American Journal of Medical Genetics Part A最新文献

Vosoritide, a C-type natriuretic peptide analogue that inhibits FGFR3 signaling, is approved for the treatment of achondroplasia (ACH) from birth in Japan, Australia, and the United States; however, data on neonatal use remain limited. We report two infants with genetically confirmed ACH who received daily subcutaneous vosoritide starting on postnatal days 8 and 9, representing the earliest initiation reported to date. Both patients tolerated treatment in the short term without serious adverse events during inpatient or outpatient monitoring. Despite early initiation, serial magnetic resonance imaging demonstrated progressive foramen magnum stenosis during infancy, and both patients required decompression surgery at 9 and 5 months of age, respectively, consistent with the known natural history of ACH, with an uncomplicated postoperative course in both cases. Growth trajectories, assessed by growth velocity (GV), were generally above the ACH-specific reference medians at comparable ages, while the characteristic slowing of GV during infancy was preserved. These observations are descriptive and hypothesis-generating only and do not support changes in current clinical practice. Further data are required to clarify the potential benefits and limitations of initiating vosoritide therapy during the neonatal period.

Sotos syndrome is an overgrowth disorder caused by nuclear receptor binding SET domain protein 1 (NSD1) haploinsufficiency, whereas reciprocal 5q35.2q35.3 microduplication produces a reversed phenotype with growth retardation, microcephaly, delayed bone age, and neurodevelopmental delay. We describe a 43-month-old Korean girl born at 36 + 1 weeks with intrauterine growth restriction (birth weight 2200 g, length 46 cm, occipitofrontal circumference 42 cm). At presentation, all growth parameters were below the 10th percentile, with dysmorphic features including epicanthal folds, telecanthus, and a wide nasal bridge. She walked at 14 months but had an approximately 25-month language delay. Chromosomal microarray revealed a de novo 1.8 Mb duplication at 5q35.2q35.3 encompassing NSD1, classified as pathogenic (triplosensitivity score 3). A growth hormone (GH) stimulation test confirmed deficiency (peak GH 9.87 and 6.42 ng/mL). Recombinant human GH therapy (0.033 mg/kg/day) improved growth to the 5-10th percentile after 6 months. This is the first reported Korean case of 5q35.2q35.3 duplication with reversed Sotos phenotype and GH deficiency, which expands the endocrine spectrum of the disorder and underscores the need for early genetic testing and endocrine evaluation. [Correction added after first online publication on 23 March 2026: The dosage of rGH therapy was corrected from "0.1 IU/kg/day" to "0.033 mg/kg/day.].

Interstitial deletions involving 3q27.1 define a distinct microdeletion syndrome characterized by prenatal-onset growth restriction, postnatal microcephaly, hypotonia, intellectual disability, and distinctive craniofacial features. While AP2M1 haploinsufficiency has been proposed as the primary driver of this phenotype, the full spectrum of dosage-sensitive genes within the locus remains unclear. Here, we report a patient with a de novo heterozygous 3q27.1 microdeletion and delineate a refined minimal smallest region of overlap (SRO) of approximately 189 kb, representing the narrowest critical interval associated with the 3q27.1 microdeletion phenotype to date. Chromosomal microarray and exome-based CNV analysis confirmed the deletion, which encompasses PSMD2, EIF4G1, and POLR2H but excludes AP2M1 and DVL3. The patient exhibited severe intrauterine growth restriction, microcephaly, global developmental delay, and mild dysmorphism, consistent with the established 3q27.1 phenotype. PSMD2 encodes a non-ATPase regulatory subunit of the 26S proteasome, and its loss may disrupt proteasome-mediated protein turnover and neuronal homeostasis. Comparison with previously published cases and an overlapping ClinVar variant (ID: 60129) with similar features supports the pathogenicity of this minimal deletion. Our findings refine the 3q27.1 critical region, propose PSMD2 haploinsufficiency as a likely molecular mechanism underlying growth and neurodevelopmental defects. Further cases and functional studies are needed to confirm PSMD2 causality and clarify the proteasome-related mechanisms underlying 3q27.1 microdeletion syndrome.

