New insights into factors influencing adult height in short SGA children: Results of a large multicentre growth hormone trial.

BACKGROUND: Growth hormone (GH) treatment is effective in improving adult height (AH) in short children born SGA. However, there is a wide variation in height gain, even after adjustment for predictive variables. It is therefore important to investigate new factors which can influence the response to GH. OBJECTIVE: To investigate the efficacy of GH treatment (1 mg/m(2/) day) in short SGA children on AH. To assess the relation between spontaneous catch-up growth after birth and growth during puberty on the total height gain SDS to AH. PATIENTS: Longitudinal GH trial in 170 children. RESULTS: Median age at start of GH was 7·1 years and height -3·0 SDS. AH was -1·8 SDS (TH-corrected AH -1·1 SDS) in boys and -1·9 SDS (TH-corrected AH -1·3 SDS) in girls. Spontaneous catch-up growth after birth was ≥0·5 SDS in 42% of children. In contrast to expectation, spontaneous catch-up growth was negatively correlated with total height gain SDS during GH (P = 0·009). During puberty, height SDS declined (-0·4 SDS in boys and -0·5 SDS in girls) resulting in a lower total height gain SDS than expected. Pubertal height gain was 25·5 cm in boys and 15·3 cm in girls, significantly lower compared to AGA children (P < 0·001). At onset of puberty, BA for boys and girls was moderately advanced (P = 0·02 and P < 0·001, respectively). Growth velocity was comparable to AGA children during the first two years of puberty, but thereafter significantly lower until reaching AH (P < 0·001). CONCLUSION: In contrast to our hypothesis, children with greater spontaneous catch-up growth after birth show a lower total height gain SDS during GH. Height SDS declines from mid-puberty, due to a marked early deceleration of growth velocity.

Phenotype-genotype correlation in a familial IGF1R microdeletion case.

BACKGROUND: IGF1R (insulin-like growth factor 1 receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype-phenotype correlations, although short stature is its well established hallmark. Several pure 15q26 monosomies (n=22) have been described in the literature, including those with breakpoints proximal to the IGF1R gene. Clinical heterogeneity is characteristic for these mainly de novo telomeric deletions and is illustrated by the involvement of several different organ systems such as the heart, diaphragm, lungs, kidneys and limbs, besides growth failure in the patient's phenotype. The clinical variability in these patients could be explained by the haploinsufficiency of multiple genes besides the IGF1R gene. In comparison, the six different IGF1R mutations revealed to date exhibit some variance in their clinical features as well, probably because different parts of the downstream IGF1R signalling cascade were affected. METHODS AND RESULTS: Using the recently developed technique multiplex ligation dependent probe amplification (MLPA), a chromosome 15q26.3 microdeletion harbouring part of the IGF1R gene was identified in a Dutch family. This deletion segregated with short height in seven out of 14 relatives across three generations. Metaphase fluorescence in situ hybridisation (FISH) and Affymetrix 250k single nucleotide polymorphism (SNP) microarray were used to characterise the deletion into more detail and showed that exons 11-21 of the IGF1R and a small hypothetical protein (LOC 145814) were deleted. CONCLUSION: Clinical work-up of this newly identified family, which constitutes the smallest (0.095 Mb) pure 15q26.3 interstitial deletion to date, confirms that disruption of the IGF1R gene does not induce major organ malformation or severe mental retardation.

Hepatocyte nuclear factor (HNF)1A and HNF4A substitution occurring simultaneously in a family with maturity-onset diabetes of the young.

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by an early age at onset, autosomal dominant inheritance and a primary defect in the function of the B-cells of the pancreas. We report a family with two members carrying a substitution in both the hepatocyte nuclear factor (HNF)1A and HNF4A gene simultaneously. CASE REPORT: A 39-year-old man was referred because of mild diabetic retinopathy. Because of a dominant presentation of diabetes in his family, genetic testing was performed. Sequence analysis of the genes involved in MODY-1-3 revealed the presence of an amino acid substitution in the HNF1A as well as the HNF4A gene. Both substitutions were also detected in his mother. The HNF1A substitution has been described previously as pathogenic, whereas the HNF4A substitution had not been found previously. The HNF4A substitution was located in a conserved region of the protein and, additionally, the proband and his mother had high birthweights and low triglyceride levels, both of which are associated with pathogenic HNF4A substitutions. CONCLUSIONS: To our knowledge this is the first reported family carrying both a substitution of HNF1A and HNF4A gene simultaneously. The exact contribution of each substitution to the phenotype of our subjects remains to be further elucidated, however, given the high birthweights and the low triglyceride levels in those with both substitutions, it is reasonable that the HNF4A substitution is pathogenic.

Bone mineral density in children and adolescents with Prader-Willi syndrome: a longitudinal study during puberty and 9 years of growth hormone treatment.

CONTEXT: Longitudinal data on bone mineral density (BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. OBJECTIVE: This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMADLS) in children with PWS. DESIGN AND SETTING: This was a prospective longitudinal study of a Dutch PWS cohort. PARTICIPANTS: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. INTERVENTION: The children received GH treatment, 1 mg/m(2)/day (≅ 0.035 mg/kg/d). MAIN OUTCOME MEASURES: BMDTB, BMDLS, and BMADLS was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. RESULTS: In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMADLSSDS remained stable. During adolescence, BMDTBSDS and BMADLSSDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lower BMADLSSDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. CONCLUSIONS: This long-term GH study demonstrates that BMDTB, BMDLS, and BMADLS remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty.

Growth until puberty after in utero exposure to coumarins.

Anticoagulation with coumarins is an effective therapy during pregnancy. Fetal exposure to coumarin derivatives during the first trimester, however, is associated with skeletal anomalies (warfarin or coumarin embryopathy). Information about long-term effects of prenatal coumarin exposure on the skeletal development is not available. We investigated growth and body proportions at school age of children exposed to coumarins in utero. A blind population-based cohort study was conducted on 307 exposed children and 267 non-exposed controls ages 8-15 years. The exposed cohort was based on a prospective registry of coumarin-treated pregnant women. Anthropometric data included height, weight, head circumference, and measurements to evaluate body proportions. The mean height of exposed children did not differ from that of the non-exposed children (mean difference 0.01 SD). In addition, no differences were found for the proportional measures. As a group, children exposed in the first trimester showed no evidence of growth impairment. Two children in this group, however, were born with signs of coumarin embryopathy and one of these displayed a deficit in height at school age. Long-term growth was not affected by a high cumulative dosage or exposure after the first trimester. We conclude that, when exposure during the first trimester is avoided, coumarin therapy during pregnancy has no demonstrable risk for the child's skeletal development.

Short-term growth in asthmatic children using fluticasone propionate.

BACKGROUND: Inhaled corticosteroids may reduce short-term growth velocity in asthmatic children and knemometry is the most sensitive tool to detect this short-term growth suppression. STUDY OBJECTIVE: To compare lower leg growth velocity, as measured by knemometry, in asthmatic children during and after treatment with inhaled fluticasone propionate (FP), 100 microg twice daily. DESIGN: Nonrandomized open trial. SETTING: University hospital, outpatient clinic for pediatric pulmonology. PATIENTS: Twenty-one asthmatic children (13 boys), aged 6 to 10 years. INTERVENTIONS: Inhalation of FP from a dry powder inhaler, 100 microg, twice daily for 6 weeks, followed by 2 weeks during which only an inhaled beta2-agonist was used on demand (washout). During treatment and washout periods, patients were seen every 2 weeks at the same time of day. MEASUREMENTS AND RESULTS: Lower leg growth velocity measured by knemometry during FP treatment was not significantly different from that during washout (p=0.33, one-way analysis of variance). CONCLUSIONS: No significant suppression of lower leg growth velocity was found in prepubertal asthmatic children using FP, 100 microg, by dry powder inhaler twice daily for 6 weeks.

