Barry H. Rich

Bone mineral density assessment in children with inflammatory bowel disease

BACKGROUND & AIMS Children with inflammatory bowel disease (IBD) are at risk for osteoporosis because of undernutrition, delayed puberty, and prolonged corticosteroid use. The aim of this study was to compare bone mineral density (BMD) in children with IBD with that in normal children and to assess the effects of nutritional and hormonal factors and corticosteroid dosages on BMD. METHODS One hundred sixty-two subjects (99 with IBD and 63 healthy sibling controls) were enrolled. Patients underwent anthropometric assessment, pubertal staging, bone age radiography, and BMD assessment by dual energy x-ray absorptiometry of the lumbar spine, femoral neck, and radius. Laboratory evaluations included serum calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone, osteocalcin, urinary N-telopeptides, albumin, insulin-like growth factor I, and testosterone or estradiol. Cumulative corticosteroid doses were calculated. RESULTS BMD Z scores at the lumbar spine and femoral neck were lower in patients with IBD, and lower in those with Crohns disease compared with those with ulcerative colitis. Low BMD persisted after correction for bone age in girls with Crohns disease (lumbar spine, P = 0.004; femoral neck, P = 0.002). Cumulative corticosteroid dose was a significant predictor of reduced BMD. BMD did not correlate with measures of calcium homeostasis, except elevated serum phosphate and urine calcium levels in girls. CONCLUSIONS Low BMD occurs in children with IBD (more in Crohns disease than in ulcerative colitis), especially pubertal and postpubertal girls. Cumulative corticosteroid dose is a predictor of low BMD, but other factors in Crohns disease remain undetermined.

LH bioactivity increases more than immunoreactivity during puberty

We have measured bioactive LH in the plasma of 60 normal boys and 45 normal girls throughout puberty because the rise in immunoreactive LH has seemed too small to account for the profound changes in sexual maturation during adolescence. Bioactive LH was determined using an in vitro bioassay (rat interstitial cell testosterone production); I-LH was measured by radioimmunoassay using the same LH standard, LER 907. Bioactive LH was measurable in all 270 plasma samples; I-LH in 218. In both boys and girls, B-LH rose more than I-LH when compared to chronological age, bone age, and pubertal stage. In boys, B-LH increased 8.2-fold (P < 0.001) from prepuberty to late puberty, whereas I-LH rose 3.0-fold (P < 0.001). Similarly, in girls B-LH increased 23.1-fold (P < 0.001) while I-LH increased 4.9-fold (P < 0.001). Between pubertal stages there was less overlap of individual values of B-LH, in comparison to those of I-LH. We conclude that B-LH increases more than I-LH during normal puberty and is a more discriminating measure of maturation. One implication of these findings is that a qualitative change in gonadotropin secretion may occur during puberty.

CENTRAL HYPOTHYROIDISM REVEALS COMPOUND HETEROZYGOUS MUTATIONS IN THE PIT-1 GENE

Mutations in the gene encoding the Pit-1 transcriptional activator interfere with the embryologic determination and ultimate functions of anterior pituitary cells that produce growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH). Central hypothyroidism is often the presenting feature of combined pituitary hormone deficiency (CPHD), but it is not detected in screening programs that rely upon elevation of TSH. We report a child whose hypothyroidism was recognized clinically at age 6 weeks, and subsequently found to have GH and Prl as well as TSH deficiency. With thyroxine and GH replacement he has reached the 70th percentile for height and has normal intelligence. Molecular analysis of genomic DNA for Pit-1 revealed the presence of compound heterozygous recessive mutations: a nonsense mutation in codon 172 and a novel missense mutation substituting glycine for glutamate at codon 174. This case is the first demonstration of CPHD due to compound heterozygous Pit-1 point mutations, as most reported cases of the CPHD phenotype involve either the dominant negative R271W allele or homozygosity for recessive Pit-1 mutations. Therefore, in cases of CPHD, the possibilities of compound heterozygosity for two different Pit-1 mutations, or homozygosity for mutations in the epigenetic gene, Prop-1, should be considered.

