALL). Forty-two survivors of ALL had the trabecular bone density of the spine evaluated by quantitative computed tomography, 6 to 98 months (mean 42 months) after completion of chemotherapy. The ALL survivors had significantly lower bone density than age-, gender-, and race-matched nonleukemic control subjects had (10% less, p less than 0.001); this decrease was accounted for solely by the subset of patients who had received cranial irradiation (n = 30; p less than 0.001). The relative reduction in bone density in ALL survivors was unrelated to age at the time of diagnosis or time without therapy. The effects on bone density of 18 Gy and of 22.5 to 25.2 Gy were indistinguishable. We conclude that survivors of ALL commonly have reduced bone density in the lumbar spine and suggest that the diminution is related to nervous system irradiation, not to the disease or to chemotherapy.

Review of slipped capital femoral epiphysis associated with endocrine disease.

Review of type and bilaterality of 131 cases (40 bilateral) of slipped capital femoral epiphysis (SCFE) in patients with known endocrinopathies (hypothyroidism, panhypopituitarism, hypogonadism) from 1960 to 1990 showed an increased frequency of patients with endocrine disorders, primarily hypothyroidism (nine of 131 patients, 6.9%); three had bilateral slips; six developed bilateral slips in an average of 11.17 months. Delayed growth plate closure is common in SCFE. Because hypothyroidism can be easily overlooked, all patients with SCFE should be screened for hypothyroidism by measuring serum T4 and TSH (such screening is inexpensive (r =

Brief Report: Treatment of Chronic Inflammatory Bowel Disease in Glycogen Storage Disease Type Ib with Colony-Stimulating Factors

60). Pituitary deficiency should be considered in children short for their age who have hypogonadism. Any child with a unilateral slip and one of these endocrine deficiencies has a high risk of subsequent bilateral involvement. Prophylactic pinning of the uninvolved hip is recommended because 100% of our patients eventually had bilateral slips.

Scleroderma-like Changes in Insulin-dependent Diabetes Mellitus: Clinical and Biochemical Studies

GLYCOGEN storage disease Type Ib is a rare hereditary metabolic disorder characterized by growth failure, hepatomegaly, hypoglycemia, lactic acidosis, and neutrophil deficiency.1 , 2 Except for the...

Vertebral bone density in insulin-dependent diabetic children

Children with insulin-dependent diabetes mellitus (IDDM) were examined for scleroderma-like changes of digital sclerosis and joint contractures. Of the 104 patients, 19 (18%) demonstrated these features; five patients had both multiple joint involvement and skin changes; three were studied in detail. All three had restrictive pulmonary disease. Histopathology of skin in these three patients demonstrated increased accumulation of collagen in the lower dermis. In two of the patients, the extractability of collagen in 0.5 N acetic acid was decreased by about 50% as compared with normal controls, which suggests increased cross-linkage of collagen. In addition, the mean nonenzymatic glycosylation of collagen in these three patients was 13 times that of controls. The results indicate that distinct histopathologic and biochemical changes can be detected in the skin of these patients. The results further support the hypothesis that nonenzymatic glycosylation may alter the turnover of collagen, thus contributing to the development of a scleroderma-like syndrome with skin, joint, and pulmonary findingsin patients with IDDM.

Inflammatory bowel disease in glycogen storage disease type Ib

To determine the effect of insulin-dependent diabetes mellitus (IDDM) on bone mass, we compared the trabecular and cortical bone density in lumbar vertebrae, measured by quantitative computed tomography (CT), in 48 white diabetic patients (23 females, 25 males; 5.2 to 19.6 years of age) with those of a control group of 48 healthy subjects, matched for race, sex, and age. Patients with neuropathy, retinopathy, nephropathy, and those with recent ketoacidosis were excluded from the study. The patient and control groups did not differ in sexual or skeletal maturation, weight, height, surface area, body mass index, abdominal fat, or paraspinal musculature. In diabetic children, cortical bone density was slightly but significantly lower than in controls (3.5% lower, P less than .02); there was no difference between patients and controls regarding trabecular bone density. The decrease in cortical bone density in the diabetic group did not correlate with age, sex, duration of diabetes, or glycosylated hemoglobin levels. These results suggest that in children with uncomplicated IDDM, decreased vertebral bone density is a minor abnormality that only affects cortical bone.

Brain infarction in children with diabetic ketoacidosis

We have observed the development of chronic inflammatory bowel disease, indistinguishable from Crohn disease, in two boys with glycogen storage disease type Ib (GSD-Ib). A chance association of these diseases in two patients is unlikely. Studies of their neutrophils showed severe chronic neutropenia (mean absolute granulocyte counts of less than 500 cells/microliter) and markedly deficient chemotactic response (less than 5% of reference values) in the patients with GSD-Ib and normal neutrophil values in four patients with glycogen storage disease type Ia (GSD-Ia). Monocyte counts and responses to chemotactic stimulation were normal in both GSD-Ia and GSD-Ib. Chronic inflammatory bowel disease appears to be associated with GSD-Ib, and neutrophil abnormalities may be involved in the pathogenesis of the bowel inflammation.