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.

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.

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.

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.

GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial.

BACKGROUND: To investigate in a group of short children born small for gestational age (SGA), the effects of 3 years of GH treatment vs. no treatment on bone age (BA), height and bone mineral density (BMD). Also, to evaluate the influence of the severity of growth retardation at start and the GH dose on the gain in height. PATIENTS AND METHODS: The study design was an open-labelled, controlled multicentre GH study for 3 years. Non-GH-deficient (GHD) children (n = 87) were randomized to either a GH group (n = 61) or an untreated control group (n = 26). In addition, 12 SGA children had GHD (GHD group) and were treated in parallel. Both the GH and the GHD group were treated with a GH dose of 33 microg/kg/day. BMD was evaluated using dual energy X-ray absorptiometry (DEXA). In addition, data of our first GH trial in which short SGA children were treated with a GH dose of 66 microg/kg/day (n = 24) were used for comparison of height gain. RESULTS: In contrast to the control group, the GH group showed a significant increase in height (P < 0.001), as did the parallel GHD group. Bone maturation [delta bone age (BA)/delta calendar age (CA)] increased significantly during the first 2 years of GH treatment but slowed-down thereafter. The 3-year deltaBA/deltaCA ratio correlated significantly with the gain in height (r = 0.6, P < 0.001). At start, mean BMD SDS and mean BMAD SDS were significantly lower than zero. During GH treatment both increased impressively (P < 0.001). The gain in height of children with severe short stature at start (< or = -3.00 SDS), did not differ between those receiving either a GH dose of 33 or 66 microg/kg/day. CONCLUSION: Three years of GH treatment in short children born SGA results in a normalization of height during childhood. Also, bone maturation increased proportionately to the height gain. At start, mean values of BMD and BMAD were significantly reduced but normalized during GH treatment. We did not find an indication to treat very short SGA children (H SDS < or = -3.00) with a higher GH dose. We rather suggest to start GH treatment at an early age in order to achieve a normal height before puberty starts.

A lower prevalence of atopy symptoms in children with type 1 diabetes mellitus.

BACKGROUND: The Th1/Th 2 concept is a model to understand the pathophysiology of certain diseases. Atopic diseases (asthma, eczema and hayfever) are characterized by a chronic inflammatory reaction that is dominated by Th 2 cells, and type 1 diabetes mellitus (DM) is Th1 cell dominated. Because it is known that Th1 and Th 2 cells reciprocally counteract each other, it can be speculated that the prevalence of Th 2-mediated disease is lower in patients with Th1-mediated disease. OBJECTIVE: To compare the prevalence of atopic diseases between children with DM and age-matched controls. METHODS: Parents of children with DM were requested by Dutch paediatricians to complete the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire on the prevalence of atopic diseases. A control group was derived from a Dutch cross-sectional survey (the ISAAC2 study). RESULTS: We received 555 completed questionnaires, which is estimated to be 25% of the total number of Dutch children with DM. The control group consisted of 777 children. After age-matching, the questionnaires of 188 DM patients were used. Symptoms of asthma, hayfever and eczema were reported less in the group of children with DM compared with the control group (wheeze last year, OR 0.796, 95% CI 0.408-1.554; hayfever symptoms last year, OR 0.642, 95% CI 0.369-1.118; eczema symptoms last year, OR 0.693, 95% CI 0.430-1.115). CONCLUSION: The lower prevalence of astma, hayfever and eczema symptoms in DM patients compared with age-matched controls, although not statistically significant, is consistent with the Th1/Th 2 concept.

Postprandial chylomicron clearance rate in late teenagers with diabetes mellitus type 1.

A delayed chylomicron (CM) clearance rate, a known risk factor for atherosclerosis, has been described in adults with diabetes type 1 (DM1). We determined the CM clearance rate in late teenagers with DM1, and the relationship between CM clearance rate and elevated plasma lipid concentrations in DM1 teenagers in poor metabolic control (as characterized by HbA(1c) percentage). Plasma lipids and CM clearance were determined in nine patients with DM1 (mean age +/- SD: 17.5 +/- 0.6 y) and four healthy controls (mean age +/- SD: 20.1 +/- 0.8 y), by measuring breath (13)CO(2), plasma triglyceride, retinyl palmitate, and (13)C-labeled oleic acid concentrations, after oral administration of a fat-rich meal together with vitamin A and (13)C-oleic acid. In patients with DM1, fasting triglyceride and cholesterol concentrations were positively correlated with HbA(1c) percentage (p < 0.05). Neither in DM1 patients, nor in controls, was an elevated triglyceride concentration (above 1.7 mmol/L) found. Yet, in 22% of DM1 patients, cholesterol concentration was above 5.2 mmol/L, but not in any of the controls. CM clearance rate in DM1 patients was similar to that in controls and did not significantly correlate with HbA(1c) percentage. Fasting lipid concentrations in DM1 patients were not significantly correlated with CM clearance rate. Present data indicate that elevated lipid concentrations in late teenagers with DM1 are not attributable to a delay in CM clearance rate. A delayed CM clearance rate at late teenager age is not a risk factor contributing to the increased risk for atherosclerosis in DM1.

