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LA Metherell, MO Savage, M Dattani, J Walker, PE Clayton, IS Farooqi, and AJ Clark

OBJECTIVE: Congenital isolated ACTH deficiency (IAD) is a rare inherited disorder that is clinically and genetically heterogeneous. Patients are characterised by low or absent cortisol production secondary to low plasma ACTH despite normal secretion of other pituitary hormones and the absence of structural pituitary defects. Onset may occur in the neonatal period, but may first be observed in later childhood. Recently, mutations in the TPIT gene, a T-box factor selectively expressed in developing corticotroph cells, have been found in cases of early-onset IAD. DESIGN: Here we report the screening of the TPIT gene in seven patients with IAD, four of whom had neonatal onset. METHODS: Genomic DNA was extracted and the sequences of the 8 TPIT exons and their intron/exon junctions were determined by automated sequencing. RESULTS: Two siblings with early-onset IAD were both compound heterozygotes for mutations in exons 2 and 6. The missense mutation (Met86Arg) in exon 2 within the T-box (or DNA binding domain) is predicted to disrupt DNA binding. A frameshift mutation in exon 6 (782delA) introduces a premature stop codon and is likely to lead to a non-functional truncated protein. No nucleotide changes were observed in exonic sequences in the other two early- or the three later-onset cases. Fifteen single nucleotide polymorphisms that were not predicted to change the TPIT transcript were also detected. CONCLUSIONS: These findings provide a further illustration of the genetic heterogeneity of IAD and are highly suggestive of one or more other genes being implicated in this disorder.

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L Kostalova, L Leskova, A Kapellerova, and V Strbak

OBJECTIVE: The aim was to investigate the relationship between body mass index (BMI), plasma leptin, glucose, insulin and C-peptide levels in the offspring of diabetic mothers (DM) and non-diabetic healthy mothers (HM). DESIGN: Seventy-two offspring (37 girls and 35 boys, age 4-20 years) of DM were investigated in a prospective study. Those 14-16 years old (Tanner stage II-IV) were compared with age-matched offspring of HM (33 girls and 33 boys). RESULTS: BMI strongly correlated with plasma leptin concentration in the offspring of both DM and HM children. There were higher BMI and plasma leptin and glucose levels in DM than in HM children. There was no difference in plasma insulin or C-peptide levels between HM and age-matched DM children. There was a highly significant positive correlation between plasma leptin and C-peptide in boys of DM. CONCLUSIONS: The higher plasma leptin found in the offspring of DM reflects their higher BMI. A moderately high but still normal glycemia might be a preclinical sign of insulin resistance or other disturbance of glucoregulation.

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Annette Mouritsen, Lise Aksglaede, Kaspar Soerensen, Casper P Hagen, J H Petersen, Katharina M Main, and Anders Juul

Background

Pubertal onset is usually defined by breast development in girls and testicular growth in boys. Pubarche is defined as the attainment of pubic hair and is considered as a sign of pubertal transition. Pubarche is preceded by a gradual increase in production of adrenal androgens, DHEA and Δ4-androstenedione (Adione), a process termed adrenarche.

Objective

To study the natural course of pubertal transition and the associations with adrenarche, body fat, and linear growth.

Design and methods

A longitudinal study of 179 healthy children (89 girls) with higher socioeconomic background examined every 6 months for 5 years. Pubic hair stage, breast stage, genital stage, testicular volume (TV), height, weight, and four skinfolds were measured.

Results

In girls, median age (25th and 75th percentiles) at thelarche (B2+) was 10.1 years (9.3–10.9). In boys, median age at attaining a TV >3 ml was 11.5 years (10.9–12.0). Median age at pubarche (PH2+) was 10.9 years (10.3–11.4) in girls and 11.6 years (10.8–12.4) in boys. Only 6.8% (4/59) of the girls and 24.6% (15/61) of the boys developed pubic hair as the first isolated sign of puberty. Serum DHEAS and Adione increased with age, although the increase in Adione was most pronounced in girls. No associations between early age at thelarche/testicular growth and increased body fat (BMI and sum of four skinfolds) were observed.

