BACKGOUND:The purpose of this study is to compare the effect of long-acting growth hormone (LAGH) to daily GH on body mass index (BMI) in children with growth hormone deficiency (GHD). METHODS:We searched the PubMed database from its inception to July 2025 and identified three relevant randomized controlled trials lasting over 6 months, with extension phases providing longitudinal BMI data. Longitudinal BMI data were available for lonapegsomatropin, somatrogon, and somapacitan, but not for polyethylene glycol LAGH. RESULTS:A total of 585 patients were included in the present analysis, of which 346 were in the LAGH group, and 239 were in the daily rhGH group, derived from seven original articles and two abstracts/ePosters. At 12 months, there was a significant difference in BMI SD scores between LAGH and daily GH groups (Mean difference [MD] 0.66 SDS [95% confidence interval [CI] 0.04-1.29]). BMI SDS significantly increased in the LAGH group (MD + 0.41 SDS [95% CI 0.04-0.77] from 0 to 12 months), whereas it did not change in the daily GH group (MD -0.35 SDS [95% CI -0.76 to +0.07] from 0 to 12 months). Between 12 and 24 months, after switching from daily GH to LAGH (daily GH/LAGH), or pursuing LAGH (LAGH/LAGH) in the extension phases of the studies, BMI SDS significantly increased in the daily GH/LAGH switching group (MD + 0.75 SDS [95% CI 0.24-1.27] from 12 to 24 months), whereas it remained steady in the LAGH/LAGH group. Omitting one study at a time from the meta-analysis did not materially affect the results. CONCLUSION:An increase in body mass index SD score is associated with the first year of LAGH use.

INTRODUCTION:Pituitary duplication is a rare congenital malformation, with fewer than 80 cases reported in the literature. It is often associated with midline malformations but can also occur in isolation. Central precocious puberty (CPP) is the most common endocrinological manifestation, but to date this has only ever been reported in female patients. CASE REPORT:A 9-year-old boy presented with precocious puberty. His medical history was notable for a ventricular septal defect. Physical examination showed Tanner stage P3 G2, a growth rate of 10 cm/year, and a bone age of 12.5 years. A GnRH test confirmed CPP. Pituitary function was otherwise normal. MRI revealed ectopic pituitary duplication with two separate stalks, two ectopic posterior pituitary, tuberomammillary fusion, and vascular anomalies involving the basilar artery and vertebral vessels. The patient was treated with GnRH agonist therapy, which normalized growth and slowed bone maturation. Whole exome sequencing did not identify any pathogenic variants. CONCLUSION:This is the first reported case of CPP in a male with pituitary duplication. The findings highlight the need for awareness of endocrine dysfunction, including CPP, in patients with pituitary malformations. The gender disparity of CPP in pituitary duplication remains unexplained, and further research into genetic and molecular mechanisms, notably Sonic Hedgehog signaling, is required to understand this association.

OBJECTIVE:This study aimed to evaluate the experiences of patients who had a joint endocrinology consultation for transition to adult care at Marseille university hospitals between 2010 and 2020, focusing on patient follow-up, satisfaction, difficulties, and expectations. METHODS:A healthcare transition questionnaire was designed and administered to patients several years after transition to adult care. RESULTS:One hundred and fifteen patients with rare endocrine disorders were included, with a mean age of 18.8 years at the transition consultation. Ninety-six percent (110/115) continued adult care after the first joint consultation, and 75% were still in follow-up when completing the questionnaire (mean follow-up, 4.5 years). Of the 81 respondents, 89% were satisfied with the transition, and 64% reported no difficulties. The most common difficulties were psychological, logistical, and medical. Fifty-three out of 74 respondents (72%) felt the transition occurred at the right time, 17 (24%) thought it was too early, and 4 (5%) felt it was too late. The main concern was the transmission of medical information between doctors. Suggestions for improvement included more joint consultations and personalized transition pathways. CONCLUSION:In this group of rare endocrine disease patients, a transition pathway based on a joint pediatric-adult consultation was associated with high patient satisfaction and long-term follow-up rates. Patients' suggestions and reported difficulties highlight issues to be addressed and complementary strategies to develop.

