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Free access

Novel GLIS3 mutations demonstrate an extended multisystem phenotype

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.

Free access

Psychological and behavioural aspects in children and adolescents with congenital hypothyroidism diagnosed by neonatal screening: comparison between parents' and children's perceptions

Nicoletta Bisacchi, Milva Orquidea Bal, Laura Nardi, Ilaria Bettocchi, Graziana D'Addabbo, Veronica Conti, Sara Monti, Franco D'Alberton, Alessandro Cicognani, and Alessandra Cassio

Objective

To compare the psychological adjustment and behaviour of congenital hypothyroidism (CH) children and their parents with a control group.

Study design

A cross-sectional study was carried out with 84 CH subjects diagnosed by neonatal screening (range 2.7–18.6 years), subdivided into four age groups: group 1 (2–5 years); group 2 (6–10 years); group 3 (11–13 years); and group 4 (14–18 years) and was compared with an age-matched control group. Patients were assessed using two questionnaires: Child Behaviour Checklist for parents and Youth Self-Report for children over 11 years of age.

Results

In groups 1, 3 and 4, total score (TS), internalising score (IS=problems within the self) and externalising score (ES=conflicts with other people) as reported by parents were not significantly different in CH patients and in controls. In group 2, parents of CH children showed values of TS (P<0.05), IS (P<0.05), ES (P<0.05) and scores on other scales significantly higher than controls. In self-reports of groups 3 and 4, the behavioural scales were not significantly different in CH patients and in controls.

Conclusions

Paediatricians should be informed about the increased risk of the development of behavioural problems at primary school age in CH patients. At this age special attention should be paid to parental worries and anxiety. However, it can be reassuring for the patients and parents to know that the problems may be related to CH, and that they may spontaneously disappear.

Free access

Pregnancy in women heterozygous for MCT8 mutations: risk of maternal hypothyroxinemia and fetal care

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

Association between thyroid function tests at baseline and the outcome of patients with sepsis or septic shock: a systematic review

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.

Free access

The pubertal transition in 179 healthy Danish children: associations between pubarche, adrenarche, gonadarche, and body composition

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.

Free access

Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1

Maik Welzel, Leyla Akin, Anja Büscher, Tülay Güran, Berthold P Hauffa, Wolfgang Högler, Julia Leonards, Beate Karges, Heiner Kentrup, Birgul Kirel, Emine Esin Yalinbas Senses, Neslihan Tekin, Paul-Martin Holterhus, and Felix G Riepe

Background

Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disease caused by mutations in the genes encoding the human mineralocorticoid receptor (MR) or the α (SCNN1A), β (SCNN1B) or γ (SCNN1G) subunit of the epithelial Na+ channel (ENaC). While autosomal dominant mutation of the MR cause renal PHA1, autosomal recessive mutations of the ENaC lead to systemic PHA1. In the latter, affected children suffer from neonatal onset of multi-organ salt loss and often exhibit cystic fibrosis-like pulmonary symptoms.

Objective

We searched for underlying mutations in seven unrelated children with systemic PHA1, all offsprings of healthy consanguineous parents.

Methods and results

Amplification of the SCNN1A gene and sequencing of all 13 coding exons unraveled mutations in all of our patients. We found five novel homozygous mutations (c.587_588insC in two patients, c.1342_1343insTACA, c.742delG, c.189C>A, c.1361-2A>G) and one known mutation (c.1474C>T) leading to truncation of the αENaC protein. All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance. Five out of seven patients exhibited pulmonary symptoms in the neonatal period.

Conclusion

The α subunit is essential for ENaC function and mutations truncating the pore-forming part of the protein leading to systemic PHA1. Based on current knowledge, the pulmonary phenotype cannot be satisfactorily predicted.

