Jean-Louis Chaussain

Near normalization of adolescent height with growth hormone therapy in very short children without growth hormone deficiency

Ten prepubertal children with stature at or below the 1st percentile for height and without growth hormone deficiency received 0.3 U recombinant growth hormone per kilogram daily for 2 years before puberty. Their growth velocity increased from 4 +/- 0.3 cm/yr before treatment to 10.7 +/- 0.6 and 8.8 +/- 0.6 cm, respectively, during the first and second years of treatment, and then remained at 5.7 +/- 0.7 cm the year after the end of growth hormone administration. This resulted in a near normalization of adolescent height. Bone maturation paralleled chronologic age, and therefore the expected final height of the children increased by approximately 10 cm. Administration of growth hormone induced a reversible hyperinsulinemia, with moderate and transient changes in glucose metabolism. A prospective, randomized study, including an untreated cohort, will be needed to confirm the effects on final height and to determine the magnitude of the response in familial short stature.

Insulin pump therapy in young children with type 1 diabetes

Six 17- to 53-month-old diabetic children had marked metabolic instability characterized by chronic hyperglycemia and frequent or severe hypoglycemia with conventional management that included twice daily insulin injections, diet, and home blood glucose monitoring. Because of the metabolic instability, all were given continuous subcutaneous insulin infusions (CSII) via portable externally worn infusion pump. During 6 months of CSII, there was marked improvement: hemoglobin A1 decreased from 192% +/- 8% (SD) to 152% +/- 31% of the normal mean (P less than 0.02), and hypoglycemic episodes decreased in both severity and frequency. CSII was incorporated into the childrens treatment with no appreciable adverse psychologic effects or interference with normal activities. CSII, under carefully controlled clinical conditions, may be of benefit in some preschool children with unacceptable metabolic control of diabetes mellitus.

Effect of Gonadotropin-Releasing Hormone Agonist Treatment in Boys with Central Precocious Puberty: Final Height Results

Objective: The small number of boys present in most studies on final height (FH) after gonadotropin-releasing hormone agonist (GnRHa) treatment for central precocious puberty (CPP) offers difficulties in the evaluation of the effects of treatment on FH in males. Method: We therefore combined FH data from The Netherlands, Italy and France to study the effect of GnRHa treatment in a large group of 26 boys with CPP. Results: The mean chronological age at the start of treatment was 7.6 ± 2.0 (SD) years, bone age (BA) was 11.0 ± 2.1 years. All boys were treated with depot formulations of the GnRHa triptorelin with established gonadal suppression for a mean treatment period of 4.7 ± 2.1 years. FH was 172.9 ± 6.6 cm. FH standard deviation score (SDS) was –0.66 ± 1.22, not significantly different from the target height SDS of –0.23 ± 0.75. FH-SDS was significantly lower in the subgroup of 12 patients with organic CPP compared to patients with idiopathic CPP (–1.34 ± 1.06 vs. –0.08 ± 1.06, respectively; p = 0.01), but no difference in height gain was observed. The mean estimated height gain, defined as the difference between predicted and actual adult height was 6.2 ± 8.7 cm using the average tables of Bayley and Pinneau, and 0.3 ± 8.6 cm using the BA advance adjusted tables. Regional differences in height gain were observed between the different countries, reflecting different local practices. Conclusion: We conclude that GnRHa treatment in boys results in a FH close to target height.

Adrenoleukodystrophy presenting as addison's disease in children and adults

X-linked adrenoleukodystrophy (ALD) is a peroxisomal genetic disorder that causes adrenal insufficiency, demyelination in the central nervous system, and increased levels of very long chain fatty acids in tissues and body fluids. Although most cases appear in childhood as a devastating degenerative disorder or in adulthood as a milder disorder affecting the spinal cord, many patients have adrenal insufficiency prior to the onset of their neurologic deterioration for many years. Addisons disease without neurologic involvement may also remain the only clinical manifestation of X-linked ALD. Because of the prognostic implications, the need for genetic counseling, and the potential benefit of therapeutic interventions, any boy or adult male with Addisons disease must be tested for X-linked ALD.

A new mutation within the deoxyribonucleic acid-binding domain of the androgen receptor gene in a family with complete androgen insensitivity syndrome

OBJECTIVEnTo study the androgen receptor gene in a large kindred with complete androgen insensitivity syndrome and positive receptor-binding activity.nnnDESIGNnEnzymatic amplification coupled with single strand conformation polymorphism and DNA sequencing were used.nnnRESULTSnIn all the affected members, single strand conformation polymorphism showed a mobility shift in exon 2, suggesting a sequence alteration. Sequencing identified a valine into phenylalanine substitution at position 581 in the first zinc finger of the DNA-binding domain.nnnCONCLUSIONSnThis valine 581 is conserved in all nuclear receptors and has an important role for the recognition of the androgen response elements by the activated androgen receptor. This amino acid substitution has not been previously described in the androgen receptor in patients with androgen insensitivity syndrome. Moreover, single strand conformation polymorphism allowed determination of the generation in which the mutation appeared and performance of carrier diagnosis in this family.

