| Category | Item | Key details/statistics | Evidence/source (author year, journal) | URL | Notes/ontology suggestions (e.g., HPO/GO/UBERON/MAXO) |
|---|---|---|---|---|---|
| Disease information | Disease name | Rothmund–Thomson syndrome (RTS), a rare autosomal recessive genodermatosis with poikiloderma as the main hallmark | Martins 2023, *Frontiers in Aging* (pqac-00000001); Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005) | https://doi.org/10.3389/fragi.2023.1296409 ; https://doi.org/10.1186/1750-1172-5-2 | MONDO not confirmed in current snippets; HPO: Poikiloderma HP:0001003 |
| Disease information | Key identifiers | OMIM #268400; Martins review also cites OMIM #618625 alongside #268400 | Martins 2023, *Frontiers in Aging* (pqac-00000001); Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005) | https://doi.org/10.3389/fragi.2023.1296409 ; https://doi.org/10.1186/1750-1172-5-2 | Orphanet/MeSH/ICD not directly confirmed in available snippets |
| Disease information | Synonyms / related names | “Congenital poikiloderma” reported as an alternative name in case series; related RECQL4 phenotypic spectrum includes RAPADILINO and Baller-Gerold syndromes | Sánchez-Padilla 2022, *Boletín Médico del Hospital Infantil de México* (pqac-00000005, pqac-00000006); Martins 2023, *Frontiers in Aging* (pqac-00000027) | https://doi.org/10.24875/bmhim.21000013 ; https://doi.org/10.3389/fragi.2023.1296409 | HPO: Congenital poikiloderma conceptually overlaps HP:0001003 |
| Epidemiology | Prevalence / rarity | Prevalence unknown; ~300 reported cases in older literature, ~400 reported patients noted in 2018 review | Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005); Colombo 2018, *IJMS* (pqac-00000007) | https://doi.org/10.1186/1750-1172-5-2 ; https://doi.org/10.3390/ijms19041103 | Aggregated disease-level literature, not EHR-derived |
| Etiology / inheritance | Inheritance pattern | Autosomal recessive | Martins 2023, *Frontiers in Aging* (pqac-00000001); Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005) | https://doi.org/10.3389/fragi.2023.1296409 ; https://doi.org/10.1186/1750-1172-5-2 | HP:0000007 Autosomal recessive inheritance |
| Genetics / subtype | RTS type 2 | Biallelic **RECQL4** variants; classically associated with skeletal abnormalities and increased cancer susceptibility, especially osteosarcoma | Martins 2023, *Frontiers in Aging* (pqac-00000003); Zirn 2021, *Skin Health and Disease* (pqac-00000004) | https://doi.org/10.3389/fragi.2023.1296409 ; https://doi.org/10.1002/ski2.12 | Gene: RECQL4; GO suggestions: DNA replication, DNA repair |
| Genetics / subtype | RTS type 1 | Biallelic **ANAPC1** defects; juvenile cataracts emphasized; osteosarcoma risk not observed in reported cases | Zirn 2021, *Skin Health and Disease* (pqac-00000004); Martins 2023, *Frontiers in Aging* (pqac-00000025) | https://doi.org/10.1002/ski2.12 ; https://doi.org/10.3389/fragi.2023.1296409 | Gene: ANAPC1; ophthalmologic surveillance relevant |
| Genetics / heterogeneity | Updated gene list | RTS is now genetically heterogeneous: **RECQL4**, **ANAPC1**, **DNA2**, **CRIPT** reported in current evidence | Martins 2023, *Frontiers in Aging* (pqac-00000000, pqac-00000003, pqac-00000025, pqac-00000026) | https://doi.org/10.3389/fragi.2023.1296409 | Useful for multigene panels / WES / WGS |
| Genetics / prevalence | RECQL4 contribution | RECQL4 variants in ~60–65% of RTS patients in older reviews; Martins notes ~60% RECQL4-positive and ~40% RECQL4-negative historically | Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005); Martins 2023, *Frontiers in Aging* (pqac-00000003, pqac-00000025) | https://doi.org/10.1186/1750-1172-5-2 ; https://doi.org/10.3389/fragi.2023.1296409 | Supports tiered testing and unresolved-case exome/genome sequencing |
| Genetics / prevalence | ANAPC1 contribution | ANAPC1 mutations account for ~10% of RTS patients in Martins review | Martins 2023, *Frontiers in Aging* (pqac-00000003, pqac-00000025) | https://doi.org/10.3389/fragi.2023.1296409 | Important intronic variant may be missed by routine exome workflows |
| Phenotype | Poikiloderma / facial rash | Hallmark feature; rash typically begins between 3–10 months (Martins) or usually 3–6 months / within first year (Larizza), spreads from face to extremities and spares trunk | Martins 2023, *Frontiers in Aging* (pqac-00000001); Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005) | https://doi.org/10.3389/fragi.2023.1296409 ; https://doi.org/10.1186/1750-1172-5-2 | HPO: Poikiloderma HP:0001003; UBERON: skin of face / skin of upper limb / lower limb |
