Issa AlSalmi

Congenital adrenal hyperplasia complicated by central precocious puberty: Linear growth during infancy and treatment with gonadotropin-releasing hormone analog

Some children with congenital adrenal hyperplasia (CAH) develop true precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis. We have seen six such children who had the diagnosis of CAH with late initiation of corticosteroid treatment and/or poor compliance who developed central precocious puberty (CPP). These patients were treated with standard-dose hydrocortisone and fludrocortisone. Administration of depot leuprorelin (3.75 mg subcutaneously every 28 days) for 2 years or longer was effective in arresting the manifestations of puberty, decelerating the pretreatment growth velocity ([GV] 10.8 +/- 1.5 v3.65 +/- 0.95 cm/yr), increasing the predicted adult height ([PAHT] 147.5 +/- 7.8 v 153.4 +/- 8.3 cm), and decreasing the bone age to statural age ratio (1.26 +/- 0.13 v 1.16 +/- 0.09). Analysis of auxanological data during the first 2 years of life showed that linear growth was significantly accelerated and bone age was advanced in patients who developed CPP compared with 11 age-matched patients. It appears that proper glucocorticoid replacement to achieve adequate control of hyperandrogenemia during early life might prevent development of CPP in these patients. Gonadotropin-releasing hormone agonist (GnRHa) therapy can improve the final adult height, bringing it closer to that expected from the genetic potential.

Recessive Robinow syndrome: With emphasis on endocrine functions

We present the characteristic features of 14 children with the recessive form of Robinow syndrome and the growth hormone (GH) response to provocation with clonidine and the serum insulin-like growth factor-I (IGF-I) concentration in 12 of these children. The gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) response to gonadotropin-releasing hormone (GnRH) was evaluated in early pubertal and pubertal patients, and the testosterone response to human chorionic gonadotropin (HCG) was evaluated in males. Children with Robinow syndrome, born at full-term, were short at birth (length, 41.4+/-2.1 cm) and had markedly slow growth velocity (GV) during the first year (13.1+/-2.1 cm/yr); consequently, they were significantly short at the end of the first year of life (length, 54.4+/-2.9 cm). This intrauterine and early extrauterine growth delay reflected low growth potential. During childhood, the GV standard deviation score (GVSDS) remained low (-2.17+/-0.83). Despite the presence of empty sella in all of the patients, they had an adequate GH response to clonidine provocation (peak, 19.3+/-5.8 microg/L) and a normal serum IGF-I concentration (309+/-142 ng/mL) for their age. During childhood and early adolescence, boys with Robinow syndrome had low basal testosterone and a low testosterone response to HCG stimulation (3,000 IU/m2/d intramuscularly [IM] for 3 days). However, their basal and GnRH-stimulated FSH concentrations were normal. Two girls (Tanner II breast development) had a normal serum estradiol (E2) concentration but high LH and FSH responses to GnRH stimulation. This suggested either defective feedback of E2 on the hypothalamic-pituitary axis or hyporesponsiveness of the ovaries to gonadotropin. Four weeks of HCG therapy (2,500 IU/m2 IM twice weekly) in three boys with Robinow syndrome increased the penile length and testicular volume, denoting a significant Leydig cell response to prolonged HCG stimulation and the presence of functioning androgen receptors. It is suggested that HCG and/or testosterone therapy during infancy may improve the severe micropenis in these patients.

Empty sellae, impaired testosterone secretion, and defective hypothalamic-pituitary growth and gonadal axes in children with Bardet-Biedl syndrome

We evaluated growth parameters and hypothalamic-pituitary-gonadal and growth functions in five children with Bardet-Biedl syndrome (BBS). Three of the five children had stature below the fifth percentile for age. Their growth hormone (GH) response to provocation was defective, and computed tomographic (CT) scanning revealed empty sellae in all of them. All the children were obese (body mass index [BMI] > 95th percentile for age). Three had hypercholesterolemia. Their basal serum testosterone concentration and testosterone response to 3-day human chorionic gonadotropin (HCG) stimulation were significantly lower than the levels in 12 age-matched obese normal children. Testosterone secretion failed to respond to HCG therapy for 4 weeks. Both basal gonadotropin levels (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and gonadotropin responses to LH-releasing hormone (LHRH) stimulation were normal and did not differ among the two study groups. It appears that primary hypogonadism is a cardinal feature of BBS, and it may be accompanied by hypothalamic and pituitary abnormalities.