CONTEXT:Congenital hypogonadotropic hypogonadism (CHH) in infant boys is a rare disorder that can manifest as micropenis and/or cryptorchidism. Mini-puberty is considered a window of opportunity for CHH diagnosis and treatment. The lack of testosterone (T) elevation during this period is the gold standard for CHH diagnosis, but hormonal evaluation is not always available at this time. OBJECTIVES:The aim was to compare inhibin B (INHB), anti-Müllerian hormone (AMH), T, LH, and FSH between infant boys (1 to 365 days) with micropenis and/or cryptorchidism due to isolated CHH (iCHH), CHH as part of combined pituitary hormone deficiency (CPHD), or of idiopathic origin (controls) and to determine discriminating cutoffs for CHH diagnosis based on sensitivity (Se) and specificity (Sp). METHODS:This multicenter study from 7 University Hospitals in France included 138 boys aged 0 to 12 months (58 with iCHH, including 28 with a positive molecular diagnosis, 32 with CPHD, and 48 controls). Four periods of interest were studied: between 1 to 4 days, 15 to 65 days (early mini-puberty, corresponding to the T peak), 66 to 179 days (late mini-puberty), and 180 to 365 days (post mini-puberty). RESULTS:Out of mini-puberty, the best-discriminating hormones were INHB between 1 to 4 days (Se/Sp 100%/75% at 150 pg/mL and 89%/100% at 85 pg/mL) and INHB and AMH after 180 days (INHB: Se/Sp 100%/100% at 100 pg/mL; AMH: Se/Sp 100%/92% at 600 pmol/L, and 75%/100% at 370 pmol/L). INHB and/or AMH discriminating performances were good (area under the receiver operating characteristic curve ≥ 0.95) across all 4 periods. CONCLUSION:Inhibin B and/or AMH can be used to diagnose CHH in boys < 1 year of age.

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.

The aim of this study is to analyze the clinical characteristics of isolated growth hormone deficiency (IGHD) patients with GH1, GHRHR, and GHSR variants and their response to growth hormone (GH) treatment. Growth characteristics were retrospectively analyzed from GH treatment initiation in the Genhypopit cohort with likely pathogenic or pathogenic variants in GH1, GHRHR, or GHSR. Twenty-one patients (GH1: n = 13, GHRHR: n = 4, GHSR: n = 4) were followed up for 8.9 years (0.4; 19.6). GHD was diagnosed earlier in patients with GH1 or GHRHR variants than in those with GHSR variants (mean age at diagnosis: 3.1 and 2.0 years vs. 6.9 years, respectively). Patients with a family history of IGHD tend to have less severe short stature at diagnosis (− 2.2 vs. − 3.2 SDS, p = 0.053). Total height gain was significantly higher in patients with GH1 and GHRHR variants (+ 3.4 and + 3.8 SDS) than in those with GHSR variants (+ 1.8 SDS; p = 0.047). Total height gain was also associated with more severe initial growth delay (p < 0.001), greater difference from target height (p = 0.003), and earlier treatment initiation (p = 0.006). Patients born small for gestational age (SGA) experienced a growth gain similar to patients born eutrophic without the need to increase GH doses. This height gain under GH treatment was higher than reported previously in patients with non-genetic IGHD. Conclusion: Identifying a genetic cause of IGHD, particularly those involving variants in GH1 and GHRHR, is associated with significant height gain under GH treatment, regardless of their SGA status.

Anorexia nervosa (AN) is a severe, potentially life-threatening psychiatric disorder characterized by an intense fear of weight gain, a distorted body perception and an extern food restriction leading to an abnormally low body weight. In AN patients, malnutrition is often associated with hepatic cytolysis. A growing body of evidence support an association between AN and auto-immunity. In this exploratory study, we revealed for the first-time the presence of autoantibodies targeting hypoxia-inducible factor 1 alpha (HIF1a) in AN. We evidenced the presence of autoantibodies against HIF1a in 22% of AN patients, which were absent in patients with other metabolic disease as type-I diabetes or in healthy subjects. In addition, we found that HIF1a autoantibodies was associated with hepatic cytolysis in 80% of AN patients and that their levels significantly correlated with those of ALT (alanine aminotransferase). In-vitro experiments demonstrated that HIF1a autoantibodies induced hepatocyte lysis, suggesting a potential link between these autoantibodies and liver dysfunction in AN patients. Altogether, our data reveal an implication of HIF1a autoantibodies in AN with hepatic cytolysis. Future investigation will explore their potential as a diagnostic or a prognostic marker in AN, but also other diseases since dysregulated hypoxia pathway has been implicated in other pathologic conditions.

