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Free access

Huseyin Demirbilek, Ved Bhushan Arya, Mehmet Nuri Ozbek, Aysehan Akinci, Murat Dogan, Fatma Demirel, Jayne Houghton, Sultan Kaba, Fatma Guzel, Riza Taner Baran, Sevim Unal, Selahattin Tekkes, Sarah E Flanagan, Sian Ellard, and Khalid Hussain

Objective

Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype–phenotype correlations and describe the treatment outcome of Turkish CHI patients.

Design and methods

A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected.

Results

Diazoxide unresponsiveness was observed in nearly half of the patients (n=17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype–phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P<0.0001).

Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydrate-rich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients.

Conclusions

This is the largest study to report genotype–phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.

Free access

Romina P Grinspon, Carolina Habib, Patricia Bedecarrás, Silvia Gottlieb, and Rodolfo A Rey

Objective

Compensatory hypertrophy has been classically described in patients with monorchidism. However, it remains unclear whether there is a functional compensatory activity of the different cell populations. Our aim was to assess the functional capacity of the solitary testis in monorchid males from infancy through puberty in order to determine whether the remaining gonad is capable of compensating the functional activity of Sertoli and Leydig cells of the absent gonad.

Design

In a retrospective, cross-sectional, analytical study performed at a tertiary paediatric public hospital, we included 89 boys with monorchidism and 358 healthy controls, aged 6 months–18 years. Testicular volume and circulating levels of reproductive hormones were compared between patients with monorchidism and normal boys. Serum anti-Müllerian hormone (AMH) and FSH were used as biomarkers of the functional mass of prepubertal Sertoli cells, whereas serum testosterone and LH were used as biomarkers of Leydig cells.

Results

In the vast majority of the cases, the testicular volume of monorchid boys was smaller than the sum of the volume of both testes of healthy controls. Serum AMH was lower and FSH was higher in patients with monorchidism than in controls aged <3 and >13 years. Serum testosterone and LH did not differ significantly between patients and controls.

Conclusion

In boys and adolescents with monorchidism, there is a dissociated capacity of the remaining testis to compensate for the absence of the other gonad: while Leydig cell function is largely compensated, Sertoli cell proliferation and function was lower than in controls.

Restricted access

H. Gerdes and W. Teller

ABSTRACT

The results are reported of routine determinations of free C21-steroids in plasma and urine by a method which involved thin layer and gas liquid chromatography. The following steroids were simultaneously determined: Cortisol, cortisone, 6β-hydroxycortisol and -cortisone, 20-hydroxycortisol and -cortisone, tetrahydrocortisol and -cortisone, and 11-deoxycortisol (Reichstein S). The specificity, reproducibility and accuracy are discussed in detail. The overall recoveries of the procedure were examined by the addition of 1,2-3H-cortisol and 1,2-3H-cortisone prior to extraction. They ranged between 50 and 60 per cent.

The method was clinically applied to various tests of adrenal cortical function and its pituitary regulation (e. g. ACTH test, dexamethasone suppression, metopirone test). The simultaneous determination in plasma and urine of a number of C21-steroid-hormones including their metabolites proved to yield valuable information about adrenal cortical function and C21-steroid metabolism. In the paediatric age group the metopirone test measuring 11-deoxycortisol in plasma rather than its tetrahydro derivative in urine was particularly useful since it avoided unpleasant 24 h-urine collections in young children.

Free access

Leo Dunkel

The Food and Drug Administration (FDA) approved the use of biosynthetic GH for the treatment of children with idiopathic short stature (ISS) in the US in 2003. Primarily, the decision was based on two studies: a randomized placebo-controlled study and a dose–response study, both demonstrating an increase in adult height over the predicted height at baseline and over placebo-treated controls by an average of 4–7 cm. Despite these data and FDA approval of GH treatment for ISS, there is still a significant controversy among paediatric endocrinologists about how, and to what extent, GH should be used in this indication. GH is clearly efficacious in several growth disorders and has the potential to alleviate debilitating short stature. However, it has been questioned whether ISS should be considered a condition warranting pharmacological treatment, whether the degree of morbidity of untreated ISS is clinically significant, and whether improved psychosocial status or well-being is achieved through GH treatment and height gain. The benefits must outweigh treatment costs and risks to justify GH treatment in ISS. The safety of GH treatment in ISS has been the main subject in two recent articles from pharmaceutical companies that conducted the pioneering studies mentioned earlier. No new safety concerns were observed in the ISS populations, but there were some limitations in study designs that prevent clinicians, their patients and families from ‘resting assured’. Studies addressing these controversial issues are needed before the widespread use of GH treatment in ISS is warranted.