Growrth hormone secretion and circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 concentrations in children with sickle cell disease

Abstract Impaired growth involving both height and weight accompanying sickle cell disease (SCD) poses diagnostic and therapeutic problems. We undertook this study to test the hypothesis that this impaired growth is associated with abnormalities of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF binding protein-3 (IGFBP-3)axis in 21 children with SCD and that SCD is associated with GH resistance. Nine of 21 children with SCD had a defective GH response to both clonidine and glucagon provosation (peak, d -xylose. A single injection of GH produced a smaller increase in circulating IGF-I in children with SCD with or without defective GH secretion versus 10 age-matched children with idiopathic short stature (ISS) and 11 children with isolated GH deficiency (GHD), suggesting partial GH resistance in the SCD group. The presence of defective GH secretion, decreased IGF-I synthesis, and partial resistance to GH in short children with SCD suggests that treatment with IGF-I may be superior to GH therapy for improving growth.

Permanent neonatal diabetes mellitus: Epidemiology, mode of presentation, pathogenesis and growth

Permanent neonatal diabetes mellitus (PNIDDM) is a rare form of IDDM with unclear etiology and pathogenesis. We determined the incidence and prevalence rates and studied the clinical and biochemical features of PNIDDM in the Sultanate of Oman. The mean incidence rate during the study period from January 1989 to December 1994 was 1.788±0.82 per 100,000 live births per year. At the end of December 1994 the prevalence rate was 2.4 per 100,000 children below the age of 5 years. They constituted 41.6% of all cases of IDDM in this age group. Diarrhoea, fever, lethargy, poor feeding and failure to thrive were the most common presenting symptoms. Dehydration and tachypnoea were the most common signs. All patients who developed IDDM during the neonatal period had intrauterine growth retardation and 4.5 presented with diabetic ketoacidosis (plasma glucose 37±9 mmol/L, pH 7.12±0.1). Hypertriglyceridemia was a constant feature (19.4±4.8 mmol/L). They were products of consanguineous marriage with significantly high prevalence of IDDM and NIDDM in their family members. None of the infants had clinical or immunological evidence of congenital viral infection. Three of the five children had HLA-DR2, the diabetes resistance alleles. C-peptide secretion was absent during and after metabolic control of hyperglycemia in all the studied infants and none had circulating islet cell antibody at presentation or during the first year after diagnosis. Despite marked growth retardation at birth, there was a significant improvement of growth after initiating insulin therapy. Four of the 5 patients had normal developmental milestones, one had mild developmental delay following a severe and prolonged attack of hypoglycemia. None of the patients had exocrine pancreatic deficiency. In summary, the very high rate of parental consanguinity, occurrence in both sexes and in two siblings in the same family, absence of islet cell antibodies and the presence of HLA-DR2 loci in 3/5 of patients suggest that PNIDDM is a different disease process to standard IDDM in childhood and an autosomal recessive mode of transmission.

Insulin and Glucagon Responses to Provocation with Glucose and Arginine in Prepubertal Children with Thalassemia Major Before and After Long-term Blood Transfusion

Hypertransfusion therapy has dramatically increased the duration and quality of life in patients with B-thalassemia major; however, it leads to chronic iron overload, and is frequently complicated by the development of diabetes mellitus or impaired glucose tolerance. To determine the early effect of iron overload on the endocrine pancreatic function, we studied glucose, insulin, and glucagon responses to oral load of glucose and to arginine provocation in 15 children with B-thalassemia major, before and after (3.1 +/- 0.6 years) high-transfusion and iron chelation and compared them with 15 age matched normal controls. In addition, we evaluated growth hormone (GH) responses to oral clonidine and measured the circulating insulin-like growth factor-I concentration in thalassemic children on long-term transfusion and controls. After long-term high-transfusion, thalassemic children had significantly decreased serum insulin concentrations and low insulin/glucose ratios at 60 and 120 min after an oral glucose load (1.75 g/kg) in comparison with values before therapy and those for controls. None of the thalassemic children had glucose intolerance after this period of frequent blood transfusion; however, their serum glucose levels at 60 and 120 min after the oral glucose load were significantly higher compared to control children. Thirty minutes after starting arginine infusion, serum insulin concentration was significantly lower in thalassemic children compared to before therapy. Basal and arginine-stimulated glucagon secretions were significantly elevated in thalassemic children on long-term blood transfusion with significantly low serum insulin/glucagon ratios. In addition, the high basal serum glucagon concentrations were not suppressed after the oral glucose load. Despite hyperglucagonaemia in all thalassemic children, their blood glucose dropped appropriately below 50 per cent of the fasting glucose level after an intravenous insulin dose (0.1 U/kg) ruling out any significant insulin-resistance. GH responses to clonidine provocation were subnormal in thalassemic children after long-term blood transfusion compared to controls. In summary, thalassemic children on long-term blood transfusion and iron chelation have progressive and early loss of B-cell mass, manifested by decreased insulin release in response to secretagogues, before the development of significant insulin resistance or impairment of glucose tolerance.

Hypoinsulinaemia has an Important Role in the Development of Oedema and Hepatomegaly During Malnutrition

Various alterations in hormonal levels have been suggested to contribute to the development of nutritional oedema and fatty liver in children with kwashiorkor. We present an infant who underwent near-total pancreatectomy at the age of 4 weeks and developed kwashiorkor after 11 weeks. The sequence of events following surgery can be divided into two phases. The first phase was characterized by hyperinsulinaemia and hypoglycaemia before feeds. During this phase, although the weight gain was slow (10 g/day) serum albumin (32 g/I) and prealbumin (0.23 g/I) concentrations were maintained with no oedema or hepatomegaly. In the second phase, insulin deficiency prevailed and he was receiving the same amount of milk (protein)/day (enriched with starch). During that phase he rapidly developed hypoalbuminaemia (18 g/l), hypoprealbuminaemia (0.1 g/l), oedema, hepatomegaly, and dermatosis. This case demonstrates clearly the important role of defective insulin secretion in the development of nutritional oedema and hepatomegaly.

Defective growth hormone (GH) secretion and short-term treatment in noonan syndrome

Auxological and endocrine data from 12 prepubertal children (3 males, 9 females) with Noonan syndrome (NS) were compared with those of 15 children with constitutional short stature (CSS), 20 children with partial GH deficiency (GHD), and 6 children with Turner syndrome (TS). Four children With NS were treated with human growth hormone (hGH) (n=4) (25 units/m2 week, divided on daily s.c. doses). In children with NS, the peak serum GH response to clonidine (5.4 ± 2.7 ug/L) and glucagon (7.4 ± 3.4 ug/L) were significantly lower than those for children with CSS (14.8 ±3.4 and 12.8 ± 2.8 ug/L respectively). Nine out of the 12 (75%) children with NS did not mount normal GH peak (10 ug/L or more) after provocation. The 12-h integrated GH secretion in the 3 children With NS who had normal GH response to provocation (2.7 ± 0.7 ug/L) was markedly lower compared to that for children with CSS (6.7 ±1.2 ug/L). The serum insulin-like growth factor-1 (IGF-l) concentrations were lower in children with NS (67 ± 32 ng/ml) vs CSS (165 ±35 ng/ml), but not different from those for GHD children (59 ± 33 ng/ml). In 4 children with NS, hGH therapy for a year increased height growth velocity from 4.1 ± 0.3 cm/yr to 7.4 ±0.6 cm/yr and height standard deviation score (Ht SDS) from -2.2 ± 0.6 to -1.45 ±0.3. This growth acceleration was accompanied by an increase in IGF-I concentration (from 52 ±21 ng/ml to 89 ± 25 ng/ml). In summary, these results prove a defect of the GH secretion in children with NS and suggest that GH therapy has an important role in the management of their short stature.

Defective growth hormone secretion and hypogonadism in the new syndrome of congenital hypoparathyroidism, growth failure and dysmorphic features

A child with extreme growth failure, dysmorphic features, hypoparathyroidism, and abnormal skeletal survey was studied. He was a product of first degree consaguineous marriage who had intrauterine growth retradation and presented at 14 days of age with hypocalcemic tetany with normal cardiovascular system and immune function. Endocrine evaluation after infancy revealed defective growth hormone (GH) secretion in 2 provocation tests and lack of clinical and testosterone response to human chorionic gonadotrophin (HCG) therapy.

Endocrine aspects of Langerhans cell histiocytosis.

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