Conclusion

Danish children rarely experience pubarche as the first sign of puberty. No associations between age at pubertal onset and body composition were found. Circulating levels of Adione, but not DHEAS, increased with the onset of puberty, although with large interindividual variability.

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Juho Kärkinen, Päivi J Miettinen, Taneli Raivio, and Matti Hero

Objective:

To describe the etiology of severe short stature in the Helsinki University Hospital district covering a population of 1.2 million that is subject to frequent growth monitoring and screening rules during childhood.

Design:

Retrospective cohort study.

Methods:

We identified all subjects born 1990 or later with a height SD score <−3, after the age of 3 years, from the Helsinki University Hospital district growth database. A total of 785 subjects (376 females and 409 males) fulfilled our inclusion criteria; we reviewed their medical records and growth data and report their underlying diagnoses.

Results:

A pathological cause for short stature was diagnosed in 76% of the girls and 71% of the boys (P = NS). Syndromes were the most numerous pathological cause (n = 160; 20%), followed by organ disorders (n = 127; 16%), growth hormone deficiency (GHD, n = 94; 12%), SGA without catch-up growth (n = 73; 9%), and skeletal dysplasias (n = 57; 7%). Idiopathic short stature (ISS) was diagnosed in 210 (27%) subjects. The probability of growth-related pathology, particularly of a syndrome or skeletal dysplasia, increased with the shorter height SD score and the greater deviation from the target height. Sitting height to height SDS was increased in subjects with ISS, GHD, and SGA (all P < 0.01).

Conclusions:

Height <−3 SDS after 3 years of age usually results from a pathological cause and should be thoroughly investigated in specialized health care. The chance of finding a specific etiology increased with the severity of short stature, and the mismatch with target height.

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Felix G Riepe, Wiebke Ahrens, Nils Krone, Regina Fölster-Holst, Jochen Brasch, Wolfgang G Sippell, Olaf Hiort, and Carl-Joachim Partsch

Objective: To clarify the molecular defect for the clinical finding of congenital hypothyroidism combined with the manifestation of calcinosis cutis in infancy.

Case report: The male patient presented with moderately elevated blood thyrotropin levels at neonatal screening combined with slightly decreased plasma thyroxine and tri-iodothyronine concentrations, necessitating thyroid hormone substitution 2 weeks after birth. At the age of 7 months calcinosis cutis was seen and the patient underwent further investigation. Typical features of Albright’s hereditary osteodystrophy (AHO), including round face, obesity and delayed psychomotor development, were found.

Methods and results: Laboratory investigation revealed a resistance to parathyroid hormone (PTH) with highly elevated PTH levels and a reduction in adenylyl cyclase-stimulating protein (Gsα) activity leading to the diagnosis of pseudohypoparathyroidism type Ia (PHP Ia). A novel heterozygous mutation (c364T > G in exon 5, leading to the amino acid substitution Ile-106 → Ser) was detected in the GNAS gene of the patient. This mutation was not found in the patient’s parents, both of whom showed normal Gsα protein activity in erythrocytes and no features of AHO. A de novo mutation is therefore likely.

Conclusions: Subcutaneous calcifications in infancy should prompt the clinician to a thorough search for an underlying disease. The possibility of AHO and PHP Ia should be considered in children with hypothyroidism and calcinosis cutis. Systematic reviews regarding the frequency of calcinosis in AHO are warranted.

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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.

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Anna G Angelousi, Drosos E Karageorgopoulos, Anastasios M Kapaskelis, and Matthew E Falagas

Abstract

Introduction

The severity of critical illness is associated with various patterns of thyroid hormone abnormalities. We sought to evaluate whether the outcome of patients with, specifically, sepsis or septic shock is associated with the thyroid function tests evaluated at diagnosis or admission in the intensive care unit (ICU).

Methods

We performed a systematic review of relevant studies by searching PubMed.

Results

We included nine studies that all had a prospective cohort design. Seven involved children or neonates, and two involved adults. Mortality was the outcome evaluated in eight studies, while the length of ICU stay was evaluated in the remaining study. In univariate analysis, six of the nine included studies showed that either, free or total, triiodothyronine or thyroxine was lower in the group of patients with sepsis or septic shock who had unfavorable outcome than in those who had favorable outcome. Two other studies showed higher TSH values in the group of patients with unfavorable outcome. No significant relevant findings were observed in the remaining study. Regarding the correlation of sepsis prognostic scoring systems with thyroid function tests, the three studies that provided specific relevant data showed variable findings.

Discussion

Most of the relevant studies identified favor the concept that decreased thyroid function at baseline might be associated with a worse outcome of patients with sepsis or septic shock. Although these findings are not consistent, the role of thyroid function in affecting or merely predicting the outcome of sepsis or septic shock merits further investigation.

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L Lazar, U Pollak, O Kalter-Leibovici, A Pertzelan, and M Phillip

OBJECTIVE: Few data are available on the pubertal development of children born small for gestational age (SGA) who fail to show catch-up growth. DESIGN: A longitudinal analysis compared the pubertal course of persistently short children born SGA compared to children with idiopathic short stature who were appropriate for gestational age (AGA). One hundred and twenty-eight short children (height SDS<-1.7), including 76 (31 boys) born SGA and 52 (22 boys) born AGA, were regularly followed from early childhood to completion of puberty. RESULTS: Puberty was attained at normal age (10.5-14 Years in boys, 9.5-13 Years in girls) for most children in both the SGA and AGA groups (boys, 80% and 77%; girls, 76% and 78% respectively). The duration of puberty was similar in the SGA and AGA groups. Menarche occurred at normal age range but was significantly earlier in the SGA girls (P<0.01 by ANOVA). Despite the similar total pubertal growth, the patterns of growth differed significantly: SGA group - accelerated growth and bone maturation rates from onset of puberty with peak height velocity at Tanner stages 2-3, followed by a decelerated growth rate and earlier fusion of the epiphyses; AGA group - steady progression of bone elongation and maturation throughout puberty (pubertal growth, P<0.05 in both sexes; bone maturation, P<0.001 in both sexes). Final height in the SGA group was compromised compared with their target height (P<0.001). CONCLUSION: Children born SGA have a normal pubertal course with a distinct pubertal growth pattern. This pattern may represent an altered regulation of their growth modalities.

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Y Rakover, A Silbergeld, I Lavi, R Masalha, and IB Shlomo

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.

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Jean-Claude Carel, Joëlle Blumberg, Christine Seymour, Catherine Adamsbaum, and Najiba Lahlou

Group-author : for the Triptorelin 3-month CPP Study Group

Objective: Depot GnRH agonists are commonly used in the treatment of central precocious puberty (CPP). The triptorelin 11.25 mg 3-month depot, currently used in adult indications, had not previously been evaluated in CPP.

Design: This was a multicenter, open-label, 12 month trial conducted in 64 CPP children (54 girls and 10 boys), treated quarterly.

Methods: Children with a clinical onset of pubertal development before the age of 8 years (girls) or 9 years (boys), pubertal response of LH to GnRH ≥7 IU/l, advanced bone age >1 year, enlarged uterus (≥36 mm) and testosterone level ≥0.5 ng/ml (boys), were included. Suppression of gonadotropic activation, as determined from serum LH, FSH, estradiol or testosterone, and pubertal signs were assessed at Months 3, 6 and 12.

Results: GnRH-stimulated peak LH ≤3 IU/l, the main efficacy criterion, was met in 53 out of 62 (85%), 60 out of 62 (97%) and 56 out of 59 (95%) of the children at Months 3, 6 and 12 respectively. Serum FSH and sex steroids were also significantly reduced, while pubertal development regressed in most patients. Mean residual triptorelin levels were stable from Month 3 through to Month 12. The triptorelin 3-month depot was well tolerated. Severe injection pain was experienced in only one instance. Five girls experienced mild-to-moderate or severe (one girl) withdrawal bleeding.

Conclusions: The triptorelin 3-month depot efficiently suppresses the pituitary–gonadal axis and pubertal development in children with CPP. This formulation allows a 3-fold reduction, over the once-a-month depot, in the number of i.m. injections required each year.