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Free access

S A van Gool, G A Kamp, R J Odink, S M P F de Muinck Keizer-Schrama, H A Delemarre-van de Waal, W Oostdijk, and J M Wit

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/m2 per day (equivalent to 75 μg/kg per day at start and 64 μg/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.

Free access

Pauliina Utriainen, Raimo Voutilainen, and Jarmo Jääskeläinen

Objectives

Premature adrenarche (PA), the early rise in adrenal androgen (AA) production, can manifest with different clinical signs of androgen effect. Premature pubarche defined as appearance of pubic hair before the age of 8/9 years in girls/boys, is the most prominent clinical sign of PA and often erroneously described as a synonym of PA. Our aim was to determine the association of circulating AA concentrations with different prepubertal signs of androgen action (SAA). Secondly, we tested whether adrenomedullary function is altered in children with SAA, as it is in congenital adrenal hyperplasia (CAH) also causing adrenal hyperandrogenism.

Design and methods

We examined 73 Finnish prepubertal children with any hyperandrogenic sign(s) having appeared before the age of 8/9 years (girls/boys) (35 with pubic and/or axillary hair=PAH; 38 without=nonPAH), and 98 age- and sex-matched controls. Circulating adrenal steroid and catecholamine concentrations were measured and correlated with clinical parameters.

Results

None of the children with SAA had CAH or virilizing tumor. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione concentrations overlapped between the SAA and control children, and they were lower in the nonPAH than PAH group (P<0.01). SAA children had similar plasma epinephrine but higher norepinephrine (NE) concentrations than their controls (mean (95% confidence interval) 1.61 (1.44, 1.77) versus 1.39 (1.30, 1.49) nmol/l, P=0.03).

Conclusions

PA forms a continuum with more pronounced increase in circulating androgens in children with PAH than in those without. Some children show SAA with fairly low androgen concentrations. The clinical significance of elevated NE concentrations associated with SAA needs to be confirmed in further studies.

Free access

L Even, V Bronstein, and Z Hochberg

The mechanism of growth retardation in Turner's syndrome has not been resolved. It is often referred to as a bone dysplasia, although endocrine derangement has not been ruled out. The present study was undertaken to evaluate the maturation of individual bones of the hand and wrist in girls with Turner's syndrome and thereby obtain information which may aid in elaborating the possible mechanism of the growth retardation in girls with Turner's syndrome. Hand and wrist films of 24 girls with Turner's syndrome, 11 normal girls with short stature and 23 normal controls were evaluated, using the references of Greulich and Pyle. Each bone or epiphysis was given an individual 'age'. During childhood the Turner patients showed the greatest delay in bone age of the phalangeal bones while the least delayed were the radius and ulna (long bones) and metacarpals. The carpal bones showed intermediate retardation. This pattern and extent of maturational retardation was clearly different from that of the short stature normal group, who showed uniform retardation of all bones. During adolescence, the phalangeal bones were further retarded and the carpal bones showed a moderate retardation. The unique profile of bone maturation in Turner's syndrome suggests an insult to chondroplasia, which may be related to estrogen deficiency or to an as yet undetermined endocrine or paracrine derangement.

Free access

Helton Estrela Ramos, Melina Morandini, Aurore Carré, Elodie Tron, Corinne Floch, Laurent Mandelbrot, Nathalie Neri, Benoit De Sarcus, Albane Simon, Jean Paul Bonnefont, Jeanne Amiel, Isabelle Desguerre, Vassili Valayannopoulos, Mireille Castanet, and Michel Polak

Context

Monocarboxylate transporter 8 (MCT8 or SLC16A2) mutations cause X-linked Allan–Herndon–Dudley syndrome. Heterozygous females are usually asymptomatic, but pregnancy may modify thyroid function and MCT8 is expressed in the placenta, suggesting that maternal and fetal abnormalities might develop even in the absence of MCT8 fetal mutation. Genetic counseling is so far based on X-linked transmission, and prenatal diagnosis is rarely performed.

Objective

To describe thyroid function and the prenatal diagnosis in pregnant mothers harboring heterozygous MCT8 mutations and management of the persistent maternal hypothyroxinemia.

