Temporal trends in acute adrenal insufficiency events in children with congenital adrenal hyperplasia during 2019-2022

Background It is unclear whether targeted monitoring of acute adrenal insufficiency (AI) related adverse events (AE) such as sick day episodes (SDE) and hospitalisation rate in congenital adrenal hyperplasia (CAH) is associated with a change in the occurrence of these events. Aim Study temporal trends of AI related AE in the I-CAH Registry. Methods In 2022, data on the occurrence of AI-related AE in children aged <18yrs with 21-hydroxylase deficiency CAH was compared to data collected in 2019. Results In 2022, a total of 513 children from 38 centres in 21 countries with a median of 8 children (range 1, 58) per centre had 2,470 visits evaluated over a 3-yr period (2019-2022). The median SDE per patient yr in 2022 was 0 (0, 2.5) compared to 0.3 (0, 6) in 2019 (p=0.01). Despite adjustment for age, CAH phenotype and duration of study period, a difference in SDE rate was still apparent between the two cohorts. Of the 38 centres in the 2022 cohort, 21 had also participated in 2019 and a reduction in SDE rate was noted in 13 (62%), an increase was noted in 3 (14%) and in 5 (24%) the rate remained the same. Of the 474 SDEs reported in the 2022 cohort, 103 (22%) led to hospitalisation compared to 299 of 1099 SDEs (27%) in the 2019 cohort (p=0.02). Conclusions The I-CAH Registry can be used for targeted monitoring of important clinical benchmarks in CAH. However, changes in reported benchmarks need careful interpretation and longer-term monitoring

Améliorer les pratiques de soins pour les personnes présentant une variation du développement du sexe en Suisse : l’Ecole de Lausanne (depuis 2005) = Improving Standards of Care for Persons with a Variation of Sex Development in Switzerland: The Lausanne School (since 2005)

Cet article présente un bref historique de l’Ecole de Lausanne, appelée parfois « modèle suisse » à l’étranger, qui a été créée dans le cadre d’un projet interdisciplinaire « SHS et genre en médecine » initié en 2005 pour améliorer les pratiques de soins pour les personnes présentant une variation du développement du sexe. Nous nous proposons de revenir ici de manière réflexive sur plus de dix ans de travail collaboratif en explicitant les conditions de possibilité, les raisons, les objectifs et les différentes modalités de développement d’une équipe enseignante et hospitalière multidisciplinaire connue pour différer toute chirurgie génitale précoce d’assignation du sexe, respectant en cela le droit des enfants concernés de participer à la décision d’être opéré ou non. L’expérience lausannoise témoigne de la possibilité non seulement de changer les pratiques cliniques au profit d’une prise en charge qui ne soit pas prioritairement chirurgicale, mais aussi de développer une éthique médicale « par le bas » pour pallier l’absence de recommandations éthiques comme c’était le cas jusqu’à récemment en Suisse. ENGLISH ABSTRACT: This article presents a short history of the Lausanne School or “Swiss model” (as it is sometimes called abroad) created in the context of an interdisciplinary “SHS and gender in medicine” project we launched in 2005 to improve medical care for persons with a variation of sex development (VSD). We reflect here on our collaborative work experience for more than 10 years now in order to highlight the conditions of possibility, the reasons, the goals and the various development modalities of a VSD teaching and hospital team committed to multidisciplinary care. Our team is also known for its commitment to differ early genital surgeries so as to respect children’s right to participate in medical treatment decisions. The Lausanne experience testifies to the possibility of changing clinical practices to implement “a less cutting, more talking” model of care and, at the same time, of developing a medical ethics “from below” to overcome the lack of ethical recommendations as it was the case until 2012 in Switzerland

Diabète de l'enfant, de l'insulino-vers l'immunothérapie: une prise en charge globale du présent vers le futur

Diabetes type I (DTI) is an autoimmune disease characterized by a progressive destruction of the insulin producing beta cells of the pancreas that requires insulin substitution therapy. Recent epidemiological data show an annual increase of the incidence of DTI of 3.9%. Children with new onset diabetes typically present with polyuria, polydipsia and weight loss. As of today no cure for DTI exists. However new therapeutic immunomodulary approaches are under investigation. In the meantime adherence to insulin therapy is mandatory to achieve near physiological glucose levels. Monogenic forms of diabetes remain rare in children, but their diagnosis is important in order to propose a specific treatment. A critical period for the diabetic patient is the transition from pediatric to adult care