OBJECTIVE:The aim of this study was to describe the quality of life (QoL) of children with a chronic illness treated in a tertiary multidisciplinary pediatric department in comparison with the general population. STUDY DESIGN:A cross-sectional study was conducted in the tertiary multidisciplinary (nephrology, hepatogastroenterology, endocrinology, diabetology, transplantation) pediatric department of Timone Hospital in Marseille, France. Patients 8-17 years of age with a chronic disease were included during regular follow-up appointments. Medical and sociodemographic variables were obtained from medical records. Self-reported QoL was assessed using the VSPA (Vécu et Santé Perçu de l'Adolescent) questionnaire and parent-reported QoL was assessed using the VSPA questionnaire for parents. RESULTS:A total of 244 patients were included. Overall QoL did not differ significantly from that of the general population. Adolescent patients' self-reported QoL scores were lower than those of the general population in the domains of physical health and leisure, and parents reported QoL scores for adolescent patients lower than those of the general population for self-esteem and physical health. Adolescents' self-reported QoL scores were higher than in the general population for relationships with parents, healthcare professionals, and teachers as well as for school achievement. Parents also reported higher QoL scores in these areas for their children. CONCLUSION:Children and adolescents with a variety of chronic diseases had similar overall QoL scores to the general population but with different QoL profiles; their scores in some domains were higher than those of the general population.

Background New technologies for the management of children with type 1 diabete (T1D) are constantly and rapidly evolving. However, few real-life studies have been conducted, and rarely in the youngest patients (<6 years). Aim To study parental satisfaction with continuous and flash glucose monitoring devices in young children with T1D. Methods A questionnaire was completed by the parents of 114 children under the age of 6 years with T1D treated with an insulin pump followed-up in one of the hospitals of the French ADIM network between January and July 2020. Results One hundred and nine patients (96 %) were equipped with a glucose monitor and 95 % (104/109) of parents stated that they were satisfied or very satisfied with their child's monitoring device, with no significant difference in satisfaction rates between flash and continuous glucose monitoring. The parameter most strongly associated with satisfaction was confidence in the reliability of the device (p = 0.008). Parents who struggled to apply the device were significantly less satisfied (p = 0.024). In real-life use, 83 % of parents (90/109) used additional adhesives, 28 % reported mild skin reactions (30/108) and 39 % severe skin reactions (42/108), 50 % stated that applying the device was not painful, and 95 % found the device easy to apply. The most commonly reported unexpected difficulties were device malfunction (by 16 respondents), the device being too large and causing scarring (6 respondents), and lengthy calibration (6 respondents). Conclusion The vast majority of parents in this group of young children with T1D were satisfied with continuous or flash glucose monitoring. Satisfaction was strongly associated with confidence in the reliability of the device. Reported adverse effects such as skin reaction and difficulties attaching the device highlight the importance of data on real-life use.

Pituitary deficiency, or hypopituitarism, is a rare chronic disease. It is defined by insufficient synthesis of one or more pituitary hormones (growth hormone, TSH, ACTH, LH-FSH, prolactin), whether or not associated with arginine vasopressin deficiency (formerly known as diabetes insipidus). In adult patients, it is usually acquired (notably during childhood), but can also be congenital, due to abnormal pituitary development. The present study focuses on congenital pituitary deficiency in adults, from diagnosis to follow-up, including special situations such as pregnancy or the elderly. The clinical presentation is highly variable, ranging from isolated deficit to multiple deficits, which may be part of a syndromic form or not. Diagnosis is based on a combination of clinical, biological (assessment of all hormonal axes), radiological (brain and hypothalamic-pituitary MRI) and genetic factors. Treatment consists in hormonal replacement therapy, adapted according to the period of life and the deficits, which may be progressive. Comorbidities, risk of complications and acute decompensation, and the impact on fertility and quality of life all require adaptative multidisciplinary care and long-term monitoring.