Patients

Two women heterozygous for MCT8 mutations (c.1690G>A and c.1393-1G>C) were monitored throughout pregnancy.

Methods

Prenatal diagnosis included sex determination, direct MCT8 sequencing, and familial linkage analysis. Ultrasonography and hormonal assays for maternal thyroid function evaluation were performed serially during pregnancy. Neonatal thyroid hormonal status was assessed.

Results

None of the three fetuses (two males and one female) carried MCT8 mutations. One of the two heterozygous mothers revealed gestational hypothyroxinemia, prompting early levothyroxine (l-T4) therapy until delivery. The second heterozygous mother showed normal thyroid function but was preventively traited by l-T4 and all of the three neonates had normal thyroid hormone levels and thyroid gland at birth, suggesting advantages of prenatal care and/or compensatory mechanisms.

Conclusion

Heterozygous MCT8 women should be monitored for requirement of l-T4 therapy to prevent fetal and neonatal hypothyroidism and to avoid risk of potential cognitive delay due to gestational hypothyroxinemia. Moreover, when the disease-causing mutation is known and/or the first child is affected, prenatal diagnosis for male fetuses should be assessed early for MCT8 mutations by direct sequencing.

Free access

P Dimitri, J T Warner, J A L Minton, A M Patch, S Ellard, A T Hattersley, S Barr, D Hawkes, J K Wales, and J W Gregory

Introduction

Mutations in the GLI-similar 3 (GLIS3) gene encoding the transcription factor GLIS3 are a rare cause of neonatal diabetes and congenital hypothyroidism with six affected cases from three families reported to date. Additional features, described previously, include congenital glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay and facial dysmorphism.

Subjects

We report two new cases from unrelated families with distinct novel homozygous partial GLIS3 deletions. Both patients presented with neonatal diabetes mellitus, severe resistant hypothyroidism in the presence of elevated thyroglobulin and normal thyroid anatomy, degenerative liver disease, cystic renal dysplasia, recurrent infections and facial dysmorphism. These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations. Gene dosage analysis showed that the parents were carriers of a deletion encompassing exons 1–2 (case 1) or exons 1–4 (case 2) of the 11 exon gene. Genome-wide SNP analysis did not reveal a common ancestral GLIS3 haplotype in patient 2.

Conclusions

Our results confirm partial gene deletions as the most common type of GLIS3 mutations, accounting for four of five families identified to date. We propose that mutations in GLIS3 lead to a wider clinical phenotype than previously recognised. We also report the first case of a recessive GLIS3 mutation causing neonatal diabetes and congenital hypothyroidism in a child from a non-consanguineous pedigree, highlighting the importance of molecular genetic testing in any patient with this phenotype.

Restricted access

Aristeidis Giannakopoulos, Alexandra Efthymiadou, and Dionisios Chrysis

Objective

The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because insulin-like growth factor 1 (IGF-I) or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature.

Design

Boys and girls (n = 429, 0.7–16 years) who attended our department for short stature participated in this study. They were followed up for an average period of 9 years. At the end of follow-up after reaching the final height, a definitive diagnosis was assigned, and all the components of ternary complex (IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and IGF-I/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis.

Results

All the components of the ternary complex were tightly correlated with each other and were positively related to age. IGF-I, IGFBP-3, ALS, and IGF-I/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-I and ALS levels were lower in GHD compared to children with familial short stature, while IGF-I and IGF-I/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-I and IGF-I/IGFBP-3 receiver operating curve cutoff points were unable to discriminate between GHD and normal groups or between GHD and CDGP groups.

Conclusion

Despite the tight correlation among all the components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-I, ALS, and IGF-I/IGFBP-3 ratio in the distinction between GHD and CDGP or between GHD and normal groups but without usable discriminating power, making auxology as the primary criterion for establishing the diagnosis.

Free access

Margaret Cristina da Silva Boguszewski and Adriane de Andre Cardoso-Demartini

Approximately 15 million babies are born preterm across the world every year, with less than 37 completed weeks of gestation. Survival rates increased during the last decades with the improvement of neonatal care. With premature birth, babies are deprived of the intense intrauterine growth phase, and postnatal growth failure might occur. Some children born prematurely will remain short at later ages and adult life. The risk of short stature increases if the child is also born small for gestational age. In this review, the effects of being born preterm on childhood growth and adult height and the hormonal abnormalities possibly associated with growth restriction are discussed, followed by a review of current information on growth hormone treatment for those who remain with short stature during infancy and childhood.

