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Pancreas agenesis is a rare condition underlying a variant of permanent neonatal diabetes mellitus. Neonates with this condition are born small for gestational age, but less is known about which components of growth are impacted, the timing of the growth restriction and potential sex differences. Our objective was to assess in which periods in gestation complete pancreas agenesis restricts fetal growth and possible sex differences in susceptibility. Published cases (n = 49) with pancreas agenesis providing relevant data (gestational age, fetal sex, birth weight, birth length, head circumference, placental weight) were identified by MEDLINE and secondary literature search covering the years 1950–January 2023. Semiquantitative analysis of these case reports used centiles based on Intergrowth-21 reference charts. Neonates with pancreas agenesis were severely growth restricted; however, median centiles for birth weight, birth length, and head circumference of those born before week 36 were significantly higher compared to those born from 36 weeks. Similar results were found when data were separated by before and from 38 weeks. Head circumference was less affected than birth weight or birth length. No sex differences were found. In conclusion, pancreas agenesis severely restricts fetal length and head circumference in addition to weight growth, with stronger effects evident from 36 weeks of gestation. In addition to the well-known effects of insulin on growth of fetal fat mass, the pronounced effect on birth length and head circumference indicates effects of insulin on fetal lean body growth as well. Lack of power may account for failure to find sex differences.
Significance statement
Neonates with complete pancreas agenesis are born small, but the details of their growth deviation, timing, and potential sex differences remain uncertain. All neonates with pancreas agenesis in our study had reduced birth weight, length, and head circumference, with milder effects in those born before 36 weeks compared to after 36 weeks. This trend persisted when data were separated into before and after 38 weeks, with no discernible sex differences. The absence of the pancreas, and therefore insulin, significantly reduces fetal growth, especially after 36 weeks of gestation. In addition to insulin’s known role in fetal fat mass, our findings suggest it has a substantial influence on birth length and head circumference, underscoring its impact on fetal lean body growth.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Glucocorticoids (GCs) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD) but cause pubertal delay. Pubertal induction with testosterone is recommended but longer-term outcome is unknown.
Objective
To assess hypothalamic–pituitary–gonadal axis, muscle volume and function 5 years after pubertal induction.
Methods
A prospective observational follow-up of a clinical study was conducted. 15 GC-treated males with DMD were treated with incremental testosterone for 2 years (end of regimen +2 years) then evaluated at +2.5 years and +5 years (final follow-up ~3 years after last injection). Data collected included testicular volume (TV), gonadotrophin, testosterone, inhibin B, muscle function, and limb muscle MRI.
Results
Participants were 18.7 years (s.d. 1.6) at the final follow-up and had been on GC for 11.2 years (s.d. 2.2). Testosterone levels were similar at +2.5 years (8.6 nmol/L (s.d. 3.4) and 5 years (11.0 nmol/L (s.d. 6.1). TV increased from 2.8 mL (s.d. 0.9) at +2 years to 7.1 mL (s.d. 1.8) then 10.6 mL (s.d. 3.5) at +2.5 years and +5.0 years (P < 0.001). Inhibin B levels increased from 55.6 pg/mL (s.d. 47.0) at baseline to 158.2 pg/mL (s.d.87.6), P =0.004 at 5 years but remained lower than reference values (mean 305 pg/mL). Muscle contractile bulk decreased.
Interpretation
Pubertal induction with testosterone in DMD is associated with HPG axis activation and ongoing increases in inhibin B, TV, and testosterone concentrations. Some patients have normal levels which is promising regarding future fertility. Given the beneficial impact of testosterone on bone health, muscle, and well-being, monitoring testosterone levels in this population and supplementation of sub-optimal levels is important.
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INSERM Unité 1203 (DEFE), Université de Montpellier, Montpellier, France
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Département d'Endocrinologie et de Gynécologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université de Montpellier, Montpellier, France
INSERM Unité 1203 (DEFE), Université de Montpellier, Montpellier, France
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Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.