Cushing's disease in a child caused by a corticotropin-releasing hormone-secreting intrasellar gangliocytoma associated with an adrenocorticotropic hormone-secreting pituitary adenoma.

Cushing's disease resulting from intrasellar corticotropin-releasing hormone (CRH)-secreting gangliocytomas is very rare, and only two such cases have been reported in the literature to date. The authors present a third case in which an adrenocorticotropic hormone-secreting pituitary adenoma was found in addition to a gangliocytoma in a 10-year-old girl with clinical and endocrinological symptoms of Cushing's disease. Computed tomographic and magnetic resonance imaging scans showed a suprasellar and parasellar tumor. A green-colored, heterogeneous tumor and a small adenoma were removed transsphenoidally. Histological examination revealed a large gangliocytoma immunoreactive for CRH and a small, mucoid cell pituitary adenoma immunoreactive for ACTH. This is the first case of such a tumor causing Cushing's disease in a child. It might exemplify induction of an ACTH-secreting pituitary adenoma by means of chronic overstimulation of CRH.

A girl treated with growth hormone presenting with neuromyopathy as first sign of acute lymphoblastic leukemia.

An 11-year-old girl being treated with DNA-recombinant growth hormone therapy presented with proximal limb weakness. Laboratory studies were negative. A few months later she presented with acute lymphoblastic leukemia (ALL). A diagnosis of carcinomatous neuromyopathy was made. After successful treatment of the leukemia the symptoms subsided and did not recur.

Bilateral epiphysiodesis around the knee as treatment for excessive height in boys.

Between 1987 and 1993, six boys who had been predicted to grown to an excessive height were treated with bilateral Phemister epiphysiodesis around the knee. Median predicted adult height was 210.4c (range: 207.4-213.4 c), the median observed adult height was 201.5 c (range: 195.5-206.7 c). Median height reduction was 9.3 c (range: 4.1-15.3 c). Median length of follow-up was 44 months (range: 21-84 months). At final follow-up, all patients had full range of motion, no infections, no pain, no angular deformities, equal leg lengths, and radiographic evidence of physeal closure. Bilateral Phemister epiphysiodesis around the knee is a good alternative to pharmacological treatment for boys with excessive height.

[The psychosocial development of boys treated with pulsatile LHRH administration for hypogonadotropic hypogonadism]. / De psychosociale ontwikkeling van jongens behandeld met pulsatiele LHRH-toediening wegens hypogonadotroop hypogonadisme.

Eight male adolescents with hypogonadotropic hypogonadism, who were being treated with pulsatile GnRH administration, were examined psychologically. We focused on the development of independence and on the manner in which they experienced their illness and treatment. The patient group was compared with a group of male adolescents of normal height and a group of male adolescents of short stature. We found that there were problems in the patient group in the development of independence, specifically relating to their own body image and social functioning. The retarded sexual development of these patients is probably of greater importance than the height growth-related problems, if any. The problems we found appeared to be caused primarily by the presence of the physical disorder and not by the stress of treatment.

[Microalbuminuria as risk factor for nephropathy in children with insulin-dependent diabetes mellitus]. / Microalbuminurie risicofactor voor nefropathie bij kinderen met van insuline afhankelijke diabetes mellitus.