Introduction Requests for hormonal transition in minors are increasing. To date, there is no national recommendation to guide these practices in France. Therefore, the SFEDP (French Society of Pediatric Endocrinology and Diabetology) has commissioned a group of experts to draft the first national consensus on this topic. Method Each chapter was prepared by one to three authors who conducted a literature review, and it was then reviewed and revised by the group as many times as necessary to achieve a consensus position. The final document was reviewed by a group of external experts. Results A consensus position was reached regarding the multi-professional nature of support for trans youth, the prescription of molecules aimed at inhibiting endogenous hormone secretion, and the use of gender-affirming hormone therapies, as well as the importance of offering gamete preservation. Non-hormonal aspects of support and various considerations, including ethical ones, were also discussed. Conclusion This work constitutes an initial set of recommendations for professionals involved in the hormonal transition of trans youth. Additional recommendations under the auspices of the French High Authority for Health would be worthy of being drafted, involving all relevant stakeholders to establish comprehensive official national guidelines that would secure the support and rights of these young individuals, especially those under 16 years old, as well as the professionals involved in their care.

Hypopituitarism (or pituitary deficiency) is a rare disease with an estimated prevalence of between 1/16,000 and 1/26,000 individuals, defined by insufficient production of one or several anterior pituitary hormones (growth hormone [GH], thyroid -stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], luteinizing hormone [LH], follicle -stimulating hormone [FSH], prolactin), in association or not with diabetes insipidus (antidiuretic hormone [ADH] deficiency). While in adults hypopituitarism is mostly an acquired disease (tumors, irradiation), in children it is most often a congenital condition, due to abnormal pituitary development. Clinical symptoms vary considerably from isolated to combined deficiencies and between syndromic and non-syndromic forms. Early signs are non-specific but should not be overlooked. Diagnosis is based on a combination of clinical, laboratory (testing of all hormonal axes), imaging (brain magnetic resonance imaging [MRI] with thin slices centered on the hypothalamic -pituitary region), and genetic (next -generation sequencing of genes involved in pituitary development, array -based comparative genomic hybridization, and/or genomic analysis) findings. Early brain MRI is crucial in neonates or in cases of severe hormone deficiency for differential diagnosis and to inform syndrome workup. This article presents recommendations for hormone replacement therapy for each of the respective deficient axes. Lifelong follow-up with an endocrinologist is required, including in adulthood, with multidisciplinary management for patients with syndromic forms or comorbidities. Treatment objectives include alleviating symptoms, preventing comorbidities and acute complications, and optimal social and educational integration. (c) 2024 The Authors. Published by Elsevier Masson SAS on behalf of French Society of Pediatrics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Introduction: The prevalence of type 1 diabetes is increasing worldwide. The advent of new monitoring devices has enabled tighter glycemic control. Aim: To study the impact of glucose monitoring devices on the everyday life of young children with type 1 diabetes (T1D) and their parents. Methods: A questionnaire was addressed to parents of children with T1D under the age of 6 years with an insulin pump treated in one of the hospitals of the ADIM network in France between January and July 2020. Results: Among the 114 families included in the study, 53% of parents (26/49) woke up every night to monitor blood glucose levels when their child had flash glucose monitoring (FGM), compared with 23% (13/56) of those whose child had continuous glucose monitoring (CGM). Overall, 81% of parents (86/108) found that glucose monitoring improved their own sleep and parents whose child had CGM were significantly more likely to report improved sleep (86% vs 73%, p = 0.006). Forty-nine percent of parents (55/113) declared that they (in 87% of cases, the mother only) had reduced their working hours or stopped working following their child's T1D diagnosis. Maternal unemployment was significantly associated with the presence of siblings (p = 0.001) but not with glycemic control (p = 0,87). Ninety-eight percent of parents (105/107) think that glucose monitoring improves school integration. Conclusion: In these families of children with T1D, new diabetes technologies reduced the burden of care but sleep disruption remained common. Social needs evaluation, particularly of mothers, is important at initial diagnosis of T1D in children.

