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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.

Open access

Prenatal exposure to glucocorticoids and the prevalence of overweight or obesity in childhood

Kristina Laugesen, Henrik Toft Sørensen, Jens Otto L Jorgensen, and Irene Petersen

Objective

Prenatal exposure to excess cortisol can affect postnatal metabolic health by epigenetic mechanisms. We aimed to investigate if prenatal exposure to pharmacological glucocorticoids increases the risk of overweight/obesity in childhood.

Design

A nationwide population registry-based cohort study.

Methods

We identified 383 877 children born in Denmark (2007–2012), who underwent routine anthropometric evaluation at 5–8 years of age. Prenatal exposure to glucocorticoids was divided into systemic and topical glucocorticoids, cumulative systemic dose, and use by trimester. The comparison cohort included children without exposure, born to maternal never-users. Negative control exposures were used to investigate confounding from an underlying disease or unmeasured characteristics. Such exposures included children without glucocorticoid exposure born to maternal users of non-steroidal anti-inflammatory drugs or immunotherapy during pregnancy, maternal former users of glucocorticoids, or paternal users of glucocorticoids during the pregnancy of their partner. We estimated sex-stratified adjusted prevalence ratios (aPR) of overweight/obesity at 5–8 years of age, as epigenetic modifications have shown to be sex-specific.

Results

In the study, 21 246 (11%) boys and 27 851 (15%) girls were overweight/obese at 5–8 years of age. Overall, neither systemic nor topical glucocorticoids were associated with overweight/obesity. In boys, high-dose systemic glucocorticoids was associated with higher prevalence of overweight/obesity vs the comparison cohort (aPR: 1.41 (95% CI: 1.07–1.86), prevalence: 16% vs 11%). Negative control exposures indicated robustness to confounding.

Conclusion

Overweight/obesity might be an adverse effect of prenatal exposure to high-dose systemic glucocorticoids in boys. We found no association for neither prenatal exposure to lower doses of systemic nor topical glucocorticoids. These results merit clinical attention.

Open access

Pubertal timing in boys and girls born to mothers with gestational diabetes mellitus: a systematic review

Anuradhaa Subramanian, Jan Idkowiak, Konstantinos A Toulis, Shakila Thangaratinam, Wiebke Arlt, and Krishnarajah Nirantharakumar

Context

The incidence of gestational diabetes mellitus (GDM) has been on the rise, driven by maternal obesity. In parallel, pubertal tempo has increased in the general population, driven by childhood obesity.

Objective

To evaluate the available evidence on pubertal timing of boys and girls born to mothers with GDM.

Data sources

We searched MEDLINE, EMBASE, CINAHL Plus, Cochrane library and grey literature for observational studies up to October 2019.

Study selection and extraction

Two reviewers independently selected studies, collected data and appraised the studies for risk of bias. Results were tabulated and narratively described as reported in the primary studies.

Results

Seven articles (six for girls and four for boys) were included. Study quality score was mostly moderate (ranging from 4 to 10 out of 11). In girls born to mothers with GDM, estimates suggest earlier timing of pubarche, thelarche and menarche although for each of these outcomes only one study each showed a statistically significant association. In boys, there was some association between maternal GDM and earlier pubarche, but inconsistency in the direction of shift of age at onset of genital and testicular development and first ejaculation. Only a single study analysed growth patterns in children of mothers with GDM, describing a 3-month advancement in the age of attainment of peak height velocity and a slight increase in pubertal tempo.

Conclusions

Pubertal timing may be influenced by the presence of maternal GDM, though current evidence is sparse and of limited quality. Prospective cohort studies should be conducted, ideally coupled with objective biochemical tests.

Open access

Early growth hormone treatment start in childhood growth hormone deficiency improves near adult height: analysis from NordiNet® International Outcome Study

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.

Open access

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline

A Nordenström, S F Ahmed, E van den Akker, J Blair, M Bonomi, C Brachet, L H A Broersen, H L Claahsen-van der Grinten, A B Dessens, A Gawlik, C H Gravholt, A Juul, C Krausz, T Raivio, A Smyth, P Touraine, D Vitali, and O M Dekkers

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.