OBJECTIVE: To assess the prevalence of microalbuminuria (> or = 30 mg/24 h) in children with insulin dependent diabetes mellitus (IDDM). DESIGN: Retrospective. SETTING: Department of Pediatrics, University Hospital, Free University of Amsterdam. METHODS: Albumin excretion rate was assessed in 24-hour voiding volumes in 71 children, mean age 11.8 yrs (range 3.5-17.9; 27 boys and 43 girls). Mean duration of IDDM was 5.4 yrs (1.0-5.0). Patients with albuminuria were compared with patients without microalbuminuria. Results of angiotensin-converting enzyme inhibition (n = 4) are presented. RESULTS: The prevalence of microalbuminuria was 16% (n = 11). In 7% (n = 5) the microalbuminuria was persistent; in 9% (n = 6) it was intermittent. The mean age of the children with microalbuminuria (14.0 years; 8.9-17.4) was significantly higher than the age of the children without this disorder (11.7 years; 3.5-17.9). Two prepubertal children had developed microalbuminuria. The group with microalbuminuria had a significantly higher age at onset of the disease (8.1 years; 1.9-13.0) than the group without microalbuminuria (5.8 jaar; 0.9-14.5). The daily dose of insulin in the group with microalbuminuria was significantly higher (1.15 U/kg; 0.6-1.56) than in the group without microalbuminuria (0.97 U/kg; 0.20-1.87). There was no correlation between microalbuminuria and the duration of the disease. CONCLUSION: Microalbuminuria may exist as early as the prepuberal period, but is found more frequently in children with IDDM who have entered puberty. There is a correlation between microalbuminuria and the age which it develops, the age at onset of the IDDM and the daily dose of insulin. Secondary prevention of diabetic nephropathy with ACE inhibition appears to be possible.

[Plantar fibromatosis in infants]. / Plantaire fibromatose bij zuigelingen.

In 2 girls aged 5 months swellings were noted shortly after birth, on the plantar surface of the anteromedial parts of both heels and the left heel, respectively. On an expectative management, the swellings grew with the feet, without causing symptoms. The clinical picture and characteristic location led to the diagnosis of plantar fibromatosis. In infants it is a rare disorder which frequently shows spontaneous regression and does not behave aggressively. To avoid unnecessary investigations or even surgery and to reassure the parents, it is important to recognize this condition in infants.

[Growth, development and prediction of body height in children with central precocious puberty after 3 years of therapy with Decapeptyl-Depot, a slow-releasing GnRH agonist]. / Rust, vývoj a predikce telesné výsky detí centrální pubertas praecox po 3 letech lécby "slow-releasing" agonistou GnRH, prípravkem Decapeptyl-Depot.

More than 100 patients with central precocious puberty are participating in this international multicenter study using monthly i.m. injections of the slow-release GnRH agonist Decapeptyl-Depot. In 15 patients, Decapeptyl-Depot treatment could be discontinued after 2 years of therapy. Gonadal suppression was promptly reversible in all of them, as shown by prepubertal low gonadotrophin and sex steroid levels. Of the remaining 90 patients, 40 have been treated for more than 3 years, including 33 girls and 7 boys. Plasma levels of LH, FSH, estradiol and testosterone dropped to the prepubertal range after one month of Decapeptyl-Depot and remained there for the whole period of therapy. At start of therapy, mean chronologic age of these 40 children was 6.6 +/- 1.4 (SD) years, mean bone age 10.2 +/- 1.9 years. Mean predicted adult height increased in the boys from 173.6 +/- 13.8 (SD) cm at start of therapy to 184.6 +/- 17.0 cm after 3 years. Predicted adult height increased in girls from 158.0 +/- 12.2 to 161.0 +/- 7.5 cm. Undue side effects were not seen, long term tolerance was good. It is concluded that Decapeptyl-Depot injected i.m. every 4 weeks suppresses the pituitary gonadal axis in children with central precocious puberty without clinical or biochemical escapes, and leads to an increase in predicted adult height by more than 3 cm in all boys and in 53% of the girls after three years of treatment.

[Central precocious puberty]. / Centrale pubertas praecox.

Precocious puberty is a stressful event for patient and environment. The diagnostic evaluation will be discussed. LHRH analogs will give a new approach in the treatment of central precocious puberty.

[Phenotypically a boy, genotypically a girl; the 46,XX male syndrome]. / Fenotypisch een jongen, genotypisch een meisje; het 46,XX male syndroom.

