Rothmund-Thomson Syndrome Revisited: Expanding the Genotypic Spectrum, Deciphering RECQL4-Related Pathomechanisms, And Redefining Long-Term Surveillance Strategies for An Underrecognized Genodermatosis

Abstract

Rothmund-Thomson syndrome (RTS) represents a paradigm of the intricate intersection between dermatologic phenomics, genomic instability, and oncologic predisposition. This comprehensive review synthesizes current knowledge regarding this ultra-rare autosomal recessive genodermatosis, which classically manifests with the pathognomonic triad of poikiloderma, juvenile cataracts, and skeletal dysplasias, while conferring a substantially elevated lifetime risk for osteosarcoma and cutaneous malignancies. Over the past decade, significant nosological refinement has emerged from the elucidation of biallelic pathogenic variants in RECQL4 and ANAPC1 as the primary molecular etiologies underlying RTS type 2 and type 1, respectively. However, the recent identification of DNA2 and CRIPT variants in affected individuals without identifiable alterations in the canonical genes has further unraveled the genetic heterogeneity of this condition, challenging traditional classification paradigms and expanding the continuum of RECQL4-related disorders. We critically examine the evolving landscape of RTS molecular diagnostics, emphasizing the genotype-phenotype correlations that distinguish RECQL4-associated multisystemic involvement—characterized by radial ray defects, patellar hypoplasia, and a striking predisposition to osteosarcoma—from the ANAPC1-related subtype wherein cataracts predominate without malignant transformation. The role of RECQL4 as a cornerstone of genomic maintenance through its participation in replication fork stabilization, double-strand break repair, and telomere homeostasis is explored in depth, providing mechanistic insights into the cellular fragility that underlies the premature aging phenotype and neoplastic progression. Current evidence regarding surveillance protocols, including the contentious role of routine imaging for osteosarcoma screening and the utility of pulsed dye laser therapy for telangiectatic lesions, is critically appraised. Furthermore, we highlight emerging therapeutic avenues, including the potential for targeted DNA damage response modulation and the importance of genotype-informed cancer risk stratification. By integrating the most recent case series, molecular discoveries, and longitudinal outcome data, this review aims to provide clinicians with a practical framework for early recognition, diagnostic confirmation, and multidisciplinary management of this often-elusive syndrome, while identifying critical knowledge gaps that warrant future investigation.