Durant le confinement du au COVID-19, une augmentation de l’incidence des PPC a été rapportée dans différents centres. Ces données n’ont pas encore été rapportées dans un centre français. L’objectif principal de notre étude est d’évaluer l’incidence de la puberté précoce centrale et puberté avancée entre la période pré-COVID (février 2018 a février 2020), la période COVID (mars 2020 a mai 2021) et la période post-COVID (juin 202 a mars 2022) dans la population marseillaise. Entre février 2018 et mars 2022, nous avons réalisé 475 hôpitaux de jours pour exploration de puberté précoce dans nos centres. Nous avons exclu les pubertés non idiopathiques et les pubertés non centrales. Nous avons collecté les données de 160 patients qui ont eu un test LHRH dans un contexte de puberté précoce ou avancée. Nous avons séparé les patients en 3 groupes en fonction de la date de réalisation du test LHRH et le confinement du au COVID-19 en France. Nous observons une augmentation significative du taux de PPC et de puberté avancée qui débute avant le confinement, qui se maintient durant la période de confinement et qui diminue ensuite. Nous constatons également une augmentation d’incidence de la puberté précoce dans notre population, mais cette augmentation semble légèrement antérieure à la période de confinement. Cette augmentation semble être influencée par un facteur environnemental qui persiste après les périodes de confinement. Il serait intéressant de poursuive notre observation de cohorte afin d’observer l’évolution de ce pic d’incidence.

AIM:To compare the outcomes of home-based and conventional hospital-based care for children newly diagnosed with type 1 diabetes mellitus.METHODS:A descriptive study was conducted of all children newly diagnosed with diabetes mellitus at the Timone Hospital in Marseille, France, between November 2017 and July 2019. The patients received either home-based or in-patient hospital care. The primary outcome was the length of initial hospital stay. The secondary outcome measures were glycemic control in the first year of treatment, families' diabetes knowledge, the effect of diabetes on quality of life, and overall quality of care.RESULTS:A total of 85 patients were included, 37 in the home-based care group and 48 in the in-patient care group. The initial length of hospital stay was 6 days in the home-based care group versus 9 days in the in-patient care group. Levels of glycemic control, diabetes knowledge and quality of care were comparable in the two groups despite a higher rate of socioeconomic deprivation in the home-based care group.CONCLUSION:Home-based care for children with diabetes is safe and effective. This new healthcare pathway provides good overall social care, especially for socioeconomically deprived families.

Background: Only few pediatric reports exist regarding the prevalence, cause and evolution of liver and renal injury in patients with anorexia nervosa (AN). The aim of this study is to describe the prevalence and the risk factors of hepatic and renal failure at admission and during hospitalization, especially during refeeding in a cohort of hospitalized adolescents with AN.Methods: In a retrospective cohort study of adolescents with AN in a single hospital of Marseille from 2013 to 2019, we compared four groups on admission: elevated aminotransferases (AT)/normal AT and renal injury/no renal injury to analyze the differences between them (demographic factors, anthropometric factors, disease duration, initial prescribed calories, speed of refeeding, aminotransferase level, glomerular filtration rate). We observed the evolution of AT and renal injury for these four groups during refeeding (by the increase of kilocalories). Results: A total of 29 subjects with AN met eligibility criteria (age: 14.2 years, female (86.2%), BMI at admission (Z-score= -2.8 standard deviation (SD)) with elevated AT (20.7 %) and renal injury (13.8 %) on admission. Lower Z-score BMI (-4.05 vs -2 SD, p = 0.013), lower expected weight for height (69% vs 76%, p = 0.034) and longer disease duration (2.1 vs 0.9 years, p =0,032) were significantly associated with elevated liver enzymes at admission. Lower Z-score BMI (-3.35 vs -2.5 SD, p = 0.002), lower expected weight for height at admission (69% vs 74,5%, p = 0.002) and loss of weight before admission (0.66 vs à 0.20 kg per day, p = 0.002) were associated with renal injury at admission. Time nadir BMI (13.5 vs 6.5 days, p = 0.034) and duration of hospitalization (55 vs 41 days, p = 0.036) were longer in elevated enzymes on admission group. During refeeding, liver enzymes (95% confidence interval (CI), odds ratio (OR) aspartate aminotransferase: -0.07 [-0.11; -0.03] and OR alanine aminotransferase: -0.16 [-0.27; -0.06]) and renal injury (95% CI, OR creatinine: -0.013 [-0.017; -0.008]) have normalized with the increase of calories, with significant association.Conclusions: The results of this study suggest that degree of malnutrition is associated with liver and renal injury on admission. Theses failures disappeared with refeeding. In the future, prospective multicentric studies could examine evolution of renal and hepatic failure undergoing refeeding in large pediatric cohort of AN.