Fractionated stereotactic radiotherapy with static field conformal and non coplanar arcs for pediatric patients with craniopharyngioma: analysis of long term visual outcome and endocrine toxicity

We assessed the efficacy and the toxicity for pediatric craniopharyngioma patients of fractionated stereotactic radiotherapy (FSRT). Between May 2000 and May 2009, 9 patients (male to female ratio, 5:4) with craniopharyngiomas underwent FSRT (median dose, 54 Gy). Among the 9 patients, 6 received radiation therapy (RT) for recurrent tumors and 3 for residual disease as adjuvant therapy after incomplete surgery. Median tumor 3 volume was 2.3 cm (range, 0.1-5.8). The median target coverage was 93.7% (range 79.3-99.8%). The median conformity index was 0.94 (range, 0.6-1.4). Dose to the hippocampal region was assessed for all patients. After a median follow-up of 62.5 months (range, 32-127)the treated volume decreased in size in four of eight patients (50%). One patient was lost to follow-up. Local control and survival rates at 3 years were 100% and there were no marginal relapses. One patient, with a chronic bilateral papillary oedema after surgery, visual defect deteriorated after FSRT to a complete hemianopsia. One male patient with normal pituitary function before FSRT presented with precocious puberty at the age of 7.4 years, 24 months after FSRT. Four patients (50%) were severely obese at their last visit. FSRT is a safe treatment option for craniopharyngioma after incomplete resection

[Enfants et adolescents avec variations du développement sexuel]

Wie werden heute Kinder mit unklarem Geschlecht in der Schweiz betreut? Diese und ähnliche Fragen beschäftigen nicht nur Spezialist(inn)en und Betroffene, sondern auch die Öffentlichkeit. Die Nationale Ethikkommission hat 2012 Empfehlungen zum Umgang mit Menschen mit Varianten der Geschlechtsentwicklung erarbeitet.Comment les enfants de sexe indéterminé sont-ils aujourd’hui pris en charge en Suisse? Cette question et des questions similaires préoccupent non seulement les spécialistes et les personnes touchées, mais également la société en général. En 2012, la Commission nationale d’éthique dans le domaine de la médecine humaine a élaboré des recommandations relatives à l’attitude à adopter à l’égard des personnes avec variations du développement sexuel

Patients avec variation du développement sexuel : un exemple de prise en charge interdisciplinaire

The medical, psychological and social aspects of disorders of sex development (DSD) represent a challenge for the management of these patients. However, advances in our understanding of the etiology and genetics of this condition, novel surgical approaches and the growing influence of patient groups as well as wider recognition of ethical issues have helped improve the care of patients with a DSD. Importantly, a multidisciplinary approach involving specialists is crucial for understanding and treating such rare and complex cases. According to the recommendations of the Swiss National Ethical Commission, we shall use the term « Variation of Sex Development » rather than « Disorder of Sex Development » in this publication. This article addresses the care of DSD patients throughout development from the point of view of specialists in complementary fields

DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, and more than 30 genes have been implicated in approximately 50% of patients with CHH. We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), are mutated in CHH. We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cell morphology, and confirmed five heterozygous DCC mutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygous mutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotes migration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons in mice

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations

Purpose Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising CHH and SHFM. Methods: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions, and/or functional assays. Results: We identified 8 probands with CHH with (n=3, Kallmann Syndrome) or without anosmia (n=5) and SHFM, 7 of whom (88%) harbor FGFR1 mutations: one individual is homozygous for p.V429E; six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, and p.L712P. All mutations were predicted to be loss-of-function by in silico analysis. Probands with FGFR1 mutations have severe GnRH deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was only observed in the patient with the homozygous p.V429E mutation; V429 maps to the FRS2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of FRS2α to FG FR 1 , thereby resulting in reduced MAPK signaling. Conclusion: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM, because the likelihood of a mutation increases from 10% in the general CHH population to 88%