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.

Hypertensive encephalopathy in a patient with neonatal thyrotoxicosis.

UNLABELLED: Neonatal hyperthyroidism may give rise to serious cardiovascular complications. A girl with severe thyrotoxicosis in whom hypertensive encephalopathy developed is described. CONCLUSION: Neonatal thyrotoxicosis can give rise to hypertension and may lead to hypertensive encephalopathy.

Predictive value of serum follicle-stimulating hormone levels in the differentiation between hypogonadotropic hypogonadism and constitutional delay of puberty.

OBJECTIVE: Gonadotropin secretion was evaluated to predict hypogonadotropic hypogonadism (HH) in 36 children suspected of having HH. METHODS: LH was measured for 24 h at 10-min intervals, and FSH and estradiol or testosterone at 1-hour intervals. Twenty boys (age 15.7, range 13.2-19.3 years) and 16 girls (age 16.1, range 13.0-20.6 years) were studied. RESULTS: LH pulses were detected in 9 boys and 5 girls. HH was confirmed in all 11 LH apulsatile boys and in 8 of 11 LH apulsatile girls. Random FSH values of < or =1.11 and < or =2.86 IU/l in boys and girls, respectively, discriminated patients with LH pulses from patients without (sensitivity for lack of LH pulses 97 and 100%, respectively). In boys testicular volume was not discriminatory. In 1 girl LH pulses were observed without estradiol production, suggesting LH neurosecretory dysfunction. CONCLUSIONS: Low FSH levels in adolescence are strongly related to a lack of LH pulses. Lack of LH pulses is highly suspect for HH. FSH may be a tool in the differentiation between HH and delayed puberty.

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.

[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.

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.

[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.

[Comparison between complete and incomplete suppression of the hypophyseal-gonadal axis in girls with central precocious puberty: effect on growth and prospective final height]. / Vergleich zwischen kompletter und inkompletter Suppression der Hypophysen-Gonaden-Achse bei Mädchen mit zentraler Pubertas praecox: Einfluss auf Wachstum und prospektive Endlänge. Deutsch-Niederländische Decapeptyl-Depot-Studiengruppe.

BACKGROUND: Whether short-acting or slow-release gonadotropin-releasing hormone agonists have different effects on growth and bone maturation in children with central precocious puberty is still unknown. METHODS: In a meta-analysis, we studied 21 previously untreated girls with central precocious puberty treated with Buserelin and 22 previously untreated girls with central precocious puberty treated with Decapeptyl Depot. Duration of treatment was at least 18 months in both groups. RESULTS: At start of therapy, chronological age, bone age, height velocity and pubertal stage were well comparable between the groups. During the first 6 months of treatment, clinical and biochemical escapes from suppression were more frequent in the Buserelin group; height velocity and bone maturation (delta bone age/delta chronological age) remained significantly higher (p < 0.0001 and p < 0.01, resp.) in Buserelin than in Decapeptyl Depot patients. In contrast to the Decapeptyl Depot group, in the Buserelin patients height standard deviation score for bone age did not change and predicted adult height decreased. From 6 to 18 months of therapy, the development of height velocity, delta bone age/delta chronological age, standard deviation score for bone age and predicted adult height showed an almost parallel course in both groups. Height velocity and bone maturation tended to be faster in the Buserelin group. Mean predicted adult height rose significantly in the Decapeptyl Depot group, but not in the Buserelin-treated girls. CONCLUSIONS: A slow-release gonadotropin-releasing hormone agonist appears to be superior to short-acting drugs not only in terms of long-term tolerance but also for achieving the auxological objectives in central precocious puberty therapy. This is mainly due to their faster and more complete suppression of gonadotropins during the first 6 months of treatment.