Open access

Tansit Saengkaew, Heena R Patel, Kausik Banerjee, Gary Butler, Mehul T Dattani, Michael McGuigan, Helen L Storr, Ruben H Willemsen, Leo Dunkel, and Sasha R Howard

Context

Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents.

Objective

To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients.

Design

Retrospective study.

Methods

Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed.

Results

Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP.

Conclusion

This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.

Restricted access

Idoia Martínez de LaPiscina, Nancy Portillo Najera, Itxaso Rica, Sonia Gaztambide, Susan M Webb, Alicia Santos, Maria Dolores Moure, Miguel Paja Fano, Maria Isabel Hernandez, Maria Jesús Chueca-Guindelain, Laura Cristina Hernández-Ramírez, Alfonso Soto, Nuria Valdés, and Luis Castaño

Objective

Pituitary adenomas (PA) are rare in young patients, and additional studies are needed to fully understand their pathogenesis in this population. We describe the clinical and genetic characteristics of apparently sporadic PA in a cohort of young patients.

Design

Clinical and molecular analysis of 235 patients (age ≤ 30 years) with PA. Clinicians from several Spanish and Chilean hospitals provided data.

Methods

Genetic screening was performed via next-generation sequencing and comparative genomic hybridization array. Clinical variables were compared among paediatric, adolescent (<19 years) and young adults’ (≥19–30 years) cohorts and types of adenomas. Phenotype–genotype associations were examined.

Results

Among the total cohort, mean age was 17.3 years. Local mass effect symptoms were present in 22.0%, and prolactinomas were the most frequent (44.7%). Disease-causing germline variants were identified in 22 individuals (9.3%), more exactly in 13.1 and 4.7% of the populations aged between 0–19 and 19–30 years, respectively; genetically positive patients were younger at diagnosis and had larger tumour size. Healthy family carriers were also identified.

Conclusions

Variants in genes associated with syndromic forms of PAs were detected in a large cohort of apparently sporadic pituitary tumours. We have identified novel variants in well-known genes and set the possibility of incomplete disease penetrance in carriers of MEN1 alterations or a limited clinical expression of the syndrome. Despite the low penetrance observed, screening of AIP and MEN1 variants in young patients and relatives is of clinical value.

Free access

GE Krassas and Z Laron

Graves' disease (GD) is the most common cause of juvenile thyrotoxicosis in children and adolescents (1, 2). Three treatment modalities are now available for the treatment of Graves' thyrotoxicosis in childhood: antithyroid drugs (ATD), surgery and radioactive iodine (RAI). However, none of these treatments has been shown to be ideal or clearly superior to the others. Physicians in different countries have different approaches concerning the optimal treatment of juvenile GD.In a European questionnaire study (3), which was conducted by the European Thyroid Association in 1993 and in which 99 individuals or groups from 22 countries participated, it was found that 22 out of 99 physicians from nine countries would consider RAI treatment as the treatment of choice for children with recurrent thyrotoxicosis after surgery, or with recurrent thyrotoxicosis 2 years after ATD. However, RAI is preferred by only a small percentage of physicians for this group of patients in Europe. Hardly any of the respondents chose RAI for the patients with a toxic adenoma or a multinodular toxic goiter (3). On the other hand, in view of the difficulties with medical therapy in children and adolescents, including poor compliance, a high rate of relapse, drug toxicity and continued thyroid enlargement, some eminent American physicians emphasize the safety, simplicity and economic advantages of (131)I ablation which should be considered more commonly in children (4, 5).We had the opportunity to conduct a similar study during a pediatric thyroidology symposium, which was organized by Professors Buyugkebiz and Laron in Izmir (Smyrna) Turkey from 30 October to 1 November 2003. During the congress a questionnaire with the following four questions was circulated among the 120 participants from eight countries who were mainly paediatric endocrinologists. Most of them were from Turkey and the rest, except for one who came from the USA, were Europeans. Sixty-one out of the 120 physicians responded.