Familial nesidioblastosis: Severe neonatal hypoglycemia in two families

Severe neonatal hypoglycemia with pathologic findings of diffuse nesidoblastosis of the pancreas is described in five children of both sexes from two families with unaffected parents. This appears to represent an autosomal recessive disorder of pancreatic development. Despite extensive testing, the diagnosis of hyperinsulinism was difficult in the index case of each family and delayed definitive treatment. Medical therapy with steroids and diazoxide was unsuccessful; pancreatectomy was required to treat persistent hypoglycemia. An abnormality of circulating glucagon found in one child with this disorder suggested that hyperinsulinism may not be the sole hormonal imbalance present, but rather that this disease is one of generalized disturbance of islet cell function. The history of severe, persistent neonatal hypoglycemia in an older sibling should lead the physician to investigate subsequent children for the presence of asymptomatic hypoglycemia.

Adrenarche as a cause of benign pseudopuberty in boys

We found elevations of plasma dehydroepiandrosterone-sulfate (DHAS) in five boys, 5.5 to 10.3 years of age (group A), with premature pubarche (pubic hair development) or acne as an isolated phenomenon. Four boys (group B) with seemingly idiopathic premature pubarche (DHAS normal for age) were discovered to have above-average dehydroepiandrosterone levels. All of these boys with premature pubarche had some evidence of cerebral dysfunction or were obese. Plasma testosterone values and bone age were not markedly increased in either group. In each case studied, the patterns of plasma steroid intermediates before and after administration of adenocorticotropin were typical of adrenarche rather than of congenital adrenal hyperplasia or Cushing syndrome. In addition, DHAS was dexamethasone suppressible, and in those patients in whom nocturnal testosterone sampling or gonadotropin-releasing hormone testing was performed, no evidence of true puberty could be found. Fifteen percent of our normal male volunteers over 10 years of age developed pubarche with plasma DHAS levels over 120 micrograms/dl without evidence of true puberty. Thus pubarche as an isolated phenomenon does not necessarily indicate a virilizing disorder or true puberty. In the majority of cases, isolated pubarche appears to be the result of isolated adrenarche, the maturational increase in adrenal production of 17-ketosteroids.

Significance of genetic testing for paternal uniparental disomy of chromosome 6 in neonatal diabetes mellitus

Two patients who presented at birth with neonatal diabetes mellitus (NDM) are described: one with paternal uniparental disomy for chromosome 6 and one with normal, biparental inheritance. The first child presented with low birth weight, macroglossia, hypertelorism, and club foot in addition to NDM. In this patient hyperglycemia was transient, and insulin treatment was discontinued at 4 months of age. The second child also presented with low birth weight but was normal in appearance, and insulin dependence continues after 5 years. Genetic analysis with polymorphic DNA markers for chromosome 6 indicated the presence of paternal uniparental disomy (UPD) in the first case and normal, biparental inheritance in the second case. Paternal UPD 6 has been reported in 8 previous cases of which 6 showed NDM. Three cases with paternal UPD 6 also included additional anomalies, such as macroglossia, not usually associated with NDM. Therefore the simultaneous finding of NDM and macroglossia should be a strong indicator for genetic testing. The genetic finding of paternal UPD 6 allows prediction of a transient, rather than permanent, form of diabetes mellitus and no increased recurrence risk of transient NDM in subsequent pregnancies.

Obesity at the Onset of Diabetes in an Ethnically Diverse Population of Children: What Does It Mean for Epidemiologists and Clinicians?

Objective. It is often difficult to determine the pathophysiology of childhood diabetes at onset, particularly in overweight children, because obesity has been associated with both type 1 and type 2 diabetes. We compared children at the diagnosis of diabetes in a multiethnic population-based registry to understand the epidemiology of the disease during a time of rapidly changing diagnostic and treatment norms. Methods. Incident diabetes was ascertained in Chicagoans who were aged 0 to 17 years from 1985 to 2001. We classified as type 2 those with polycystic ovary syndrome, acanthosis, or a physicians note indicating type 2 or those who reported subsequent use of oral agents (n = 203); 73% of them were also obese. Patients with obesity at onset but no other indicator of possible type 2 (n = 197) were classified as having obesity-related/undetermined type. The remaining 842 cases were classified as type 1. Logistic regression analyses were conducted. Results. Fully 32% of cases were classified as non–type 1, including 37% of non-Hispanic blacks, 30% of Latinos, and 14% of non-Hispanic whites. The proportion of obesity-undetermined and type 2 increased over the 17 years. Comparing the 3 patient groups, type 2 cases were more often female, non-Hispanic black, and older and had a first-degree diabetic relative, whereas Latino boys were overrepresented among the obese/undetermined. Conclusion. Obesity is prevalent in youths with newly diagnosed diabetes, particularly during recent years. The growth in non–type 1 diabetes in children since 1985 likely reflects both a true increase and greater physician awareness of the possibility that type 2 diabetes may occur in children.