Open access

MECHANISMS IN ENDOCRINOLOGY: The pathophysiology of transient congenital hypothyroidism

Catherine Peters and Nadia Schoenmakers

Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following the withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in the incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, for example, iodine deficiency and excess, anti- TSHR antibodies and exposure to antithyroid or iodine-rich medications, may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.

Open access

Real-life GH dosing patterns in children with GHD, TS or born SGA: a report from the NordiNet® International Outcome Study

Oliver Blankenstein, Marta Snajderova, Jo Blair, Effie Pournara, Birgitte Tønnes Pedersen, and Isabelle Oliver Petit

Objective

To describe real-life dosing patterns in children with growth hormone deficiency (GHD), born small for gestational age (SGA) or with Turner syndrome (TS) receiving growth hormone (GH) and enrolled in the NordiNet International Outcome Study (IOS; Nbib960128) between 2006 and 2016.

Design

This non-interventional, multicentre study included paediatric patients diagnosed with GHD (isolated (IGHD) or multiple pituitary hormone deficiency (MPHD)), born SGA or with TS and treated according to everyday clinical practice from the Czech Republic (IGHD/MPHD/SGA/TS: n = 425/61/316/119), France (n = 1404/188/970/206), Germany (n = 2603/351/1387/411) and the UK (n = 259/60/87/35).

Methods

GH dosing was compared descriptively across countries and indications. Proportions of patients by GH dose group (low/medium/high) or GH dose change (decrease/increase/no change) during years 1 and 2 were also evaluated across countries and indications.

Results

In the Czech Republic, GH dosing was generally within recommended levels. In France, average GH doses were higher for patients with IGHD, MPHD and SGA than in other countries. GH doses in TS tended to be at the lower end of the recommended label range, especially in Germany and the UK; the majority of patients were in the low-dose group. A significant inverse association between baseline height standard deviation score and GH dose was shown (P < 0.05); shorter patients received higher doses. Changes in GH dose, particularly increases, were more common in the second (40%) than in the first year (25%).

Conclusions

GH dosing varies considerably across countries and indications. In particular, almost half of girls with TS received GH doses below practice guidelines and label recommendations.

Open access

An optimal growth pattern during pregnancy and early childhood associates with better fertility in men

Johanna Laru, Marja Ojaniemi, Stephen Franks, Marjo-Riitta Järvelin, Elisa Korhonen, Terhi T Piltonen, Sylvain Sebert, Juha S Tapanainen, and Laure Morin-Papunen

Objective

This study aimed to evaluate the association between birth weight (BW), childhood and adolescent BMI, with reproductive capacity in men.

Design

A prospective, population-based cohort study (Northern Finland birth cohort 1966).

Methods

Around 6196 men born in 1966 were followed from birth to age 50 years. Weight and height were measured repeatedly by professionals. Reproductive capacity (infertility assessment, male factor infertility and infertility treatment by age 46 years) was evaluated by questionnaires at ages 31 and 46 years. The number of children by the age of 50 years was recovered from registers. After excluding the men who reported never having attempted to have children or not answering the question at age 31 or 46 years (n = 2041), 4128 men were included in the final study population. Results were adjusted for BW, BW for gestational age (GA), mother’s smoking status, marital status, educational level and smoking status.

Results

Being small for GA (10.5% vs 8.2%, P = 0.012) or having a lower BW (3495 g vs 3548 g, P = 0.003) were associated with childlessness. The association was however no longer significant after adjusting for marital status. Being underweight in early childhood was associated with an increased risk of infertility assessment (adjusted, aOR: 2.04(1.07–3.81)) and childlessness (aOR: 1.47(1.01–2.17)) compared to the normal weight group. Conversely, overweight or obesity in early childhood was associated with a decreased risk of infertility assessment (aOR: 0.60 (0.41–0.87)), treatment (aOR: 0.42 (0.25–0.70)) and male factor infertility (aOR: 0.45 (0.21–0.97)). BMI in mid-childhood or puberty had no association with infertility or childlessness.

Conclusion

In boys, an optimal growth trajectory during pregnancy and early childhood seems to be very important for life-long fertility.

Open access
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Gender, smoking during pregnancy and gestational age influence cord leptin concentrations in newborn infants

Simon Kayemba-Kay's, Michael P P Geary, Jane Pringle, Charles H Rodeck, John C P Kingdom, and Peter C Hindmarsh

Background

Low birth weight (BW), small head circumference, reduced length, increased preterm births and neuro-endocrine dysfunctions are among known consequences of smoking during pregnancy. Few studies have linked leptin to clinical features of growth restriction associated with maternal smoking and explored interaction with other determinants of size at birth, such as gender.

Methods

Cord serum leptin concentrations were measured in 1215 term infants born to Caucasian mothers at completion of uneventful pregnancy. Serum concentrations were related to BW, gestational length, gender and maternal smoking and interaction with other determinants of size at birth evaluated.

Results

Smoking was more frequent in younger (P<0.001) and shorter mothers (P=0.03) from lower socio-economic groups (SEGPs) (P<0.001). Infants born to smokers were lighter (190 g less), shorter and with smaller head circumference. Cord serum leptin concentrations were higher in girls (9.8 s.d. 7.6 ng/ml) than in boys (7.05 s.d. 5.8 ng/ml) (P<0.001). Boys were heavier (BW 3.52 s.d. 0.49 kg) than girls (3.39 s.d. 0.44 kg) (P<0.001), but girls had greater skinfold thickness measurements (sub-scapular and quadriceps skinfold thicknesses 5.5 s.d. 1.6 mm and 7.6 s.d. 1.9 mm respectively; boys 5.3 s.d. 1.6 vs 7.24±1.90 mm, P<0.001 respectively). Multivariate analyses showed gender (P<0.001), BW SDS (P<0.001), gestational length (P<0.001) and maternal smoking (P<0.042) as factors that influenced umbilical cord serum leptin concentrations in newborns.

Conclusion

Maternal smoking restrains foetal growth through placental vascular effects, and likely also via associated effects on leptin metabolism. More studies are needed to determine the influence that maternal smoking may have on placental syncytiotrophoblast and foetal adipose tissue.

Open access

Broad-spectrum XX and XY gonadal dysgenesis in patients with a homozygous L193S variant in PPP2R3C

Dilek Cicek, Nick Warr, Gozde Yesil, Hatice Kocak Eker, Firdevs Bas, Sukran Poyrazoglu, Feyza Darendeliler, Gul Direk, Nihal Hatipoglu, Mehmet Eltan, Zehra Yavas Abali, Busra Gurpinar Tosun, Sare Betul Kaygusuz, Tuba Seven Menevse, Didem Helvacioglu, Serap Turan, Abdullah Bereket, Richard Reeves, Michelle Simon, Matthew Mackenzie, Lydia Teboul, Andy Greenfield, and Tulay Guran

Context

Homozygous and heterozygous variants in PPP2R3C are associated with syndromic 46,XY complete gonadal dysgenesis (Myo-Ectodermo-Gonadal Dysgenesis (MEGD) syndrome), and impaired spermatogenesis, respectively. This study expands the role of PPP2R3C in the aetiology of gonadal dysgenesis (GD).

Method

We sequenced the PPP2R3C gene in four new patients from three unrelated families. The clinical, laboratory, and molecular characteristics were investigated. We have also determined the requirement for Ppp2r3c in mice (C57BL6/N) using CRISPR/Cas9 genome editing.

Results

A homozygous c.578T>C (p.L193S) PPP2R3C variant was identified in one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. The patients with complete GD had low gonadal and adrenal androgens, low anti-Müllerian hormone, and high follicle-stimulating hormone and luteinizing hormone concentrations. All patients manifested characteristic features of MEGD syndrome. Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos at 14.5, 9.5, and 8.5 days post coitum(dpc) revealed evidence of dead embryos. We conclude that loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier.

Conclusion

Our data indicate the essential roles for PPP2R3C in mouse and human development. Germline homozygous variants in human PPP2R3C are associated with distinctive syndromic GD of varying severity in both 46,XY and 46,XX individuals.