Iraj Rezvani

Cerebral edema causing death in children with maple syrup urine disease

Four children with the classic form of maple syrup urine disease (MSUD) died of cerebral edema during an intercurrent infection that caused severe dehydration and acidosis. The diagnosis of MSUD had been established during the neonatal period in all four patients, on day 1 of life in three of them. All were in satisfactory control before the intercurrent illness. Two patients underwent peritoneal dialysis. Signs of brain-stem compression occurred after treatment, when biochemical abnormalities were improving. Computed tomography of the head, which was done in two patients, revealed cerebral edema; one of these patients also had subarachnoid hemorrhage. Autopsy in one case revealed cerebral edema with herniation. Our experience documents that cerebral edema may occur in the older child with MSUD as well as in the neonate. The pathogenesis of cerebral edema in MSUD remains unclear. Early treatment of dehydration and acidosis may prevent the catastrophic consequences that we have observed.

Increasing Incidence of Type 1 Diabetes in Youth: Twenty years of the Philadelphia Pediatric Diabetes Registry

OBJECTIVE The purpose of this study was to describe the incidence of type 1 diabetes in children in Philadelphia from 2000–2004, compare the epidemiology to the previous three cohorts in the Philadelphia Pediatric Diabetes Registry, and, for the first time, describe the incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS Diabetes cases were obtained through a retrospective population-based registry. Hospital inpatient and outpatient records were reviewed for cases of type 1 and type 2 diabetes diagnosed from 1 January 2000 to 31 December 2004. The secondary source of validation was the School District of Philadelphia. Time series analysis was used to evaluate the changing pattern of incidence over the 20-year period. RESULTS The overall age-adjusted incidence rate in 2000–2004 of 17.0 per 100,000 per year was significantly higher than that of previous cohorts, with an average yearly increase of 1.5% and an average 5-year cohort increase of 7.8% (P = 0.025). The incidence in white children (19.2 per 100,000 per year) was 48% higher than in the previous cohort. Children aged 0–4 years had a 70% higher incidence (12.2 per 100,000 per year) than the original cohort; this increase was most marked in young black children. The overall age-adjusted incidence of type 2 diabetes was 5.8 per 100,000 per year and was significantly higher in black children. CONCLUSIONS The incidence of type 1 diabetes is rising among children in Philadelphia. The incidence rate has increased by 29% since the 1985–1989 cohort. The most marked increases were among white children ages 10–14 years and black children ages 0–4 years. The incidence of type 1 diabetes is 18 times higher than that of type 2 in white children but only 1.6 times higher in black children.

Action of Human Growth Hormone (hGH) on Extrathyroidal Conversion of Thyroxine (T4) to Triiodothyronine (T3) in Children with Hypopituitarism

Summary: To study the action of human growth hormone (hGH) on peripheral metabolism of serum thyroxine (T4), an oral loading dose of levothyroxine (1.2 mg/m2) was administered to seven children with hypopituitarism before initiation of hGH therapy. Serum concentrations of triiodothyronine (T3), T4, reverse triiodothyronine (rT3), and thyroxine-binding globulin (TBG) capacity were measured sequentially for 6 days. The study was repeated after 4 wk of treatment with hGH. Serum concentrations of T4 were not affected by hGH therapy. In contrast, mean basal serum concentration of T3 increased significantly after treatment with hGH. Also, changes in serum concentrations of T3 and in the ratio of T3/T4 after an oral dose of levothyroxine were significantly augmented during hGH therapy. Serum concentrations of rT3 changed in the opposite direction of T3 during therapy. After treatment with hGH, the mean basal level of serum rT3, decreased, and increases in serum concentrations of rT3, after oral levothyroxine were significantly attenuated. No changes in mean serum concentrations of thyroid stimulating hormone (TSH) and TBG capacity were observed.These data suggest that administration of hGH to children with hypopituitarism enhances the extrathyroidal conversion of T4 to T3 and concomitantly decreases the serum concentration of rT3.Speculation: The increase in serum concentration of triiodothyronine after administration of human growth hormone may play a role in the growth-promoting action of growth hormone in children with hypopituitarism.

Effects of growth hormone administration in pediatric renal allograft recipients

The efficacy of recombinant human growth hormone (rGH) was assessed in five pediatric allograft recipients with severe growth retardation despite successful renal transplants. rGH 0.05 mg/kg per dose was given six times weekly by subcutaneous injection to five prepubertal children (mean age 15.2±2.0 years) all of whom had bone ages less than or equal to 12 years (10.0±1.4 years), a height standard deviation score of less than −2.5 (−4.9±1.5), no evidence of catch-up growth, a calculated glomerular filtration rate (GFR) of more than 40ml/min per 1.73 m2 (51±6.8 ml/min per 1.73 m2), and stable renal function on alternate-day prednisone (16.7±2.6 mg/m2 per dose). Growth hormone profiles were abnormal in all children before treatment. rGH administration led to a significant increase in both growth rate (3.5±1.6 cm/year pre therapy, 8.5±1.4 cm/year post therapy,P<0.001) and percentage of expected growth velocity for bone age (67±31% pre therapy, 163±27% post therapy,P<0.001) with evidence of true catch-up growth. During the study period, three children had the appearance of secondary sexual characteristics, and one had premature advancement of his bone age. GFR decreased in three children, and in one rGH was discontinued due to a steady rise in serum creatinine. No significant changes were seen in serum calcium, phosphorus, cholesterol, triglycerides, glucose, or thyroid function, although a significant increase in alkaline phosphatase was found. In summary, growth-retarded pediatric renal allograft recipients may have abnormal endogenous GH production and respond favorably to rGH. The potential risk of deterioration in renal function due to rGH-induced hyperfiltration must be investigated.