Open access

Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations

Huseyin Demirbilek, Ved Bhushan Arya, Mehmet Nuri Ozbek, Jayne A L Houghton, Riza Taner Baran, Melek Akar, Selahattin Tekes, Heybet Tuzun, Deborah J Mackay, Sarah E Flanagan, Andrew T Hattersley, Sian Ellard, and Khalid Hussain

Background

Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes and usually presents in the first 6 months of life. We aimed to describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM patients from a single centre and estimate an annual incidence rate of NDM in South-Eastern Anatolian region of Turkey.

Design and methods

NDM patients presenting to Diyarbakir Children State Hospital between 2010 and 2013, and patients under follow-up with presumed type 1 diabetes mellitus, with onset before 6 months of age were recruited. Molecular genetic analysis was performed.

Results

Twenty-two patients (59% males) were diagnosed with NDM (TNDM-5; PNDM-17). Molecular genetic analysis identified a mutation in 20 (95%) patients who had undergone a mutation analysis. In transient neonatal diabetes (TNDM) patients, the genetic cause included chromosome 6q24 abnormalities (n=3), ABCC8 (n=1) and homozygous INS (n=1). In permanent neonatal diabetes (PNDM) patients, homozygous GCK (n=6), EIF2AK3 (n=3), PTF1A (n=3), and INS (n=1) and heterozygous KCNJ11 (n=2) mutations were identified. Pancreatic exocrine dysfunction was observed in patients with mutations in the distal PTF1A enhancer. Both patients with a KCNJ11 mutation responded to oral sulphonylurea. A variable phenotype was associated with the homozygous c.-331C>A INS mutation, which was identified in both a PNDM and TNDM patient. The annual incidence of PNDM in South-East Anatolian region of Turkey was one in 48 000 live births.

Conclusions

Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The high rate of detection of a mutation likely reflects the contribution of new genetic techniques (targeted next-generation sequencing) and increased consanguinity within our cohort.

Free access

Transient neonatal hyperthyrotropinemia is a risk factor for developing persistent hyperthyrotropinemia in childhood with repercussion on developmental status

Eduardo Cuestas, María Isabel Gaido, and Raúl Horacio Capra

Objective

Transient neonatal hyperthyrotropinemia (TNH) is defined as a neonatal abnormality of thyroid function, which reverts to normal at re-examination after 2 weeks of life. The thyroid function of these infants has not been sufficiently studied in terms of the risk of developing persistent hyperthyrotropinemia (PH) in later childhood and its impact on growth and development.

Design

A prospective cohort study included all babies born in our hospital between 2001 and 2006 and screened for hypothyroidism, whose thyroid function was re-examined 6 years later. Exclusion criteria included the following conditions: preterm birth, birth weight <2500 g, Down's syndrome, descendants of mothers with immune thyroid disease, congenital malformations, cardiac, renal, hepatic, and metabolic diseases, and steroid or dopamine medication. The variables included are TSH and thyroxine at neonatal screening and 6 years later. Main outcomes are the risk of developing PH in childhood, linear growth, and development using Parents' Evaluation of Developmental Status (PEDS).

Results

Out of 5040 normal-term newborns, 301 (6.0%, 95% CI 5.3–6.6%) have TSH ≥10 mU/l (TNH). Six years later, we re-examined 65 randomly selected children with TNH and 185 controls. In the TNH cohort, we found six out of 65 children (9.2%, 95% CI 1.4–17.0%) with PH (TSH ≥6.4 mU/l), and three out of 185 (1.6%, 95% CI 0.3–4.7%) among controls, relative risk 5.7 (95% CI 1.5–22.1), P=0.0114. TSH and developmental delay were found to be significantly higher in the TNH cohort (4.7±1.3 mU/l vs 2.1±0.5 mU/l, P<0.0001 and 15/65 (23%, 95% CI 12–34.1) vs 21/185 (11.3%, 95% CI 6.5–16.2) P=0.0348).

Conclusions

Newborns with TNH have a higher risk of developing PH in childhood, with repercussion on developmental status.

