Anomalie du gène TCF2/HNF1b et troubles de la glycoregulation (Analyse préliminiare de la cohorte pédiatrique française)

Les anomalies du gène TCF2/HNF1b sont responsables du Renal Cysts And Diabetes syndrome (RCAD), MIM # 137920, qui comprend un diabète de type MODY-5. Il existe peu de données concernant l'apparition du diabète chez les enfants atteints d'une anomalie de ce gène. L'objectif de notre étude était d'effectuer la description de l'état de régulation de la glycémie des enfants inclus dans la cohorte HNF1b française et de rechercher des éléments prédictifs d'évolution vers un diabète MODY -5. Méthodes Analyse descriptive des données concernant la régulation de la glycémie issues de la cohorte HNF1b française dans laquelle sont inclus. depuis 2007, les enfants de 0 à 18 ans porteurs d' une anomalies du gène TCF2/HNF1b et dont le suivi clinico- biologique est effectué de manière prospective tous les ans. Résultats La cohorte regroupe 157 patients avec des données analysables pour 141 patients. Il s'agit d'une cohorte jeune. L'âge moyen est de 6.6 +- 5,1 ans avec une médiane d'âge à 5 ans et un 3ème quartile à 10 ans. II n'y a pas de patient diabétique. Un tiers des patients a une HbA1c supérieure à 5,5% donc anormale. 22,2 % des patients sont suspects d'insulinoresistance, définie par un indice HOM A supérieur à 2,25. 87,5 % des patients présentent une atrophie pancréatique. Conclusion Nous rapportons pour la première fois un état de pré-diabète chez certains enfants porteurs d'une anomalie du gène TCF2/HNF1b. Nous proposons d'approfondir les explorations de ce pré-diabète et d'envisager une prise en charge thérapeutique.MONTPELLIER-BU Médecine UPM (341722108) / SudocSudocFranceF

Pseudohypoaldostéronisme de type I

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Should We Really Screen for Genital Variants Before Birth?

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Diazoxide Causality Assessment of a Pericardial Effusion in a Child with Kabuki Syndrome

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A novel <i>TBX19</i> gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin

International audienceIsolated ACTH deficiency (IAD) is a life-threatening condition, particularly in the neonatal period, while a main consequence of undiagnosed isolated ACTH deficiency in survivors is cognitive impairment. TBX19 is involved in the differentiation and proliferation of corticotropic cells and TBX19 mutations are responsible for more than 60% of neonatal cases of IAD. We describe a new variant of the main TBX19 transcript (NM 005149.3, c.840del (p.(Glu280Asp fs*27)), classified as pathogenic, whose pathogenicity is assumed to be due to nonsense mediated decay leading to non-expression of T-box transcription factor TBX19. Moreover we summarize the TBX19 mutations published as individual cases since our last large cohort. Interestingly, this pathogenic variant was identified in four patients from three apparently unrelated families. Two of these families were consanguineous, and after investigations all of three were discovered to have roots in the same mountainous region of northern Morocco, suggesting a founder effect. Early diagnosis, timely treatment (hydrocortisone therapy) and preventive education allowed normal development, growth and quality of life in all patients

Off-label use of cinacalcet in pediatric primary hyperparathyroidism: A French multicenter experience

Background Cinacalcet is a calcimimetic approved in adults with primary hyperparathyroidism (PHPT). Few cases reports described its use in pediatric HPT, with challenges related to the risk of hypocalcemia, increased QT interval and drug interactions. In this study, we report the French experience in this setting. Methods We retrospectively analyzed data from 18 pediatric patients from 7 tertiary centers who received cinacalcet for PHPT. The results are presented as median (interquartile range). Results At a median age of 10.8 (2.0–14.4) years, 18 patients received cinacalcet for primary HPT ( N = 13 inactive CASR mutation, N = 1 CDC73 mutation, N = 1 multiple endocrine neoplasia type 1, N=3 unknown etiology). Cinacalcet was introduced at an estimated glomerular filtration rate (eGFR) of 120 (111–130) mL/min/1.73 m 2 , plasma calcium of 3.04 (2.96–3.14) mmol/L, plasma phosphate of 1.1 (1.0–1.3) mmol/L, age-standardized (z score) phosphate of −3.0 (−3.5;−1.9), total ALP of 212 (164–245) UI/L, 25-OHD of 37 (20–46) ng/L, age-standardized (z score) ALP of −2.4 (−3.7;−1.4), PTH of 75 (59–123) ng/L corresponding to 1.2 (1.0–2.3)-time the upper limit for normal (ULN). The starting daily dose of cinacalcet was 0.7 (0.6–1.0) mg/kg, with a maximum dose of 1.0 (0.9–1.4) mg/kg per day. With a follow-up of 2.2 (1.3–4.3) years on cinacalcet therapy, PTH and calcium significantly decreased to 37 (34–54) ng/L, corresponding to 0.8 (0.5–0.8) ULN ( p = 0.01), and 2.66 (2.55–2.90) mmol/L ( p = 0.002), respectively. In contrast, eGFR, 25-OHD, ALP and phosphate and urinary calcium levels remained stable. Nephrocalcinosis was not reported but one patient displayed nephrolithiasis. Cinacalcet was progressively withdrawn in three patients; no side effects were reported. Conclusions Cinacalcet in pediatric HPT can control hypercalcemia and PTH without significant side effects

Pycnodysostosis: Natural history and management guidelines from 27 French cases and a literature review

International audiencePycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis, facial features and an increased risk of fractures. The clinical heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow-up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = -3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non-invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow-up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow-up

Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population

International audienceAim: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.Methods: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.Results: Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, 'CaSR group'; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, 'cell proliferation group'; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in 'cell proliferation group' patients compared to those in the 'CaSR group' (P = 0.001 and 0.028, respectively).Conclusion: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients

Changes in the clinical management of 5α-reductase type 2 and 17β-hydroxysteroid dehydrogenase type 3 deficiencies in France

International audienceObjectives To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Methods Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 ( n = 31) or HSD17B3 ( n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994–2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Results Fifty-eight percent ( n = 30) patients were diagnosed during the perinatal period, 33% ( n = 17) during infancy, and 9% ( n = 5) during adolescence or adulthood. Over the studied period, the patients’ age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0–53.2) years for patients born before 2007 and 0.4 (0–9.3) years for those born in 2007 or later ( P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent ( n = 2) patients requested female-to-male reassignment during adulthood. Conclusion This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males

Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population

International audienceAim To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population. Methods Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018. Results Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, ‘CaSR group’; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1 , CDC73 , CDKN1B and RET genes, ‘cell proliferation group’; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups ( P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in ‘cell proliferation group’ patients compared to those in the ‘CaSR group’ ( P = 0.001 and 0.028, respectively). Conclusion Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients