先天異常症候群

INTRODUCTION: Patients affected by Turner syndrome (TS) suffer from bone fragility and a high risk of fractures. The health of bone microarchitecture has proven to be a very important element in reducing the risk of fractures. The present study aimed to describe bone characteristics of patients with TS and highlight clinical factors that can influence bone microarchitecture, evaluated by the trabecular bone score (TBS). METHODS: This single-centre retrospective study included 41 patients with TS who attended the Endocrinology Day Hospital of the CTO Hospital of Rome between 2016 and 2024. Anthropometric, clinical, and densitometric data were collected and analysed using unadjusted univariate models, age- and body mass index-adjusted models, and multivariate analysis to investigate their effects on TBS. RESULTS: There was a positive association between TBS and duration of estrogen replacement therapy (ERT). Patients who were constantly treated with ERT showed higher bone mineral density (BMD) at the lumbar spine and femoral neck (p=0.026 and p=0.040, respectively) and TBS (p=0.031). The presence of metabolic diseases appeared to have a negative influence on TBS (p=0.034). DISCUSSION: Regular ERT and longer treatment duration appear to be the most important factors to significantly improve BMD and TBS levels in patients with TS. On the contrary, diagnosis of metabolic diseases significantly affect bone microarchitecture. CONCLUSION: Healthcare providers should pay particular attention to timely ERT and the prevention of metabolic complications, since these are the main factors that appear to improve bone architecture in this specific population.

BACKGROUND: Baker-Gordon syndrome (BGS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in SYT1, which encodes synaptotagmin-1, a key Ca2⁺ sensor for synaptic vesicle exocytosis. CASE PRESENTATION: We describe a 13-month-old Chinese boy who presented with global developmental delay, axial hypotonia, stereotypic hand-flapping movements, limited vocalization, and mild facial dysmorphism. Brain magnetic resonance imaging revealed a simplified gyral pattern involving the frontal and parietal lobes. Trio-based whole-exome sequencing with read-depth copy-number variant (CNV) analysis identified a novel de novo heterozygous deletion spanning exons 6-8 of SYT1, which was subsequently confirmed by quantitative PCR. CONCLUSION: This study broadens the mutational spectrum of BGS and provides further evidence that intragenic multi-exon deletions affecting key functional domains may represent an alternative pathogenic mechanism in addition to the predominantly reported missense variants. Our findings also highlight the value of exon-level CNV analysis in the genetic diagnosis of neurodevelopmental disorders.

BACKGROUND: Charcot-Marie-Tooth disease 1A (CMT1A) and Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS)/Replication Factor Complex subunit 1 (RFC1)-related disease affect large nerve fibers, but small fiber dysfunction may contribute to pain and dysautonomia. We applied a multimodal protocol, including potentials elicited by a micropatterned electrode targeting intraepidermal nerve endings, to characterize small fiber involvement. METHODS: In this cross-sectional study, healthy controls (HC) and patients with CMT1A or RFC1 disease underwent neurologic examination, autonomic assessment with the composite autonomic symptom score-31 (COMPASS-31) and compound autonomic dysfunction test (CADT), electrochemical skin conductance (ESC), nociceptive evoked potentials (NEPs), pain-related evoked potentials (PREPs), somatosensory evoked potentials (SEPs), and skin biopsy. RESULTS: Twenty-one patients with CMT1A, 16 with RFC1 disease, and 21 HC were included. Neuropathic pain occurred in 33% of CMT1A and 81% of RFC1 patients. Dysautonomia was prominent in RFC1 disease, with abnormal CADT scores in 94%, COMPASS-31 scores of 7-46, and abnormal ESC in 63%, compared with 24% in CMT1A. N40 NEP latencies were prolonged in both patient groups versus HC (p<0.001), with absent responses in 33% and 44%, respectively. PREPs showed prolonged N2 latencies in CMT1A (p=0.003), with absent N2 responses in 57%; in RFC1 disease, N2 responses were absent in 50%. Skin biopsy showed length-dependent intraepidermal nerve fiber density loss in CMT1A and severe non-length-dependent epidermal denervation in RFC1 disease. DISCUSSION: Multimodal assessment integrating ESC, NEPs, PREPs, and skin biopsy identifies distinct Aδ- and C-fiber dysfunction patterns in CMT1A and RFC1 disease and may support phenotyping and small-fiber biomarker development in peripheral neuropathies.

UNLABELLED: To derive age- and sex-specific serum creatinine centile curves for children and adolescents with Down syndrome (DS) and compare them with DS-specific references. This retrospective reference-interval study included cytogenetically confirmed, post-neonatal individuals with DS followed at a tertiary center in Türkiye from 2015 to 2025. Individuals with kidney/urinary disease or other conditions expected to affect creatinine distribution were excluded. Kinetic Jaffe creatinine measurements were modeled separately by sex using Generalized Additive Models for Location, Scale, and Shape (GAMLSS), with subject-level bootstrap confidence intervals. Derived centiles were compared descriptively with published DS-specific references. The analytic cohort included 523 children and adolescents contributing 2172 creatinine measurements. Serum creatinine increased nonlinearly with age in both sexes, with progressive sex separation during adolescence. The 97.5th centile increased from 0.44 mg/dL (39 μmol/L) in early infancy to 1.32 mg/dL (117 μmol/L) at 17 to 18 years in boys, and from 0.42 mg/dL (37 μmol/L) to 1.01 mg/dL (89 μmol/L) in girls. Compared with previous DS-specific cohorts, the curves were closely aligned with French GAMLSS-derived centiles during childhood, while upper-centile values were higher than Japanese age-banded references, most notably in adolescent boys (maximum difference, 0.21 mg/dL at 16 to < 17 years). CONCLUSION: These DS-specific centiles support age- and sex-adapted interpretation of serum creatinine. Differences from previous DS-specific references suggest that creatinine centiles may vary by cohort, anthropometry, assay method, and modeling approach. WHAT IS KNOWN: • Children with Down syndrome have distinct growth and body-composition patterns and increased kidney and urinary tract morbidity, supporting syndrome-specific interpretation of serum creatinine. • Down syndrome-specific pediatric creatinine data remain limited to a few cohorts. WHAT IS NEW: • This study provides age- and sex-specific serum creatinine centile curves from the post-neonatal period to < 18 years. • The curves show nonlinear age-related changes, increasing sex separation during adolescence, and between-cohort variation compared with previous references.

RUNX2 (Runt-related transcription factor 2) is a master regulator of osteogenesis, and its genetic mutations are associated with ~65% cases of cleidocranial dysplasia (CCD), an autosomal dominant abnormal bone development disorder in humans with defective intramembranous bone formation. However, how these mutations affect bone formation remains to be investigated. Here, we report that RUNX2 interacts with the F-box protein JFK and is destabilized by the SKP1-CUL1-JFK E3 ubiquitin ligase complex (SCFJFK). We find that several CCD-associated mutations of RUNX2 acquire an increased affinity toward SCFJFK thus an accelerated proteasomal degradation. We demonstrate that SCFJFK-mediated RUNX2 degradation suppresses osteoblast differentiation. Consistently, Jfk-null mice exhibit increased trabecular bone volume and bone mineral density and are resistant to Runx2 haploinsufficiency-induced CCD-like syndrome. Interestingly, RUNX2 binds to the JFK promoter and represses its transcription, establishing a feedback loop to promote osteoblast differentiation, and remarkably, the CCD-associated RUNX2 mutants also display an impaired transcription repression of JFK. Our study demonstrates SCFJFK as an E3 ligase for RUNX2 and uncovers a feedback regulatory loop between SCFJFK and RUNX2 that is implemented in bone development and implicated in CCD, supporting the pursuit of JFK as a potential target to ameliorate CCD-like syndrome.