Free access

Ovarian function after allogeneic hematopoietic stem cell transplantation in childhood and adolescence

A Vatanen, M Wilhelmsson, B Borgström, B Gustafsson, M Taskinen, U M Saarinen-Pihkala, J Winiarski, and K Jahnukainen

Objective

The aim of the study was to evaluate long-term ovarian function after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood and adolescence.

Subjects and methods

Predictive factors for ovarian function were evaluated among 92 adult or pubertal female survivors transplanted at Huddinge and Helsinki University Hospital during 1978–2000, at a mean age of 9±4.3 years (range 1–19). At the time of the study a mean±s.d. of 13±5.5 years (range 6–27) had elapsed since the HSCT and the mean age of the participants was 22±6.3 years (range 9–41).

Results

Spontaneous puberty based on breast development occurred in 40 and menarche in 30 of the 70 girls who were prepubertal at transplantation. Six out of 20 girls who received HSCT after initiation of pubertal development recovered their ovarian function. Younger age at HSCT, conditioning without total body irradiation (TBI), and a non-leukemia diagnosis predicted the spontaneous menarche. The incidence of menarche was higher after fractioned vs single fraction TBI (P<0.05), cyclophosphamide (Cy) vs busulfan (Bu)-based conditioning (P<0.05), and among leukemia patients transplanted at first remission vs later remissions (P<0.01) and with no cranial irradiation (cranial radiotherapy, CRT) vs given CRT (14–24 Gy) (P<0.01). The majority of recipients conditioned with only Cy vs TBI (P<0.001) or vs Bu-based regimens (P<0.01) showed preserved ovarian function and required no estrogen replacement at their latest follow-up visit at a mean age of 23±6.3 years (range 15–41). Ten women became pregnant.

Conclusions

Patients conditioned with TBI or Bu-based regimes are at high risk of ovarian failure. Intensive anti-leukemia therapy before HSCT including CRT especially among relapsed patients may further decrease the possibility of spontaneous menarche.

Free access

Decreased prevalence of hypercholesterolaemia and stabilisation of obesity trends in 5-year-old children: possible effects of changed public health policies

Katarina Sedej, Primož Kotnik, Magdalena Avbelj Stefanija, Urh Grošelj, Andreja Širca Čampa, Lara Lusa, Tadej Battelino, and Nataša Bratina

Background

Overweight/obesity in children is a worldwide public health problem. Together with hypercholesterolaemia they are associated with early atherosclerotic complications.

Objectives

In this study, we aimed to investigate the anthropometric characteristics and total cholesterol (TC) levels in a population of 5-year-old children, to determine trends in the prevalence of overweight/obesity and hypercholesterolaemia in 5-year-old children over a period of 8 years (2001–2009) and to assess the impact of modified national nutritional guidelines for kindergartens implemented in 2005.

Design

Cross-sectional studies of overweight/obesity prevalence in the years 2001, 2003–2005 and 2009, and hypercholesterolaemia in years 2001 and 2009, in 5-year-old children.

Subjects

Altogether, 12 832 (6308 girls/6524 boys) children were included.

Methods

Overweight/obesity was defined by IOTF criteria. Hypercholesterolaemia was defined by TC level >5 mmol/l. Multivariable logistic regression models were used.

Results

No correlation between BMI values and TC levels was found. Overweight and obesity prevalence were stabilised from 2001 to 2009 (odds ratio (OR) (95% CI): 1.13 (0.99–1.3) and 1.13 (0.89–1.42) respectively). Girls were more frequently overweight/obese than boys (OR (95% CI): 0.71 (0.65–0.79) and 0.75 (0.64–0.89) respectively). Prevalence of hypercholesterolaemia significantly decreased from 2001 to 2009 (OR (95% CI): 0.47 (0.41–0.55)). It was less frequent in boys than in girls (OR (95% CI): O.7 (0.61–0.8)).

Conclusions

This is the first study to describe a negative trend in the prevalence of hypercholesterolaemia in pre-pubertal children. In addition, the prevalence of overweight/obesity in these children has been stabilised. Nationwide changes in public health policies could have influenced these observations.