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations. Diagnosis is usually straightforward in symptomatic patients, but can be challenging in children and adolescents with mild liver disease, borderline urinary copper excretion, or inconclusive genetic findings. Reduced penetrance of several ATP7B variants and the limited sensitivity of conventional biomarkers further complicate diagnostic assessment. Relative exchangeable copper (REC) has recently emerged as a highly accurate biomarker capable of distinguishing WD from other liver diseases and differentiating homozygotes from heterozygotes. We report a 14-year-old girl presenting with transient neurological symptoms and normal biochemical liver tests, except for markedly low serum ceruloplasmin. Standard urinary copper excretion was normal and only mildly increased after penicillamine challenge. Whole-genome sequencing revealed compound heterozygosity for the pathogenic ATP7B variant p.Gly626Ala and the variant of uncertain significance p.Met665Ile. Despite the inconclusive genotype, REC was markedly elevated (17.04%), indicating early impairment of copper homeostasis. Because REC is not yet validated for diagnosis in asymptomatic children, liver biopsy was performed, demonstrating steatosis and a hepatic copper content of 250 μg/g dry weight, confirming WD. This case illustrates the potential of REC as a sensitive metabolic biomarker able to detect early ATP7B dysfunction and to support diagnosis in patients with borderline biochemical findings or hypomorphic variants such as p.Met665Ile.

To describe clinical and laboratory characteristics, emphasizing the evolution of patients with hepatic glycogen storage diseases (GSDs) followed in Brazilian reference centers. Multicenter, retrospective study involving 13 centers, using RedCap platform. 132 patients were included: 63 (47.8%) GSD type I (56 Ia, 7 Ib), 13 (9.8%) with type III (12 IIIa, 1 IIIb), 1 (0.8%) type IV, 6 (4.5%) type VI, and 49 (37.1%) with type IX (28 IXa, 7 IXb, and 14 IXc). Type I patients presented earlier (4 months) and had more episodes of hypoglycemia at clinical presentation (p < 0.001). Anthropometric data at admission revealed impaired growth, with a tendency toward short stature across the groups (median -2.06, -1.89, and -1.96 among type I, III, and IX respectively). The median body mass index (BMI) z-scores at admission for all three types were above +1. Only patients with type IX demonstrated significant improvement in height (p = 0.007) and BMI (p = 0.020) z-scores during follow-up. Regarding laboratory tests, significant decreases were observed in total cholesterol, triglycerides, venous lactate and aminotransferases in patients with types I and IX. Hepatic GSDs are heterogeneous diseases. There is a significant height impairment with a troublesome trend to overweight and obesity, especially in type I. Although there is improvement in aminotransferases, cholesterol, and triglycerides with follow-up, adherence to treatment remains a challenge.

Down syndrome (DS) is the most common chromosomal abnormality associated with intellectual disabilities. Many metabolic issues begin in childhood, and children without DS are reported to have a high prevalence of metabolic syndrome (MS) according to various studies. However, our understanding of the risk of MS in children with DS is limited. A cross-sectional study assessed the prevalence of MS in DS children aged 10-18 during 2022-2024. Demographic details and anthropometric measurements were recorded for all participants. Fasting blood samples were collected for blood glucose, insulin, and lipid profile analysis. The modified NCEP-ATP III criteria were used to classify the MS. We also evaluated insulin resistance (IR) using HOMA-IR and body adiposity patterns with a DEXA scan in DS children aged 6-18. Seventy-six children aged 10-18 and 38 aged 6-9 were enrolled. The prevalence of MS was 18% in our cohort. Dyslipidemia (high triglycerides and low HDL) was observed in 21% and 15.8% of children aged 6-9 and 10-18, respectively. IR was observed in 27.6% and 7.8% of children aged 10-18 and 6-9, respectively. IR was positively correlated with BMI, whereas no correlation was observed with MS or dyslipidemia. Total body fat mass was positively correlated with MS. Our study observed a higher prevalence (18.0%) of MS than age-matched general population studies (pooled prevalence: 5.0%). Additionally, we observed a high prevalence of dyslipidemia and IR from 6 years of age. The results indicate the need to review the management guidelines and consider incorporating metabolic workups.

Waardenburg syndrome (WS) is a genetically heterogenous condition characterized by variable clinical features including congenital sensorineural hearing loss, pigmentation differences, dysmorphic features including dystopia canthorum, and other manifestations. Pathogenic variants in WS genes, including PAX3, MITF, SOX10, EDNRB, EDN3, and KITLG, account for approximately 3% of congenital hearing loss cases. The genetic heterogeneity, variable expressivity, and different subtypes of WS have made diagnosis challenging. Recent literature suggests that W-index measurements evaluating for dystopia canthorum may not accurately differentiate between WS Types 1 and 2. This retrospective chart review investigated genotype-phenotype correlations in patients with WS at the Children's Hospital of Philadelphia. This study included 56 patients with a clinical or genetic diagnosis of WS. In addition, data was collected from 1744 patients with hearing loss and W-index measurements. Phenotypic characteristics were recorded for all 56 patients and an additional 230 patients with an elevated W-index (> 1.95) lacking a diagnosis of WS to determine the predictiveness of the W-index for WS. This study updates genotype-phenotype correlations in WS, characterizes novel variants, investigates the utility and predictiveness of W-index values in children with hearing loss, and provides rationale for increasing the W-index cutoff for dystopia canthorum to reduce negative testing results.

