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Purpose: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families., Methods: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts., Results: In 1 family with 2 affected males, we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation., Conclusion: We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron-containing genes due to germline variation in ZRSR2., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: JBa is a clinical investigator for industry-sponsored clinical trials on the use of calcimimetics (cinacalcet and etelcalcetide) in pediatric dialysis (Amgen). JBa has received research grants from Amgen (RENOCLASTE study: ID-RCB 2017-A03241-52). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bernardor, Flammier, Salles, Amouroux, Castanet, Lienhardt, Martinerie, Damgov, Linglart and Bacchetta.)

The human adrenal cortex is a complex organ which is composed of various cell types including not only steroidogenic cells but also mesenchymal cells, immunocompetent cells and neurons. Intermingling of these diverse cell populations favors cell-to-cell communication processes involving local release of numerous bioactive signals such as biogenic amines, cytokines and neuropeptides. The resulting paracrine interactions play an important role in the regulation of adrenocortical cell functions both in physiological and pathophysiological conditions. Especially, recent evidence indicates that adrenocortical cell microenvironment is involved in the pathogenesis of adrenal disorders associated with corticosteroid excess. The paracrine factors involved in these intraadrenal regulatory mechanisms may thus represent valuable targets for future pharmacological treatments of adrenal diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sodium and water homeostasis are drastically modified at birth, in mammals, by the transition from aquatic life to terrestrial life. Accumulating evidence during the past ten years underscores the central role for the mineralocorticoid signaling pathway, in the fine regulation of this equilibrium, at this critical period of development. Interestingly, regarding evolution, while the mineralocorticoid receptor is expressed in fish, the appearance of its related ligand, aldosterone, coincides with terrestrial life, as it is first detected in lungfish and amphibian. Thus, aldosterone is likely one of the main hormones regulating the transition from an aquatic environment to an air environment. This review will focus on the different actors of the mineralocorticoid signaling pathway from aldosterone secretion in the adrenal gland, to mineralocorticoid receptor expression in the kidney, summarizing their regulation and roles throughout fetal and neonatal development, in the light of evolution., (Copyright © 2021 Elsevier B.V. All rights reserved.)