Gonadotropin Releasing Hormone Agonist Treatment for Central Precocious Puberty

Several methodological problems complicate the evaluation of final statural height (FH) benefit after treatment with gonadotropin releasing hormone (GnRH) agonists for central precocious puberty (CPP). Since no controlled study has been performed, we have to rely on indirect methods, comparison with predicted height or with historical controls. FH of 58 girls, uniformly treated with triptorelin slow release formulation (triptorelin-SR, Decapeptyl®) for CPP were compared with predicted height before treatment and with FH of an historical group of patients not treated with GnRH agonist. The comparison with predicted height revealed an improvement of 4.8 ± 5.8 cm; comparison with the historical control group showed a mean improvement of 8.3 cm. The post-treatment growth spurt (ΔFH – height at the end of treatment) was a strong predictor of FH in multivariate analysis. The data suggest that continuing treatment beyond the age of 11 in girls does not improve and could actually decrease FH.

Growth Hormone Therapy for Turner Syndrome: Evidence for Benefit

Growth hormone (GH) is registered for children with Turner syndrome (TS) in several countries. Improving the final heights (FH) is certainly the most worthy goal of therapy, but evaluation of treatment effect is complicated by methodological difficulties. Several series of FH results have now been published, with estimated benefits ranging from 0-9.3 cm, as compared to predicted height before treatment. The majority of studies report height gains of less than 5 cm, but in these studies, GH was started at a relatively late age and used at low doses. Several approaches can be utilized to improve FH results in TS, including early initiation of GH therapy, increased or optimized GH dose regimens, or optimization of sexual steroid utilization.

Maladie de Cushing de l'enfant et de l'adolescent. Résultats thérapeutiques

Resume La chirurgie hypophysaire par voic trans-sphenoidale est actuellement le traitement de choix de la maladie de Cushing de lenfant. Patients et methodes. — Nous rapportons les resultats therapeutiques chez 20 patients successifs pris en charge dans le service dendocrinologie pediatrique de lhopital Saint-Vincent-de-Paul. Resultats. — Une remission du syndrome de Cushing a ete obtenue chez 12 patients operes sur 16 (75 %). Parmi ces 12 patients initialement en remission, trois ont rechute (25 %) 21 a 80 mois apres lintervention. Quatre patients ont dabord ete trailes par anticortisolique de synthese, soit parce quils avaient ete pris en charge dans un autre centre, soil parce que le diagnostic biologique ou radiologique de maladie de Cushing etait incertaia. Trois de ces patients ont ete secondairement operes, permettant dobtenir une remission. Parmi les sept patients chez qui la chirurgie hypophysaire a echoue (echec primaire ou rechute), deux ont ete reoperes, permettant dobtenir une remission. Ainsi sur 21 interventions, nous avons observe quatre echecs immediats (19 %), trois rechutes tardives (14 %) et 14 remissions ȧ moyen ou long terme (67 %, recul moyen 40 ± 35 mois). Aucun des criteres biologiques, radiologiques ou operatoires netait predictif des resultats therapeutiques, en particulier a long terme. Conclusion. — Nos resultats illustrent lefficacite mais aussi les limites de la chirurgie par voie trans-sphenoidale et soulignent la necessite dune surveillance a tres long terme. La prise en charge des echecs initiaux et des rechules est particulierement delicate et demande une concertation entre medecins, radiologues et chirurgiens.

Insulin-Specific Binding to Erythrocytes in 6 Girls with Acanthosis nigricans

6 girls, aged 4-16 years, with acanthosis nigricans and hirsutism were studied. Fasting and postglucose hyperinsulinism was present in the 5 older girls. In the youngest, a transitory diabetes with hyperinsulinism was induced by a cortisone therapy for hepatitis. Insulin resistance, suggested by the failure to significantly decrease blood glucose after insulin injection (0.1 U/kg), was demonstrated in three steps: (1) Patient plasma failed to bind 125I-insulin after a 5-day incubation followed by precipitation by antihuman globulin serum. (2) Specific 125I-insulin binding to rat liver membranes was identical in the presence of patient plasma and control plasma. (3) Specific 125I-insulin binding to the erythrocytes of the 6 patients (3.5-7.0%) was significantly lower (p less than 0.01) than in controls (4.5-19.5%). Moreover, the significant correlation present in controls between total binding and reticulocyte counts (r = 0.824, p less than 0.001) was absent in the patients. These data demonstrate further that, in the juvenile type of acanthosis nigricans, insulin resistance which may precede hyperinsulinism is not related to anti-insulin antibodies nor to antireceptor antibodies, but results from a primary defect of insulin receptors.

Pharmacological testing for thediagnosis of growth hormone deficiency

Evaluation of growth hormone (GH) secretion using pharmacological GH stimulation tests (GHSTs) remains current practice, although the reliability of GHSTs has been questioned and many pitfalls have been pointed out. We have analysed all the 6,373 GHSTs which led to the initiation of GH therapy in 3,233 children treated in France from 1973 to 1989. Eleven different pharmacological tests were used, and 62 out of the 66 theoretical pairs of tests were used at least once. The most frequent combination of tests was used in 12.7% of patients. Reliability of GH peak measured by comparing the results of two tests in the same patient was poor, as measured by intraclass correlation coefficients (all under 0.8). Multivariate analysis identified several parameters positively or negatively associated with peak plasma GH. We believe that several of these factors (i.e. weight standard deviation score (SDS), genetic target height SDS and nature of the agent) identify biases in the diagnosis of GH deficiency (GHD). In addition, we re-evaluated GH secretion in 208 young adults formerly treated with GH for childhood onset GHD. Peak plasma was superior or equal to 10 ng/ml in 81% of patients with former idiopathic GHD. We conclude that the current use of GHSTs as well as the criteria for idiopathic childhood GHD should be questioned.