Prospective Study of Maple-Syrup-Urine Disease for the First Four Days of Life

Maple-syrup-urine disease, also known as branched-chain ketoaciduria, results from a primary defect in oxidative decarboxylation of the ketoacids derived from the branched-chain amino acids leucine...

Disproportionate suppression of dehydroepiandrosterone sulfate (DHEAS) in treated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Summary: Serum concentrations of dehydroepiandrosterone sulfate (DHEAS) were measured in 28 patients (18 females, 10 males) with congenital adrenal hyperplasia due to 21-hydroxylase deficiency who were treated with oral hydrocortisone (non-salt losers) or hydrocortisone and 9-α-fluorohydrocortisone (salt-losers). Adequacy of therapy was assessed by clinical findings, determination of bone age, urinary excretion of 17-ketosteroids, and serum concentration of 17-hydroxyprogesterone. These allowed the separation of patients into three groups: poorly controlled, adequately controlled and overtreated. Individual values for serum levels of DHEAS were compared to mean normal values for age. In the adequately controlled and overtreated patients, mean serum concentrations of DHEAS were significantly lower than normal values for age (P < 0.05). In the poorly treated patients, the mean serum concentration of DHEAS was not significantly different from normal values for age (P = 0.50).These data indicate that the serum concentration of DHEAS is overly suppressed in treated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. This finding suggests that measurement of the serum levels of DHEAS has limited value in assessing the adequacy of therapy in this disease.

Cryptorchidism: a pediatrician's view

Cryptorchidism is one of the most common congenital anomalies afflicting male children. This article reviews some of the existing literature regarding this condition for the purpose of presenting the pediatrician with a synopsis of possible diagnosis and treatment options.

Serum concentrations of branched chained amino acids (BCAA) in neonates with classic maple syrup urine disease (MSUD) in the first 4 days of life

Although serum levels of BCAA are elevated in MSUD at the time of diagnosis, data on serum levels of amino acids prior to development of symptoms are very limited. We have measured serum levels of BCAA during the first 4 days of life in 7 neonates from 3 families with affected offsprings. Three infants had MSUD and 4 were normal. All infants received 5% glucose in water for the first 12-24 hours and then were started on a formula devoid of BCAA. Valine and isoleucine were mildly elevated in cord sera of all 3 affected infants but leucine levels overlapped with those of normal siblings. Serumlevels of all BCAA increased as early as 4 hours after birth while these levels decreased in normal infants during the same period. Isoleucine levels decreased below normal in affected infants at 2nd and 4th days of life while other BCAA continued to rise. These data indicate that diagnosis of MSUD can be made within a few hours of life even before feeding. (Supported by GCRC grant n. RR-75).

441 EFFECT OF HUMAN GROWTH HORMONE (hGH) ON PLASMA LEVELS OF EPINEPHRINE (E) AND NOREPINEPHRINE (NE) IN HYPOPITUITARY CHILDREN

Plasma levels of E and NE in response to insulin induced hypoglycemia were measured in 4 children (ages 7 to 14 years) with isolated hGH deficiency before initiation of hGH therapy and one month after treatment with hGH (2 U three times/week). Since plasma levels of E and NE are directly related to the degree of hypoglycemia, attempts were made to induce a similar degree of hypoglycemia before and after treatment with hGH (Table). Plasma levels of E and NE were measured by radioenzymatic assay. Although basal plasma levels of E and NE remained unchanged after hGH therapy, the response of plasma E to hypoglycemia was decreased in all patients after treatment (Table). The response of plasma NE was not affected by hGH therapy. These data indicate that basal plasma levels of E and NE are not affected by hGH while response of E to hypoglycemia is exaggerated in patients with hGH deficiency. This may be a compensatory mechanism for combating hypoglycemia in these patients. Treatment with hGH diminishes the need for E and normalizes the response. The reason for the wide range of plasma levels of E during hypoglycemia remains unclear.

440 SERUM DEHYDROEPIANDROSTERONE SULFATE (DHEAS) AS A PREDICTOR OF PUBERTY IN CHILDREN WITH HYPOPITUITARISM

Evaluation of gonadotropin secretion in prepubertal children with hypopituitarism yields little information and it is often impossible to predict whether a patient will undergo pubertal changes. In normal children, an increase in serum levels of DHEAS precedes pubertal development by several years. Whether this hormone plays any role in the pubertal process of children with hypopituitarism remains unclear. We have measured serum levels of DHEAS sequentially (prospectively and retrospectively over a 7 year period) in 17 patients with hypopituitarism (idiopathic=12) who are currently over 15 years of age. The levels were compared to those obtained in 82 normal children (6 to 18 years of age). Patients could be divided into 2 distinct groups, one (11 patients) with very low or undetectable levels and a second group (6 patients) with normal levels of DHEAS for their bone age. None of the patients from group I entered puberty and all are now receiving replacement therapy. All patients from group II developed puberty spontaneously (Stages II to IV). Retrospectively, all patients in group II had had normal levels of DHEAS for their bone age and the levels had increased gradually with advancement of bone age. These data indicate that serum levels of DHEAS may be utilized to predict which children with hypopituitarism will undergo spontaneous puberty.