Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome

Abstract

Biallelic mutations in RECQL4 gene, a caretaker of the genome, cause Rothmund-Thomson type-II syndrome (RTS-II) and confer increased cancer risk if they damage the helicase domain. We describe five families exemplifying clinical and allelic heterogeneity of RTS-II, and report the effect of pathogenic RECQL4 variants by in silico predictions and transcripts analyses. Complete phenotype of patients #39 and #42 whose affected siblings developed osteosarcoma correlates with their c.[1048_1049del], c.[1878+32_1878+55del] and c.[1568G>C;1573delT], c.[3021_3022del] variants which damage the helicase domain. Literature survey highlights enrichment of these variants affecting the helicase domain in patients with cancer outcome raising the issue of strict oncological surveillance. Conversely, patients #29 and #19 have a mild phenotype and carry, respectively, the unreported homozygous c.3265G>T and c.3054A>G variants, both sparing the helicase domain. Finally, despite matching several criteria for RTS clinical diagnosis, patient #38 is heterozygous for c.2412_2414del; no pathogenic CNVs out of those evidenced by high-resolution CGH-array, emerged as contributors to her phenotype.

Gastrointestinal Malignancy Presenting with a Virchow’s Node in a Patient with Rothmund-Thomson Syndrome

“…Rothmund-Thomson syndrome (RTS) is a rare disorder that presents in childhood with characteristic skin findings, short stature, and congenital skeletal malformations [ 1 ]. It was described by both German ophthalmologist Rothmund (1898) as well as British dermatologist Thomson (1936), and approximately 300 cases have been described in the published literature to date [ 1 , 2 ]. A subset of RTS patients also have a predisposition to sarcomas, skin cancers, and hematological malignancies [ 1 , 3 ].…”

“…It was described by both German ophthalmologist Rothmund (1898) as well as British dermatologist Thomson (1936), and approximately 300 cases have been described in the published literature to date [ 1 , 2 ]. A subset of RTS patients also have a predisposition to sarcomas, skin cancers, and hematological malignancies [ 1 , 3 ]. A single case of gastric carcinoma has been reported in the literature, dating back to 1975, which is the only other reported case of gastrointestinal malignancy in RTS [ 4 ].…”

“…RTS has been subdivided into two subgroups. RTS type II has been recognized as a genetically transmitted disorder of the RECQL4 gene, affecting the RECQL4 DNA helicase and thus leading to genomic instability [ 1 ]. Affected individuals characteristically have facial erythema, poikiloderma (altered skin pigmentation, atrophy, and telangiectasias), hyperkeratosis, small stature, and skeletal defects [ 3 ].…”

“…RTS type I is defined by the absence of RECQL4 mutations in the presence of the RTS phenotype; the genetic defect of these individuals is currently unknown. This subgroup of patients also differs from RTS type II as they do not appear to have an increased risk of malignancy [ 1 ]. However, patients with type I have an increased risk of bilateral juvenile cataracts [ 1 ].…”

“…This subgroup of patients also differs from RTS type II as they do not appear to have an increased risk of malignancy [ 1 ]. However, patients with type I have an increased risk of bilateral juvenile cataracts [ 1 ]. Patients with RTS are routinely managed by an interdisciplinary team and screened for skeletal abnormalities, cataracts, osteosarcoma, and skin cancer in childhood [ 3 ].…”