Open access

Michel Polak, Jo Blair, Primoz Kotnik, Effie Pournara, Birgitte Tønnes Pedersen, and Tilman R Rohrer

Objective

To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD).

Design

NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting.

Methods

Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8–10; boys, 9–11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS).

Results

Age at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); −1.14 (0.15); late, n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start.

Conclusions

Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.

Free access

Brigitte Odenwald, Uta Nennstiel-Ratzel, Helmuth-Günther Dörr, Heinrich Schmidt, Manfred Wildner, and Walter Bonfig

Objective

To evaluate adrenal crises after the start of treatment up to the age of 6 years in children with classic congenital adrenal hyperplasia (CAH).

Design

Analysis of data extracted from a population-based prospective long-term follow-up study of children detected in neonatal screening.

Methods

Data of 102 Bavarian children with classic CAH due to 21-hydroxylase deficiency were analyzed, using parental questionnaires and medical reports. Parent-reported hospital admissions of children diagnosed with acute health impairment were included in the analysis if salt loss (hyponatremia) or hypoglycemia was documented in the discharge summary.

Results

A total of 74 children (72.5%) had no report of hospital admissions with salt loss or hypoglycemia during the observational period. However, in 27.5% of the children, 22 salt-wasting crises (seven of these also with low blood glucose) and 16 hypoglycemic episodes without salt loss were reported. Furthermore, the cumulative incidence for seizures was elevated; 13 children experienced seizures during hyponatremia or hypoglycemia. Most adrenal crises were triggered by infections, often with inappropriate emergency management, but in 11 cases hypoglycemia occurred unexpectedly, without evidence of severe illness and without any management errors. Frequency of adrenal crises was 6.5 per 100 patient years (95% CI: 4.6–8.8).

Conclusions

Crisis prevention remains a permanent challenge for families and physicians caring for children with classic CAH. Expert care and compliance with emergency recommendations are crucial. Further research on the interactions among glucocorticoid deficiency, adrenomedullary dysfunction, and glucose metabolism is necessary for the prevention of hypoglycemia, especially in young CAH patients.

Free access

S Bargagna, D Dinetti, A Pinchera, M Marcheschi, L Montanelli, S Presciuttini, and L Chiovato

OBJECTIVE: Evaluation of school attainments in children with congenital hypothyroidism (CH) detected by neonatal screening and treated early in life. PATIENTS AND METHODS: Text comprehension, mathematics, reading, writing and verbal and spatial memory, as indices of school learning, were evaluated in nineteen 5- to 10-year-old children with CH attending nursery or elementary school. l-Thyroxine substitution (starting dose 8-10 microg/kg body weight per day) was initiated at a mean age of 30+/-10 days of life. The control group included 298 unaffected children matched with the CH children for age and school grade. Thirty per cent of controls were classmates of CH children. Intelligence quotients (IQ), language performances and motor development were evaluated in CH children at age 5 years, and were related to their school attainments. School performances of CH children were also compared with their neonatal serum thyroxine (T4) concentration, and with the social-cultural level of the family. RESULTS: Four out of 19 (21%) children with CH, 3 in the nursery and 1 in the elementary school, displayed a generalized learning disorder. Symbol copy, geometric copy, phrase repetition, dictation writing and spontaneous writing were particularly defective in nursery school CH children, while orthographic error recognition was defective in elementary school CH children. School learning disorders in CH children were significantly correlated with a borderline-low IQ, poor language performances and a low social-cultural level of the family, but not with motor skills or neonatal T4 concentration. CONCLUSION: School attainments of early treated CH children were within the normal range in most affected cases. However, about 20% of CH children, most of them attending nursery school, showed a generalized learning disorder. Low IQ scores and poor language performances at age 5 years were associated with defective learning, mainly in CH children living in a poor social-cultural environment. In this subset of CH children, prompt initiation of speech and psychomotor rehabilitation therapy is recommended in order to prevent subsequent school learning disorders.