A three and a half years old boy with obesity, a small penis, and cryptorchism appeared to have a 46,XX karyotype in cultured peripheral lymphocytes. The clinical features of this rare syndrome and theories of etiology of 46,XX male subjects are discussed. Furthermore we stress the importance of thorough investigation in case of non-palpable testicles in an individual having a penis.

[Effects of diabetes education in children]. / De effecten van diabetes-educatie bij kinderen.

This article presents the results of a research project on psychological as well as medical effects of diabetes-education on young children. The education programme influences some aspects of the emotional attitude of children towards their diabetes in a positive way. Significant results are found on three topics: the emotional attitude towards diabetes(care), speaking up about diabetes in the social environment, and taking own responsibility towards diabetes(care). The medical effects tested are not significantly influenced. Children and parents experience (the results of) the education programme commonly in a positive way.

Eight years of growth hormone treatment in children with Prader-Willi syndrome: maintaining the positive effects.

BACKGROUND: The most important reason for treating children with Prader-Willi syndrome (PWS) with GH is to optimize their body composition. OBJECTIVES: The aim of this ongoing study was to determine whether long-term GH treatment can counteract the clinical course of increasing obesity in PWS by maintaining the improved body composition brought during early treatment. SETTING: This was a multicenter prospective cohort study. METHODS: We have been following 60 prepubertal children for 8 years of continuous GH treatment (1 mg/m(2)/d ≈ 0.035 mg/kg/d) and used the same dual-energy x-ray absorptiometry machine for annual measurements of lean body mass and percent fat. RESULTS: After a significant increase during the first year of GH treatment (P < .0001), lean body mass remained stable for 7 years at a level above baseline (P < .0001). After a significant decrease in the first year, percent fat SD score (SDS) and body mass index SDS remained stable at a level not significantly higher than at baseline (P = .06, P = .14, resp.). However, body mass index SDSPWS was significantly lower after 8 years of GH treatment than at baseline (P < .0001). After 8 years of treatment, height SDS and head circumference SDS had completely normalized. IGF-1 SDS increased to +2.36 SDS during the first year of treatment (P < .0001) and remained stable since then. GH treatment did not adversely affect glucose homeostasis, serum lipids, blood pressure, and bone maturation. CONCLUSION: This 8-year study demonstrates that GH treatment is a potent force for counteracting the clinical course of obesity in children with PWS.

High-dose GH treatment limited to the prepubertal period in young children with idiopathic short stature does not increase adult height.

OBJECTIVE: To assess the long-term effect of prepubertal high-dose GH treatment on growth in children with idiopathic short stature (ISS). DESIGN AND METHODS: Forty children with no signs of puberty, age at start 4-8 years (girls) or 4-10 years (boys), height SDS <-2.0 SDS, and birth length >-2.0 SDS, were randomly allocated to receive GH at a dose of 2 mg/m(2) per day (equivalent to 75 microg/kg per day at start and 64 microg/kg per day at stop) until the onset of puberty for at least 2 years (preceded by two 3-month periods of treatment with low or intermediate doses of GH separated by two washout periods of 3 months) or no treatment. In 28 cases, adult height (AH) was assessed at a mean (S.D.) age of 20.4 (2.3) years. RESULTS: GH-treated children (mean treatment period on high-dose GH 2.3 years (range 1.2-5.0 years)) showed an increased mean height SDS at discontinuation of the treatment compared with the controls (-1.3 (0.8) SDS versus -2.6 (0.8) SDS respectively). However, bone maturation was significantly accelerated in the GH-treated group compared with the controls (1.6 (0.4) versus 1.0 (0.2) years per year, respectively), and pubertal onset tended to advance. After an untreated interval of 3-12 years, AH was -2.1 (0.7) and -1.9 (0.6) in the GH-treated and control groups respectively. Age was a positive predictor of adult height gain. CONCLUSION: High-dose GH treatment restricted to the prepubertal period in young ISS children augments height gain during treatment, but accelerates bone maturation, resulting in a similar adult height compared with the untreated controls.