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Free access

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

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.

Free access

Ponce Cedric Fouejeu Wamba, Jie Mi, Xiao-Yuan Zhao, Mei-Xian Zhang, Yu Wen, Hong Cheng, Dong-Qing Hou, and Katherine Cianflone

Objective

Childhood obesity is increasing worldwide and is increasingly associated with metabolic syndrome (MetS). Our aim was to examine acylation stimulating protein (ASP) and its precursor complement C3, in normal, overweight, and obese Chinese children and adolescents, and the relationships with body size, blood parameters, pubertal development, family environment, and MetS.

Methods

Children and adolescents (n=1603) from 6 to 18 years, boys (n=873) and girls (n=730), including normal weight (n=603), overweight (n=291) and obese (n=709) were assessed for body size parameters, pubertal development, blood lipids, glucose, insulin, ASP, and C3.

Results

ASP levels were increased in overweight and obese versus normal weight (P<0.001), while C3 showed little variation. This effect of overweight/obesity remained throughout early stages when boys and girls were separated by pubertal development or age, although age and pubertal status itself had no effect. Separation based on ASP quintiles demonstrated significant associations with blood cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-Chol), glucose, insulin, and homeostatic model assessment of insulin resistance in boys, and LDL-Chol, high-density lipoprotein cholesterol, and glucose in girls. A positive correlation with mother's body mass index in boys and girls (P=0.002 and P=0.014 respectively) as well as birth weight (P<0.001) was noted. MetS was strongly associated with increased ASP, the presence of a single MetS factor (especially hypertension, central obesity, or hyperglycemia) was associated with increased ASP.

Conclusion

Changes in the plasma adipokine ASP in early obesity are associated with blood lipid and glucose modifications, family environment, and distinct MetS risk factors.

Free access

Myriam Rosilio, Jean-Claude Carel, Emmanuel Ecosse, and Jean-Louis Chaussainon

Group-author : on behalf of the 0908 Lilly Study Group

Objective: Human GH (hGH) treatment leads to catch-up growth in children with short stature born small for gestational age (SGA). However, long-term efficacy and safety results in this patient group remain scarce. The present study assessed the efficacy and safety of late childhood treatment with biosynthetic hGH (Humatrope) in a group of short children born SGA (height <−2 standard deviation scores (SDS)).

Design: Patients in this open-label, Phase III, multicenter study received a daily hGH dose of 0.067 mg/kg for 2 years, and then received no treatment for the following 2 years. After the fourth year on study, patients whose height had decreased more than 0.5 SDS but who still showed growth potential based on bone age were allowed to resume treatment until they reached adult height.

Methods: Height gain SDS was assessed for 11 girls and 24 boys (mean age±s.d. 9.6±0.9 years) at the end of the 2 years of hGH treatment, during the subsequent 2-year off-treatment period, and upon reaching adult height.

Results: At the end of the initial 2-year treatment period, 83% of patients had reached a height within the normal range, with a mean increase in height SDS vs baseline of 1.3±0.3 (P <0.001). Adult heights (n = 20) were within the normal range for 50% of patients, and mean height gain from baseline was statistically significant (0.7±0.8 SDS, P <0.001). Fasting glucose and glycosylated hemoglobin levels were not significantly modified during treatment.

Conclusions: High-dose hGH treatment for a minimum of 2 years in short children born SGA was well tolerated and resulted in a significant increase in adolescent and adult height.

Free access

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.

Free access

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

Werner F Blum, Cheri Deal, Alan G Zimmermann, Elena P Shavrikova, Christopher J Child, Charmian A Quigley, Stenvert L S Drop, Gordon B Cutler Jr, and Ron G Rosenfeld

Objective

We assessed the characteristics of children initially diagnosed with idiopathic isolated GH deficiency (IGHD) who later developed additional (multiple) pituitary hormone deficiencies (MPHD).

Design

Data were analyzed for 5805 pediatric patients with idiopathic IGHD, who were GH-naïve at baseline and GH-treated in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study.

Methods

Development of MPHD was assessed from investigator diagnoses, adverse events, and concomitant medications. Analyses were performed for all patients and for those who developed MPHD within 4.5 years or had ≥3.5 years, follow-up and continued to have IGHD (4-year cohort).

Results

MPHD developed in 118/5805 (2.0%) children overall, and in 96/1757 (5.5%) in the 4-year cohort. Patients who developed MPHD had more profound GHD, with decreased height SDS, IGF1 SDS and peak stimulated GH, and greater height decrement vs target, compared with children who continued to have IGHD (P<0.001 for each variable). Delivery complications, congenital anomalies, and perinatal/neonatal adverse events occurred more frequently in patients who developed MPHD. The most frequent additional deficiency was TSH (82 patients overall); four patients developed two pituitary hormone deficiencies and one developed three deficiencies. Multivariable logistic regression indicated that years of follow-up (odds ratio 1.55), baseline age (1.17), baseline height SDS (0.69), and peak stimulated GH (0.64) were associated with the development of MPHD.

Conclusions

MPHD is more likely to develop in patients with more severe idiopathic IGHD. Older baseline age, lower baseline height SDS, and longer follow-up duration are associated with increased risk of development of MPHD.

Free access

T Meissner, U Wendel, P Burgard, S Schaetzle, and E Mayatepek

BACKGROUND: The term congenital hyperinsulinism (CHI) comprises a group of different genetic disorders with the common finding of recurrent episodes of hyperinsulinemic hypoglycemia. OBJECTIVE: To evaluate the clinical presentation, diagnostic criteria, treatment and long-term follow-up in a large cohort of CHI patients. PATIENTS: The data from 114 patients from different hospitals were obtained by a detailed questionnaire. Patients presented neonatally (65%), during infancy (28%) or during childhood (7%). RESULTS: In 20 of 74 (27%) patients with neonatal onset birth weight was greatly increased (group with standard deviation scores (SDS) >2.0) with a mean SDS of 3.2. Twenty-nine percent of neonatal-onset vs 69% of infancy/childhood-onset patients responded to diazoxide and diet or to a carbohydrate-enriched diet alone. Therefore, we observed a high rate of pancreatic surgery performed in the neonatal-onset group (70%) compared with the infancy/childhood-onset group (28%). Partial (3%), subtotal (37%) or near total (15%) pancreatectomy was performed. After pancreatic surgery there appeared a high risk of persistent hypoglycemia (40%). Immediately post-surgery or with a latency of several Years insulin-dependent diabetes mellitus was observed in operated patients (27%). General outcome was poor with a high degree of psychomotor or mental retardation (44%) or epilepsy (25%). An unfavorable outcome correlated with infancy-onset manifestation (chi(2)=6.1, P=0.01). CONCLUSIONS: The high degree of developmental delay, in particular in infancy-onset patients emphasizes the need for a change in treatment strategies to improve the unfavorable outcome. Evaluation of treatment alternatives should take the high risk of developing diabetes mellitus into account.

Open access

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

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.