Free access

HL Fideleff, HR Boquete, MG Suarez, GF Ruibal, PG Sobrado, M Azaretsky, AB Pujol, AM Sequera, J Giuseppucci, and R Ponzio

OBJECTIVE: To study hormonal and histological parameters of paediatric-adolescent varicocele in order to know certain aspects of its natural history, in an attempt to find prognostic markers of testicular damage. DESIGN AND METHODS: In a prospective cross-sectional study, we evaluated 93 children and adolescents with left unilateral varicocele and 29 healthy males as control group. All of them were classified according to Tanner stage. Scrotal Doppler in both testes and GnRH and human chorionic gonadotrophin (hCG) tests were performed in all subjects. Surgery was performed in 28 patients and homolateral testicular biopsy in 18. RESULTS: Hormonal measurements of patients with varicocele were compared with a control group for each Tanner stage. Testicular biopsy specimens were analysed by light and electron microscopy. We only observed statistical differences in Tanner III patients in basal FSH (median and range) controls=1.70 (1.10-3.70) IU/l vs varicocele=4.20 (1.00-7.50) IU/l, P<0.05 and in Tanner IV patients in LH post-GnRH: controls=11.0 (7.50-15.0) IU/l vs varicocele=18.0 (5.10-29.0) IU/l, P<0.05 and in testosterone post-hCG: controls=9.50 (7.7-10.0) ng/ml vs varicocele=12.0 (6.2-23.0) ng/ml, P<0.01. No correlation was found between the various clinical grades of varicocele and hormonal measurements for each Tanner stage. No statistically significant differences were found between pre- and post-operative hormonal findings, either in basal levels or in maximal responses. On the other hand, no morphological abnormalities were observed by electron microscopy in germ cells, tubular wall and interstice. CONCLUSIONS: There appears to be no reliable biochemical marker in children and adolescents that may predict impaired testicular function. A significant size discrepancy between both testes, testicular pain and a hyperresponse to GnRH stimulation should continue to be, for the time being, the indications for surgery.

Free access

Eva Al Taji, Heike Biebermann, Zdeňka Límanová, Olga Hníková, Jaroslav Zikmund, Christof Dame, Annette Grüters, Jan Lebl, and Heiko Krude

Objective: Mutations in NKX2.1, NKX2.5, FOXE1 and PAX8 genes, encoding for transcription factors involved in the development of the thyroid gland, have been identified in a minority of patients with syndromic and non-syndromic congenital hypothyroidism (CH).

Design: In a phenotype-selected cohort of 170 Czech paediatric and adolescent patients with non-goitre CH, including thyroid dysgenesis, or non-goitre early-onset hypothyroidism, PAX8, NKX2.1, NKX2.5, FOXE1 and HHEX genes were analysed for mutations.

Methods: NKX2.1, NKX2.5, FOXE1 and HHEX genes were directly sequenced in patients with syndromic CH. PAX8 mutational screening was performed in all 170 patients by single-stranded conformation polymorphism, followed by direct sequencing of samples with abnormal findings. The R52P PAX8 mutation was functionally characterized by DNA binding studies.

Results: We identified a novel PAX8 mutation R52P, dominantly inherited in a three-generation pedigree and leading to non-congenital, early-onset, non-goitre, non-autoimmune hypothyroidism with gradual postnatal regression of the thyroid size and function. The R52P PAX8 mutation results in the substitution of a highly conserved residue of the DNA-binding domain with a loss-of-function effect. Conclusions: The very low frequency of genetic defects in a population-based cohort of children affected by non-goitre congenital and early-onset hypothyroidism, even in a phenotype-focussed screening study, suggests the pathogenetic role of either non-classic genetic mechanisms or the involvement of genes unknown so far. Identification of a novel PAX8 mutation in a particular variant of non-congenital early-onset hypothyroidism indicates a key function of PAX8 in the postnatal growth and functional maintenance of the thyroid gland.

Free access

Yasmine El Allali, Coralie Hermetet, Justine Bacchetta, Cyril Amouroux, Anya Rothenbuhler, Valérie Porquet-Bordes, Marie-Alexandrine Champigny, Sabine Baron, Pascal Barat, Hélène Bony-Trifunovic, Karine Bourdet, Kanetee Busiah, Maryse Cartigny-Maciejewski, Florence Compain, Régis Coutant, Jessica Amsellem-Jager, Marc De Kerdanet, Nathalie Magontier, Brigitte Mignot, Odile Richard, Sylvie Rossignol, Sylvie Soskin, Aurélie Berot, Catherine Naud-Saudreau, Jean-Pierre Salles, Agnès Linglart, Thomas Edouard, and Anne Lienhardt-Roussie

Aim

To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.

Methods

Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.

Results

Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, ‘CaSR group’; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, ‘cell proliferation group’; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in ‘cell proliferation group’ patients compared to those in the ‘CaSR group’ (P = 0.001 and 0.028, respectively).

Conclusion

Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.