Complex chromosomal rearrangements (CCRs) are structural variants involving multiple breakpoints. Among these, intrachromosomal balanced CCRs containing inversions pose significant diagnostic and interpretative challenges, as conventional cytogenetic methods including G-banded karyotype, FISH, and chromosomal microarray lack the resolution needed to determine their structural complexity. Paracentric inversions are traditionally associated with a negligible risk of a viable unbalanced offspring. Here, we describe a familial intrachromosomal rearrangement comprising a complex paracentric inversion of chromosome 6q, transmitted across multiple generations, that resulted in five affected children with recombinant chromosomes harboring reciprocal interstitial gains and losses on 6q. High-resolution optical genome mapping revealed a ~75 Mb parental balanced CCR, formed by multiple sequential paracentric inversions that contain a single ~13 Mb correctly oriented segment. Bias meiotic recombination between homologous chromosomes 6 within this segment is responsible for recurrent unbalanced products resembling recombinant chromosomes typically associated with pericentric inversions. These findings challenge the prevailing assumption that paracentric inversions rarely result in viable recombinant chromosomes and demonstrate how complex chromosomal architecture can directly influence meiotic behavior and reproductive outcomes. Our study underscores the importance of high-resolution genomic technologies for accurate diagnosis, interpretation of a molecular mechanism, and reproductive risk assessment in carriers of CCR.

Pulmonary arteriovenous malformations (PAVMs) are rare vascular anomalies most commonly seen in hereditary hemorrhagic telangiectasia (HHT), a condition associated with mutations in ENG, ACVRL1, SMAD4, or GDF2. In contrast, BMPR2 variants are well-established in heritable pulmonary arterial hypertension (PAH), but their relationship to PAVMs remains poorly understood. We report the case of a 41-year-old woman with an incidentally discovered PAVM, initially treated with embolization and subsequent surgical resection. She remained asymptomatic for several years until progressive exertional dyspnea led to a diagnosis of severe precapillary PAH. Genetic testing identified a heterozygous BMPR2 splice-site variant (c.967 + 5G>A), previously reported in a PAH cohort but currently classified as a variant of uncertain significance. This report is notable for the delayed evolution from isolated PAVM to PAH in the context of a BMPR2 variant, raising the possibility of a mechanistic link outside the canonical HHT pathway. We review published reports of BMPR2-associated PAVMs, some of which include subtle HHT-like features, such as mucocutaneous telangiectases and epistaxis, despite negative testing for classical HHT genes. These observations suggest a potential phenocopy vascular syndrome driven by disruption of the shared bone morphogenetic protein 9 (BMP9)-ALK1 signaling axis. We also discuss the implications of sotatercept, a transforming growth factor-beta (TGF-β) superfamily ligand trap, which in this case was associated with symptomatic improvement and stable shunt burden. These findings contribute to the emerging recognition of atypical vascular phenotypes in BMPR2 variant carriers, particularly those presenting with PAVMs in the absence of HHT. It highlights the importance of considering genetic testing in isolated AVM presentations, as well as the need for longitudinal surveillance and mechanistic investigation into overlapping TGF-β/BMP signaling disorders.

Evaluate the application efficacy of trio exome sequencing (Trio-ES) in prenatal families with a history of developmental delay/intellectual disability (DD/ID). This cohort study enrolled prenatal families with a family history of DD/ID from a single center between January 2020 and May 2025. We included 104 prenatal families that had excluded copy number variation abnormalities but had not undergone single nucleotide variant testing. Based on family history, these families were divided into two groups: those with a history of DD/ID births but phenotypically normal parents (lacking proband samples), and those without a history of DD/ID births but with one or both parents having ID. The overall positive rate of prenatal Trio-ES among 104 families with a history of DD/ID was 21.15% (22/104). Among 81 families with a history of DD/ID births but phenotypically normal parents, the positive rate was 13.58% (11/81), including 7.41% (6/81) affected fetuses and 6.17% (5/81) only parents as carriers, both primarily exhibiting a recessive inheritance pattern. Additionally, the positive rate in non-syndromic DD/ID families was 11.54% (6/52), while it reached 17.24% (5/29) in syndromic DD/ID families (associated with epilepsy, dystonia, hearing impairment, abnormal head circumference, etc.). Among 23 families without a history of DD/ID births but with one or both parents having ID, the positive rate significantly increased to 47.83% (11/23), primarily driven by dominant variants. This study represents the first focused evaluation of the clinical utility of Trio-ES in prenatal families with a history of DD/ID when proband samples are unavailable. We recommend actively employing Trio-ES for prenatal genetic evaluation in such families, particularly those presenting with a syndromic phenotype.