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Hypogonadism is a clinical syndrome resulting from failure to produce physiological concentrations of sex steroid hormones with accompanying symptoms, such as slowed growth and delayed pubertal maturation. Hypogonadism may arise from gonadal disease (primary hypogonadism), dysfunction of the hypothalamic–pituitary axis (secondary hypogonadism) or functional hypogonadism. Disrupted puberty (delayed or absent) leading to hypogonadism can have a significant impact on both the physical and psychosocial well-being of adolescents with lasting effects. The diagnosis of hypogonadism in teenagers can be challenging as the most common cause of delayed puberty in both sexes is self-limited, also known as constitutional delay of growth and puberty (CDGP). Although an underlying congenital cause should always be considered in a teenager with hypogonadism, acquired conditions such as obesity, diabetes mellitus, other chronic diseases and medications have all been associated with low sex steroid hormone levels. In this review, we highlight some forms of functional hypogonadism in adolescents and the clinical challenges to differentiate normal variants from pathological states.
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Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤−2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader–Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, 4 (11%) a variant affecting GH–insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent’s height (P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent’s heights ≤−2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, and gene variants affecting the growth plate are the most common. Shorter parent’s height and BA are clinical predictors of monogenic FSS.
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Diagnosis and management strategy of disorders of sex development (DSD) are difficult and various due to heterogeneous phenotype and genotype. Under widespread use of genomic sequencing technologies, multiple genes and mechanisms have been identified and proposed as genetic causes of 46,XY DSD. In this study, 178 46,XY DSD patients were enrolled and underwent gene sequencing (either whole-exome sequencing or targeted panel gene sequencing). Detailed clinical phenotype and genotype information were summarized which showed that the most common clinical manifestations were micropenis (56.74%, 101/178), cryptorchidism (34.27%, 61/178), and hypospadias (17.42%, 31/178). Androgen synthesis/action disorders and idiopathic hypogonadotropic hypogonadism were the most frequent clinical diagnoses, accounting, respectively, for 40.90 and 21.59%. From all next-generation sequencing results, 103 candidate variants distributed across 32 genes were identified in 88 patients. The overall molecular detection rate was 49.44% (88/178), including 35.96% (64/178) pathogenic/likely pathogenic variants and 13.48% (24/178) variants of uncertain significance. Of all, 19.42% (20/103) variants were first reported in 46,XY DSD patients. Mutation c.680G>A (p.R227Q) on SRD5A2 (steroid 5-alpha-reductase 2) (36.67%, 11/30) was a hotspot mutation in the Chinese population. Novel candidate genes related to DSD (GHR (growth hormone receptor) and PHIP (pleckstrin homology domain-interacting protein)) were identified. Overall, this was a large cohort of 46,XY DSD patients with a common clinical classification and phenotype spectrum of Chinese patients. Targeted gene panel sequencing covered most of the genes contributing to DSD, whereas whole-exome sequencing detected more candidate genes.
Department of Child and Adolescent Medicine, Section of Pediatric Cardiology, University Hospital Jena, Am Klinikum, Jena, Germany
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Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), University of Leipzig, Liebigstrasse, Leipzig, Germany
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Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), University of Leipzig, Liebigstrasse, Leipzig, Germany
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Background and objectives
As part of the LIFE Child study, we previously described the associations between N-terminal-pro-hormone brain natriuretic peptide (NT-proBNP) and hs-troponin T (hs-TnT) levels and an individual’s sex, age and pubertal status, as well as with body mass index (BMI) and serum lipid levels. For NT-proBNP, we found inverse associations with advancing puberty, increasing BMI and serum lipid levels. These findings led us to further question the putative influences of the developing individual’s metabolic and growth status as represented by levels of insulin-like growth factor-1 (IGF-1) and IGF-1-binding protein-3 (IGF-BP3) as well as hemoglobin A1c (HbA1c) and Cystatin C (CysC).
Material and methods
Serum values, medical history and anthropometric data provided by 2522 children aged 0.25–18 years were collected and analyzed as per study protocol.
Results
A strong negative association between NT-proBNP values and IGF-1, IGF-BP3 and HbA1c levels was identified. For IGF-BP3, this interaction was modulated by sex and age, for HbA1c only by age. For hs-TnT, a positive association was found with IGF-BP3, IGF-1 and CysC. The association between hs-TnT and IGF-1 was sex dependent. The association between CysC and hs-TnT was stronger in girls, but the interaction with age was only seen in boys. Between hs-TnT and HbA1c, the association was significantly negative and modulated by age.
