Hormone Research in Paediatrics最新文献

Background: Paediatric endocrinology became recognised in Western European countries in the 1960s and 1970s. It is now a thriving paediatric sub-speciality in many countries but remains non-existent or in its infancy in others. We have had the privilege to work in Western centres of excellence, and this review outlines the key stages in the development of modern centres, discussing the human and organisational issues that have underpinned progress in the establishment of this paediatric sub-speciality.

Summary: Human determination, vision, and ambition to create a modern centre and become a national flag bearer in the field are key components of success. The realisation that learning by spending time as a fellow away from one's home institution, so that knowledge can be acquired and brought back home, is also a key factor. Career structures should be designed to mentor and guide the trainee returning from a fellowship abroad. Scientific societies such as the European Society for Paediatric Endocrinology (ESPE) are key resources for networking, support, and discussion with experienced colleagues who may have faced similar challenges. Training and acquisition of knowledge through on-site or e-learning initiatives are beneficial and numerous examples exist, including the telemedicine model of store-and-forward consultations. Leadership skills can be learnt, and good working relationships with adult endocrinology colleagues result in benefits and political support.

Key messages: The development of paediatric endocrinology in a region with hitherto no such facilities constitutes a major contribution to local, regional, and, in all likelihood, national patient care.

Introduction: Turner syndrome (TS) is associated with primary ovarian insufficiency (POI) and most adolescents and young adults (AYA) with TS require treatment with hormone replacement therapy (HRT). International consensus guidelines are unclear on the optimal formulation and dosing for HRT after pubertal induction. This study assessed current HRT practice patterns of endocrinologists and gynecologists in North America.

Methods: Email listserv members of the North American Society for Pediatric and Adolescent Gynecology (NASPAG) and the Pediatric Endocrine Society (PES) were invited to complete a 19-question survey to assess HRT treatment preferences for the management of POI after completion of pubertal induction in AYA with TS. Descriptive analysis and multinomial logistic regression to predict factors associated with preferred HRT are presented.

Results: 155 providers (79% pediatric endocrinology, 17% pediatric gynecology) completed the survey. Although 87% (135) reported confidence in prescribing HRT, only half (51%, 79) were aware of published guidelines. Factors significantly associated with preferred HRT included specialty (p = 0.032) and number of patients with TS seen every 3 months (p = 0.024). Gynecologists were 4 times less likely than endocrinologists to prefer hormonal contraceptives and 4 times more likely to favor transdermal estradiol dose of 100 μg/day as compared to lower doses.

Conclusion: Although most endocrinologists and gynecologists report confidence in prescribing HRT to AYA with TS after pubertal induction, there are clear differences in provider preferences based on specialty and higher volume of patients with TS in their practice. Additional studies on comparative effectiveness of the HRT regimens and evidence-based guidelines are necessary for AYA with TS.

Introduction: The management of childhood type 1 diabetes requires the active participation of parents. The aim of the present study was to describe the main characteristics of parents of children with type 1 diabetes, including objective burden regarding time spent on diabetes care, emotional distress (exhaustion, need for respite, quality of life), and symptoms of depression as well as anxiety.

Methods: In this observational study, parents of children with type 1 diabetes completed a questionnaire, anonymously. Different questions were asked to the parent about the objective burden of diabetes and its repercussion, their exhaustion, and their need for respite. Two validated instruments (HADS, WHOQOL-BREF) have been integrated into the questionnaire.

Results: Eighty-eight parents were included in the study. Among them, 76 (86%) were mothers. All the parents with a child aged 6 years or younger (10/10) reported having to take care of their child's diabetes twice or more a day; this was the case for 37/39 (94.9%) parents of children aged 7-13 and for 16/36 (44.4%) parents of children aged 14 years or above. In the total population, 33/86 (38.4%) parents declared getting up every night because of their child's diabetes. The median daily time spent on diabetes management was 40 min. There were 54 parents (62.8%) who reported moderate-strong exhaustion and 27 (30.7%) who expressed a moderate-strong need for respite. Regarding the result of the HADS, 46 parents (55.4%) reported symptoms of anxiety and/or depression.

Conclusion: Parents of children with type 1 diabetes must carry out multiple daily care tasks, at all times of day and night. Their emotional state can be impacted with, in particular, a risk of exhaustion. Screening for these difficulties should be a part of the overall management of a child with type 1 diabetes and his family to limit various complications.

Introduction: Although the majority of growth hormone insensitivity syndrome (GHIS) cases are classical, the spectrum of clinical phenotypes has expanded to include "atypical" GHIS subjects with milder phenotypes due to very rare heterozygous growth hormone receptor (GHR) mutations with dominant negative effects.

Case presentation: A 13-year-old pubertal boy presented with short stature (-1.7 SDS) and delayed bone age (11.5 years). His serum IGF-1 was low (16 ng/mL; reference range: 179-540). IGFBP-3 (1.3 mg/L; 3.1-9.5) and ALS (565 mU/mL; 1,500-3,500) were also low. GH stimulation test was normal, and GHBP was markedly elevated (6,300 pmol/L; 240-3,000). Additionally, the boy had insulin resistance and liver steatosis. His final height reached -1.8 SDS, which was 3.0 SDS below his mid-parental height. GHR gene from genomic DNA and established primary fibroblast culture was analyzed and a synonymous heterozygous GHR: c.945G>A variant, in the last nucleotide of exon 9 (encoding intracellular domain of GHR) was identified. In vitro analysis of the GHR cDNA demonstrated a splicing defect, leading to the heterozygous excision of exon 9. The final predicted product was a truncated GHR protein which explained the elevated GHBP levels.

Conclusion: We describe the first synonymous heterozygous GHR splicing variant in the exon 9-encoding part of the intracellular domain of GHR identified in a patient with mild short stature, thus supporting the continuum of genotype-phenotype of GHIS.

Introduction: Suprasellar tuberculoma are extremely rare in children and most of those patients present with headache, vomiting, visual disturbances, and hypofunction of the pituitary gland. In this case report, we present a girl with tuberculosis, who developed significant weight gain in combination with pituitary dysfunction, which recovered after antituberculosis treatment.

Case presentation: An 11-year old girl presented with headache, fever and anorexia that progressively evolved into an encephalopathic status with cranial nerves III and VI paresis. Brain MRI showed meningeal contrast capture along cranial nerves II (including optic chiasm), III, V and VI bilaterally and multiple contrast enhancing brain parenchyma lesions. Tuberculin skin test was negative but interferon-gamma release assay was positive. The clinical and radiological working diagnosis was consistent with tuberculous meningoencephalitis. Pulse corticosteroids for 3 days and quadruple antituberculosis therapy were started and the girl demonstrated obvious improvement of her neurological symptoms. However, after a few months of therapy she developed remarkable weight gain (+20 kg in 1 year) and growth arrest. Her hormone profile revealed insulin resistance (homeostasis model assessment-estimated insulin resistance [HOMA-IR] 6.8) despite putative growth hormone deficiency (circulating insulin-like growth factor-I [IGF-I] 104 μg/L [-2.4 SD]). Follow-up brain MRI showed a decrease in basal meningitis, but increased parenchymal lesions in the suprasellar region extending medially into the nucleus lentiformis, with now a voluminous tuberculoma at this site. Antituberculosis treatment was continued for a total of 18 months. The patient improved clinically, she regained her pre-illness Body Mass Index (BMI) SDS and her growth rate increased slightly. On the hormonal side, disappearance of insulin resistance (HOMA-IR 2.5) and an increase in IGF-I (175 μg/L, -1.4 SD) was noted, and her last brain MRI showed a remarkable volume reduction of the suprasellar tuberculoma.

Conclusion: Suprasellar tuberculoma can have a very dynamic presentation during the active stage of the disease, which can be reversed by prolonged antituberculosis treatment. Previous studies showed that the tuberculous process can also cause long term and irreversible changes in the hypothalamic-pituitary axis. Prospective studies are however needed in the pediatric population to know the exact incidence and type of pituitary dysfunction.

Background: The thalidomide disaster resulted in tremendous congenital malformations in more than 10,000 children in the late 1950s and early 1960s.

Summary: Although numerous putative mechanisms were proposed to explain thalidomide teratogenicity, it was confirmed only recently that thalidomide, rather its derivative 5-hydroxythalidomide (5HT) in a complex with the cereblon protein, interferes with early embryonic transcriptional regulation. 5HT induces selective degradation of SALL4, a principal transcriptional factor of early embryogenesis. Genetic syndromes caused by pathogenic variants of the SALL4 gene phenocopy thalidomide embryopathy with congenital malformations ranging from phocomelia, reduced radial ray, to defects of the heart, kidneys, ear, eye, and possibly cerebral midline and pituitary. SALL4 interacts with TBX5 and a handful of other transcriptional regulators and downregulates the Sonic hedgehog signaling pathway. Cranial midline defects, microcephaly, and short stature due to growth hormone deficiency have been occasionally reported in children carrying SALL4 pathogenic variants associated with generalized stunting of growth rather than just the loss of height attributable to the shortening of leg bones in many children with thalidomide embryopathy.

Key messages: Thus, SALL4 joins the candidate gene list for monogenic syndromic pituitary insufficiency. In this review, we summarize the journey from the thalidomide disaster through the functions of the SALL4 gene to its link to the hormonal regulation of growth.

Introduction: Among children born small for gestational age, 10-15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort.

Methods: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <-2 SD for gestational age and life-minimum height <-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines.

Results: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children.

Conclusions: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.

Introduction: Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. An elevated, more unfavorable ratio between acylated and unacylated ghrelin (AG/UAG ratio) might play a role in the underlying mechanisms of this switch. We aimed to assess the evolution of the appetite-regulating hormones acylated ghrelin (AG) and unacylated ghrelin (UAG) and the AG/UAG ratio and their association with the change in eating behavior in children with PWS, compared to healthy age-matched controls.

Methods: A longitudinal study was conducted in 134 children with PWS and 157 healthy controls, from the Netherlands, France, and Belgium. Levels of AG and UAG and the AG/UAG ratio were measured and nutritional phases as reported for PWS were scored.

Results: The AG/UAG ratio was lower in the first years of life in PWS than in controls and started to increase from the age of 3 years, resulting in a high-normal AG/UAG ratio compared to controls. The AG levels remained stable during the different nutritional phases (p = 0.114), while the UAG levels decreased from 290 pg/mL in phase 1a to 137 pg/mL in phase 2b (p < 0.001). The AG/UAG ratio increased significantly from 0.81 in phase 2a to 1.24 in phase 2b (p = 0.012).

Conclusions: The change from failure to thrive to excessive weight gain and hyperphagia in infants and children with PWS coincides with an increase in AG/UAG ratio. The increase in AG/UAG ratio occurred during phase 2a, thus before the onset of hyperphagia.