Cardiovascular Endurance and Heart Rate Variability in Adolescents With Type 1 or Type 2 Diabetes

Background. Incidence rates of both type 1 and type 2 diabetes mellitus (DM) are increasing in youth and may eventually contribute to premature heart disease in early adulthood. This investigation explored the influence of type of diabetes, gender, body mass index (BMI), metabolic control (HbA 1c ), exercise beliefs and physical activity on cardiovascular endurance (CE), and heart rate variability (HRV). Differences in exercise beliefs, physical activity, HRV, and CE in youth with type 1 versus type 2 DM were determined. Methods. Adolescents with type 1 DM (n = 105) or with type 2DM (n = 27) completed the Exercise Belief Instrument and the Physical Activity Recall. Twenty-four HRV measures were obtained via Holter monitoring and analyzed using SpaceLabs Vision Premier™ software system. The McMaster cycle test was used to measure CE (V0 2peak). Results. Regardless of the type of DM, females and those with higher BMI, poorer metabolic control, and lower amounts of physical activity tended to have lower levels of CE. Exercise beliefs consistently predicted both frequency and time domain HRV measures. Measures of exercise beliefs, self-reported physical activity, CE (V0 2peak), and HRV were significantly lower in adolescents with type 2 DM in comparison to those with type 1 DM. Conclusions and Recommendations. Early findings of poor physical fitness, lower HRV, fewer positive beliefs about exercise, and less active lifestyles highlight the importance of developing culturally sensitive interventions for assisting youth to make lifelong changes in their physical activity routines. Females, those with poorer metabolic control, and minority youth with type 2 DM may be particularly vulnerable to later cardiovascular disease.

Bioactive LH: A test to discriminate true precocious puberty from premature thelarche and adrenarche

Since luteinizing hormone levels by radioimmunoassay (I-LH) have rarely been useful in distinguishing true isosexual precocity from other less serious disorders of puberty, we have studied bioassayable B-LH in 17 prepubertal girls, seven girls with premature adrenarche, 12 girls with premature thelarche, and six girls with true isosexual precocity. The I-LH levels were three times higher in the girls with true precocious puberty than in the other groups but there was overlap between those with premature thelarche and true precocious puberty. The B-LH levels were 16 times higher in the girls with isosexual precocity than in the others, and there was no overlap. We conclude that B-LH better discriminates between true isosexual precocity and other disorders of puberty and may be a very useful laboratory test for the early diagnosis of true precocious puberty.

Biventricular dynamics during quantitated anteroseptal infarction in the porcine heart.

The porcine heart has been shown to have close anatomic similarity to the human heart and was used as the experimental model in this study to gain further understanding of the early responses of both ventricles during acute anteroseptal myocardial infarction. High fidelity pressure and flow data were measured and multiple preejection and ejection variables were calculated for both ventricles. Infarct weight and distribution in both ventricles were quantitated. The standard infarction resulted from single stage ligation of the left anterior descending coronary artery just beyond its midpoint and second left ventricular branch. It comprised an average of 15.8 percent of total ventricular myocardium with an infarct/perfused ratio of 0.62 and a periinfarction transition zone of 7.5 mm, and involved significant portions of both ventricles and the interventricular septum. Performance characteristics of both ventricles were altered significantly by anteroseptal infarction and involved all phases of contraction--end-diastole, isovolumic systole and ventricular ejection. Although contractile alterations in the right ventricle were significant, they were somewhat delayed, yielding relatively low correlation coefficients with analogous left ventricular contractile indexes. These correlations became quite distinct during specific ventricular stresses. Comparison of anterolateral and anteroseptal infarction, matched in terms of infarct size, indicated that the right ventricular changes in the latter were related to direct involvement of the right ventricular free wall and septum rather than secondary to left ventricular alterations.