Abdollah Sadeghi-Nejad

Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger's syndrome)

A boy with Riegers syndrome was short and lacked GH. His father and sister, each of whom had Riegers syndrome, also had an isolated deficiency of GH. The paternal grandmother and a paternal uncle, in all likelihood, were similarly affected. Therapy with GH led to enhanced growth in the propositus. The GH-deficient subjects were sensitive to insulin and had a normal increase of insulin in response to arginine and to orally administered glucose. It is suggested that GH deficiency, in this family, is an inconstant component of Riegers syndrome and follows an autosomal dominant mode of transmission. A common embryologic developmental defect of the neural crest is postulated.

Effect of recombinant growth hormone treatment on children with Crohn's disease and short stature: a pilot study.

Background: Growth failure frequently complicates Crohns disease in childhood. Abnormalities in the growth hormone (GH)/insulin‐like growth factor‐1 axis may occur. The effects of administered GH on growth have not been studied previously in a randomized trial. Methods: Seven children (6 boys and 1 girl; age, 11.9‐16 yr) with Crohns disease and growth failure were enrolled. In phase 1, patients were randomized to either GH (0.05 mg/kg per day) or placebo; in phase 2, patients who received placebo during the first year received GH for various time periods. Follow‐up was every 3 months for up to 2 years. Results: During placebo treatment (4 patients), mean height‐for‐age z score (haz) increased 0.23 in the first half year and 0.55 in the second half year. The mean improvement in haz during the first half year of GH treatment (7 patients) was 0.13; during the second half year (5 patients), haz decreased 0.01. Effects of GH varied among patients; 2 patients grew only when nutritional supplementation was added. Observed changes were not statistically significant; however, the number of patients studied was small, and statistical analyses could have been affected by sample size. Serum insulin‐like growth factor‐1 levels correlated with height velocity. Only 2 patients later reached expected adult height. Conclusions: In this pilot study, GH treatment at the dose given did not stimulate growth in children with Crohns disease and short stature. Whether or not GH plus nutritional therapy would be effective in promoting sustained catch‐up growth remains to be determined.

Adrenomyeloneuropathy Presenting as Addison's Disease in Childhood

Adrenoleukodystrophy, a sex-linked peroxisomal disorder that results in the impaired oxidation of long-chain saturated fatty acids and causes neurologic impairment, is a rare cause of Addisons disease in children. Adrenomyeloneuropathy is the name given to a biochemically identical but milder and more slowly progressive variant of adrenoleukodystrophy that affects young adults, in whom adrenal insufficiency may long precede nervous system dysfunction. The transmission of adrenomyeloneuropathy, like that of most cases of adrenoleukodystrophy, is sex-linked. Because of a preponderance of male patients among a group of patients with the onset of adrenal failure in childhood, we questioned whether this condition might be the initial manifestation of adrenomyeloneuropathy. We therefore measured the plasma concentrations of very-long-chain saturated fatty acids in eight patients with adrenal insufficiency; of these, five had elevated plasma hexacosanoic acid concentrations (range, 2.42 to 6.43 mumol per liter; mean normal level [+/- SD], 0.83 +/- 0.45), confirming the presence of adrenomyeloneuropathy. Magnetic resonance imaging showed clear evidence of brain involvement in all five patients. Reexploration of the family histories revealed additional missed cases. We conclude that the possibility of adrenomyeloneuropathy should be considered in any boy with Addisons disease.

The effect of medroxyprogesterone acetate on adrenocortical function in children with precocious puberty.

Hypothalamic-pituitary-adrenal function of 8 girls and 3 boys with true sexual precocity, treated with weekly or biweekly injections of medroxyprogesterone acetate (MPA) for 6 to 61 months, was evaluated. The studies were done twice, prior to the onset of therapy and again during the treatment period. Base-line studies were normal in all. During MPA therapy, 8 of the 11 patients showed varying degrees of adrenal suppression. The data suggest that in addition to its action on the hypothalamic-pituitary-gonadal axis, MPA has glucocorticoid-like properties in man which decrease the secretion of adrenocorticotropic hormone and causes adrenal suppression.

