ロスムンド・トムソン症候群

BACKGROUND: Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genodermatosis typically associated with mutations in the RECQL4 gene. However, some clinically diagnosed cases lack such variants, indicating genetic heterogeneity. ANAPC1, encoding a subunit of the anaphase-promoting complex (APC/C), has been implicated in RTS type 1, but its involvement in hair disorders remains unexplored. CASE PRESENTATION: We report the case of a 29-year-old man who presented with lifelong sparse, fine scalp hair, bilateral malar erythema, soft fingernails, and dental anomalies (malocclusion with multiple caries). Routine laboratory tests were unremarkable except for reduced vitamins B1, B2, B6, and B9 (November 2024). Whole-exome sequencing (approximately 20,000 genes) identified a variant of uncertain significance in ANAPC1 (NM_022662.4:c.4907T>C, p.Val1636Ala); no reportable variants were found in ACMG-recommended secondary findings genes. Combination therapy (trazodone 50 mg qn, tanshinone capsules 1 g qid, isotretinoin 20 mg qod, topical halcinonide 10 mL mixed with minoxidil 60 mL 1 mL bid, and multivitamins 2 tablets tid) was initiated in November 2024. After 6 months, follow-up trichoscopy (May 2025) showed increased hair density and shaft thickness. CONCLUSION: We describe a patient with a Rothmund-Thomson syndrome-like phenotype who carried a heterozygous ANAPC1 variant of uncertain significance (VUS) and showed trichoscopic improvement after combination therapy. This singular observation hints at a possible phenotypic expansion associated with ANAPC1 but cannot establish a new genotype-phenotype correlation. The clinical improvement underscores that symptomatic management can be beneficial in complex genodermatoses, even in the absence of a definitive molecular diagnosis. The pathogenicity of the ANAPC1 VUS remains unconfirmed, necessitating functional validation and segregation studies in future research.

RECQL4, a RecQ family helicase, is essential for DNA replication and genome stability. Mutations in RECQL4 cause severe human disorders yet we do not fully understand its functions, particularly regarding ATP-dependent helicase activity. To understand RECQL4's functions further, we performed a genome-wide forward genetic screen using a murine model harbouring patient-like RECQL4 mutations. We identify KLHDC3, a substrate-binding subunit of the Cullin-RING ligase E3 complex, loss as the most significant rescue allele. KLHDC3 loss restores proliferation and replication in RECQL4-deficient cells by stabilizing trace levels of a truncated RECQL4 fragment containing the N-terminal 480 amino acids, lacking the helicase and C-terminal regions. This RECQL4 fragment forms after Cre-mediated recombination of the Recql4fl allele and contains a neo-degron sequence specific for KLHDC3. Although this mechanism does not apply to human mutations, it demonstrates that minimal RECQL4 levels, without any ATPase domain/activity, are sufficient to support DNA replication. This demonstrates that RECQL4 is an essential and non-redundant regulator of DNA replication and cell viability and that this activity does not require its ATP-dependent helicase activity.

This case report presents two Ecuadorian patients with Rothmund-Thomson syndrome type 2 (RTS2), an autosomal recessive disorder, who share a RECQL4 variant previously identified in another Ecuadorian patient, supporting the recurrent presence of this variant in the Ecuador population. Additionally, in the Case 2 patient with a suspected compound heterozygosity, a second pathogenic variant was identified that had not been previously reported in Ecuador. These findings underscore the importance of molecular diagnosis for accurate classification of RTS2, informed risk assessment, and improved clinical care, particularly in underrepresented populations.

Osteosarcoma is a highly malignant bone tumor, and a subset of cases is closely associated with hereditary syndromes. These syndrome-related osteosarcomas exhibit unique clinical features, molecular mechanisms, and therapeutic challenges. This review summarizes the current understanding of specific types of syndrome-related osteosarcomas, including those associated with Rothmund-Thomson syndrome, Li-Fraumeni syndrome, secondary osteosarcoma in retinoblastoma survivors, Werner syndrome, and Bloom syndrome. These syndromes are typically characterized by specific gene mutations or chromosomal instability, significantly increasing the risk of osteosarcoma development. However, the rarity and heterogeneity of syndrome-related osteosarcomas pose significant challenges for diagnosis and treatment, including difficulties in early detection, incomplete elucidation of molecular mechanisms, and limitations of conventional therapeutic approaches. This article aims to systematically review the clinical characteristics, molecular mechanisms, and therapeutic challenges of these syndromes, providing a comprehensive reference for clinicians and directions for future research.