Conclusion
Based on our large pediatric cohort, we could identify age- and sex-dependent interactions between the metabolic status represented by IGF-1, IGF-BP3, CysC and HbA1c levels and the cardiac markers NT-proBNP and hs-TnT.
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The current study aims to assess the development of the knowledge generation program of the European Reference Network on Rare Endocrine Conditions (Endo-ERN) from its start in 2019 until December 2021, with special reference to webinars. We analyzed the number of webinars and live/postevent participants and whether participation and engagement of the attendees changed over time. A total of 30 (86%) self-prepared webinars comprising 300 h of knowledge and competence sharing were broadcasted (2019 – 3; 2020 – 13; 2021 – 14). A total of six webinars were broadcasted live prior to the coronavirus disease 2019 pandemic (https://endo-ern.eu/events/webinars/). The most active main thematic group (MTG) was MTG3 Genetic Disorders of Glucose and Insulin Homeostasis with eight (27%) webinars. Two (25%) MTGs fulfilled the goal to prepare at least two to three webinars per year. Patients were actively involved in 20% of the accounted webinars as both creators and presenters. The total number of live and postevent participants was 3023. The availability of the webinars after the live broadcast increased their outreach with a larger number of postevent viewers (n = 1629, 54%). Within the formal structured evaluation of the webinars, 40–85% of the participants replied on separate occasions and helped improve content. The free webinar access is among the perceived reasons for the rapidly increasing number of total hits to the Endo-ERN website. In conclusion, for its short existence, the Endo-ERN rapidly developed educational outreach, and further efforts to attract creators and learners are warranted.
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Universidade de São Paulo, Zebrafish Facility, São Paulo, São Paulo, Brazil
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Context
Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition.
Objectives
The aim of this study is to conduct WES in a patient with congenital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel CDH2 variant.
Design
Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic variants were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or hypothalamus. Genomic DNA from 145 patients was screened for CDH2 by Sanger sequencing.
Results
One female patient with deficiencies in growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibroblast lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large aggregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with variant CDH2 or non-transfected.
Conclusion
A homozygous CDH2 allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different populations.
Significance statement
A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic, CDH2 variant that impairs cell aggregation in vitro. No other likely pathogenic variants in CDH2 were identified in 145 hypopituitarism patients.
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Objective
This Italian survey aims to evaluate real-life long-term efficacy and safety of recombinant human growth hormone (rhGH) therapy in children with short stature homeobox-containing gene deficiency disorders (SHOX-D) and to identify potential predictive factors influencing response to rhGH therapy.
Design and methods
This is a national retrospective observational study collecting anamnestic, anthropometric, clinical, instrumental and therapeutic data in children and adolescents with a genetic confirmation of SHOX-D treated on rhGH. Data were collected at the beginning of rhGH therapy (T0), yearly during the first 4 years of rhGH therapy (T1, T2, T3 and T4) and at near-final height (nFH) (T5), when available.
Results
One hundred and seventeen SHOX-D children started rhGH therapy (initial dose 0.23 ± 0.04 mg/kg/week) at a mean age of 8.67 ± 3.33 years (74% prepubertal), 99 completed the first year of treatment and 46 reached nFH. During rhGH therapy, growth velocity (GV), standard deviation score (SDS) and height (H) SDS improved significantly. Mean H SDS gain from T0 was +1.14 ± 0.58 at T4 and +0.80 ± 0.98 at T5. Both patients carrying mutations involving intragenic SHOX region (group A) and ones with regulatory region defects (group B) experienced a similar beneficial therapeutic effect. The multiple regression analysis identified the age at the start of rhGH treatment (β = −0.31, P = 0.030) and the GV during the first year of rhGH treatment (β = 0.45, P = 0.008) as main independent predictor factors of height gain. During rhGH therapy, no adverse event of concern was reported.
Conclusions
Our data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless the wide variety of genotype.
Significance Statement
Among children with idiopathic short stature, the prevalence of SHOX-D is near to 1/1000–2000 (1.1–15%) with a wide phenotypic spectrum. Current guidelines support rhGH therapy in SHOX-D children, but long-term data are still few. Our real-life data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless of the wide variety of genotypes. Moreover, rhGH therapy seems to blunt the SHOX-D phenotype. The response to rhGH in the first year of treatment and the age when rhGH was started significantly impact the height gain.