Hypoketonemia and age-related fasting hypoglycemia in growth hormone deficiency

Body fuels were measured in 45 normal children and 17 growth hormone-deficient patients after 24 hours of fasting. After three months of therapy with human Growth Hormone (hGH) 16 of the patients were restudied. In all groups, beta-hydroxybutyrate (BOHB) concentrations correlated inversely with age and with glucose concentrations. When adjusted for these factors, the concentrations of BOHB were significantly lower in the growth hormone-deficient patients than in the control children, before (P less than 0.01) as well as after therapy (P less than 0.01). Only the five youngest patients became hypoglycemic. During fasting, ketones, which serve as an alternative fuel for the brain, spare glucose. Thus, a shortage of ketones would compromise the ability of the patient to conserve glucose and predispose the patient to fasting hypoglycemia. Accordingly, we propose that hypoketonemia is a critical factor in the genesis of fasting hypoglycemia in growth hormone deficiency.

Hypersecretion of insulin after the administration of l-leucine to obese children

The administration of l -leucine by mouth to 8 markedly obese children resulted in elevations in the concentrations of insulin in the blood which were strikingly greater than those observed in control subjects. Such changes were not dependent on differences in the absolute doses of leucine. Despite the marked elevations of insulin after administration of leucine, the fall in concentrations of glucose differed little from that in the control subjects, reflecting a relative insensitivity to insulin in obese subjects. The increased secretion of insulin after administration of leucine to obese subjects correlates with an increased basal secretory capability of the islets and appears to be in keeping with a hyperresponsiveness of the islets of Langerhans to a variety of stimuli.

Studies in Type I glycogenosis of the liver: The genesis and disposition of lactate

Using a constant infusion of 14 C lactate, we have investigated the mechanism responsible for the increased concentration of lactate in four patients with Type I glycogenosis of the liver. The patients exhibited significantly increased rates of formation and disposal of lactate as well as increased incorporation of lactate into glucose. The results are interpreted as compatible with a dynamic pool of lactate generated by a recycling process between glycogen and lactate.

Fat-derived fuels during a 24 hour fast in children

We examined the availability of fat-derived fuels in 23 normal children aged 1.9 to 16.7 years who fasted for 24 h. we found a rapid and progressive rise in the blood concentrations of free fatty acids (FFA) and ketones. There was a highly significant negative correlation between the concentrations of β-hydroxybutyrate (βOHB) and glucose and also between βOHB and age.With time, the ratio of βOHB to acetoacetate (AcAc) progressively increased.We briefly review the vital role of ketones in the adaptation to fasting and point out that qualitative tests of ketones can be misleading. Our results indicate that quantitative determinations are essential in the evaluation of suspected disorders of fuel metabolism and that the results must be interpreted according to the age of the child, the duration of fasting, and the concomitant concentrations of glucose.

An effect of ketones on the concentrations of glucose and of free fatty acids in man independent of the release of insulin

Ketones were infused into dogs, obese hyperinsulinemic patients, children whose weights were in the normal range, and subjects with long-standing, insulin-dependent, juvenile diabetes mellitus. Six of the obese group also had a second infusion two hours after the first one. A significant rise in the serum concentration of insulin was seen in the dogs and in the obese children but only with the first infusion. No increase in the levels of insulin was seen in the control children nor in the obese group with the second infusion. Bv contrast, the blood levels of glucose and of free fatty acids (FFA) declined consistently, even in the absence of a significant increase in the serum concentrations of insulin, and also in the diabetic children who were unable to secrete insulin. It appears that the effect of ketones in lowering levels of glucose and of FFA in the blood may be accompanied by, but need not depend upon, the release of insulin.

Original articleStudies in Type I glycogenosis of the liver: The genesis and disposition of lactate

Using a constant infusion of 14 C lactate, we have investigated the mechanism responsible for the increased concentration of lactate in four patients with Type I glycogenosis of the liver. The patients exhibited significantly increased rates of formation and disposal of lactate as well as increased incorporation of lactate into glucose. The results are interpreted as compatible with a dynamic pool of lactate generated by a recycling process between glycogen and lactate.