Le déficit constitutionnel en TSH (TSHD) peut être isolé, secondaire à des anomalies de gènes impliqués dans la biosynthèse de la TSH ou associé à d’autres déficits hypophysaires du fait de mutations de gènes impliqués dans l’ontogenèse hypophysaire. Notre objectif était de déterminer les causes génétiques de TSHD isolé (ITSHD) ou associé à un déficit somatotrope (TSHDGHD) dans la cohorte de patients du réseau GENHYPOPIT. Analyse par NGS d’une cohorte de patients présentant un ITSHD ou un TSHDGHD non syndromique. Les variants ont été classés selon la classification ACMG revue par le réseau NGS-Diag et corrélés avec le phénotype. Les variants nucléotidiques simples (SNV) de classe 3, 4 et 5 ont été vérifiés par séquençage Sanger. Soixante-quatre cas index (22 ITSHD et 42 TSHDGHD) ont été inclus dans cette cohorte. Une cause génétique a été identifiée chez 26,5 % des patients, dont 36,3 % dans le groupe ITSHD (variants dans TSHβ et IGSF1) et 21,4 % dans TSHDGHD (variants dans IGSF1, TSHβ, TRHR, GH1, POU1F1, PROP1). Quarante-deux pour cent des variants identifiés concernaient IGSF1, parfois avec des phénotypes atypiques. Six de ces variants n’avaient jamais été rapportés. Les variants d’IGSF1 représentent la première étiologie génétique identifiée de TSHD. Malgré une approche NGS systématique et l’identification de nouveaux variants, la plupart des patients restent sans diagnostic moléculaire. Des études de type whole genome seront prochainement réalisées sur ce groupe de patients de phénotype homogène pour identifier de nouveaux acteurs du développement hypophysaire.

Short stature in children can be caused by congenital pituitary disorders involving at least one form of growth hormone deficiency. Clinical and radiological evaluations of the index case and family history assessments are essential to guide genetic diagnostic testing and interpret results. The first-line approach is panel testing of genes involved in pituitary development with variants known to be pathogenic in this context. It identifies a genetic cause in less than 10% of cases, however. Whole-exome and whole-genome sequencing techniques may provide original information but also raise new questions regarding the pathophysiological role of identified variants. These new tools can make genetic counselling more complex. The role of clinicians in these interpretations is therefore important. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Introduction: Congenital central hypothyroidism (CCH) is a rare disorder that can be caused by X-linked mutations in the immunoglobulin superfamily member 1 (IGSF1) gene. Here, we describe four familial cases with a variable presentation due to a novel IGSF1 pathogenic variant. Case Presentation: In the index case, an investigation at birth of a suspected brain-lung-thyroid syndrome surprisingly revealed a central hypothyroidism. Next-generation sequencing uncovered a novel IGSF1 pathogenic variant: a hemizygous single base duplication (G) resulting in a premature stop codon (NM_001555.4: c.2485dup, p.Ala829Glyfs*15). Further family investigations revealed missed neonatal CCH for the older brother who presented with prolonged jaundice (thyroid stimulating hormone 3.06 mUI/L, FT4 9.4 pmol/L, FT3 4.2 pmol/L). It also led to the diagnosis of CCH at 11 months of age for the younger brother, whose thyroid function was considered normal at birth. Neuropsychological evaluations showed no cognitive impairment for the eldest two brothers, but a slightly reduced processing-speed index compared with the other parameters for the oldest. Furthermore, a maternal uncle was diagnosed with biochemical CCH at 34 years of age, despite having few symptoms, and a complete workup revealed prolactin deficiency and macroorchidism. Discussion: This report of a rare case of neonatal CCH caused by IGSF1 deficiency highlights the importance of recognizing the neonatal signs of hypothyroidism to diagnose CCH as early as possible. Our results also show the importance of performing family genetic screening if a pathogenic variant is identified, to properly monitor carriers as CCH may develop over time. We suggest that these families should be followed up in the long term to better understand the natural history of this syndrome and evaluate the need for hormone substitution.