| Phenotype | Poikiloderma frequency by gene group | RECQL4 41/43; ANAPC1 11/11; CRIPT 4/4; DNA2 7/7 in Martins table | Martins 2023, *Frontiers in Aging* (pqac-00000000, pqac-00000026) | https://doi.org/10.3389/fragi.2023.1296409 | Cross-gene hallmark of RTS spectrum |
| Phenotype | Sparse hair / eyebrows / eyelashes | Highly prevalent; by gene group RECQL4 29/43, ANAPC1 10/11, CRIPT 5/5, DNA2 7/7 | Martins 2023, *Frontiers in Aging* (pqac-00000000, pqac-00000026) | https://doi.org/10.3389/fragi.2023.1296409 | HPO: Sparse scalp hair HP:0008070; Sparse eyebrow HP:0045075; Sparse eyelashes HP:0000653 |
| Phenotype | Short stature / growth failure | Common across RTS spectrum; RECQL4 34/43 with prenatal short stature reported, ANAPC1 7/11, CRIPT 6/6, DNA2 7/7 | Martins 2023, *Frontiers in Aging* (pqac-00000000, pqac-00000026) | https://doi.org/10.3389/fragi.2023.1296409 | HPO: Short stature HP:0004322; prenatal onset where applicable |
| Phenotype | Cataracts | Bilateral juvenile cataracts are cardinal in classic RTS descriptions; cataracts nearly exclusive to ANAPC1 and DNA2 groups in Martins table: ANAPC1 10/10 juvenile; DNA2 7/7, 6/7 congenital; RECQL4 0/26 in table | Martins 2023, *Frontiers in Aging* (pqac-00000025, pqac-00000026); Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005) | https://doi.org/10.3389/fragi.2023.1296409 ; https://doi.org/10.1186/1750-1172-5-2 | HPO: Cataract HP:0000518; juvenile cataract / congenital cataract subtypes |
| Phenotype | Skeletal abnormalities | Includes radial ray defects, patella hypoplasia/aplasia, osteopenia, irregular metaphyses, joint dislocations; RECQL4 group particularly prone to radial ray defects (14/40 in Martins table) | Martins 2023, *Frontiers in Aging* (pqac-00000025, pqac-00000026); Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005) | https://doi.org/10.3389/fragi.2023.1296409 ; https://doi.org/10.1186/1750-1172-5-2 | HPO: Radial ray defect HP:0004074; Osteopenia HP:0000938 |
| Phenotype | Neurodevelopment | Usually normal in classic RECQL4 RTS, but **CRIPT**-related RTS spectrum shows developmental delay/seizures and severe speech compromise in all six updated cases | Martins 2023, *Frontiers in Aging* (pqac-00000025, pqac-00000026) | https://doi.org/10.3389/fragi.2023.1296409 | HPO: Developmental delay HP:0001263; Seizure HP:0001250 |
| Cancer risk | Osteosarcoma | Estimated prevalence/risk ~30%; median age 11.5 years; only clearly observed in RECQL4 group in current cross-gene review | Martins 2023, *Frontiers in Aging* (pqac-00000003, pqac-00000026) | https://doi.org/10.3389/fragi.2023.1296409 | HPO/DO: osteosarcoma; UBERON: bone tissue |
| Cancer risk | Skin cancer | Estimated prevalence ~5%; includes squamous cell carcinoma, basal cell carcinoma, Bowen disease in reported literature | Martins 2023, *Frontiers in Aging* (pqac-00000003); Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005) | https://doi.org/10.3389/fragi.2023.1296409 ; https://doi.org/10.1186/1750-1172-5-2 | UBERON: skin; dermatologic surveillance concept |
| Cancer risk | RECQL4 genotype–cancer correlation | Variants damaging the helicase domain are enriched among patients with cancer outcome; strict oncologic surveillance recommended | Colombo 2018, *IJMS* (pqac-00000007) | https://doi.org/10.3390/ijms19041103 | Variant class/region may inform risk stratification |
| Risk factors | Heterozygous RECQL4 LOF and pediatric osteosarcoma | In 5,562 pediatric cancer patients, 24/5562 (0.43%) had RECQL4 LOF; 5/249 osteosarcoma cases (2.0%) carried LOF; enrichment vs gnomAD: OR 7.1, 95% CI 2.9–17, P=0.00087 | Maciaszek 2019, *Cold Spring Harbor Molecular Case Studies* (pqac-00000019, pqac-00000020, pqac-00000021) | https://doi.org/10.1101/mcs.a004218 | Germline susceptibility evidence; not diagnostic of RTS itself |
| Risk factors | Recurrent RECQL4 variant in cancer cohort | c.1573delT (p.Cys525Alafs) present in 9/24 (38%) RECQL4 LOF-positive pediatric cancer patients; enriched vs gnomAD (P=0.0024, OR 3.3, 95% CI 1.7–6.7) | Maciaszek 2019, *Cold Spring Harbor Molecular Case Studies* (pqac-00000019, pqac-00000023) | https://doi.org/10.1101/mcs.a004218 | Supports helicase-domain disruption as relevant to oncogenesis |
| Bone / morbidity | Fracture burden and low BMD | In 29 RTS individuals: fractures in 45% of children (9/20) and 67% of adults (6/9); among those with fracture, 67% (10/15) had ≥2 fractures; RECQL4 status RR 5.32 for fracture count (95% CI 2.27–15.68) | Cao 2017, *Human Molecular Genetics* (pqac-00000018, pqac-00000013) | https://doi.org/10.1093/hmg/ddx178 | HPO: Fracture HP:0002757; low bone density/osteopenia |
| Mechanism / pathophysiology | RECQL4 core biology | RECQL4 is a genome-maintenance helicase family member with roles in DNA replication and repair; RTS is a genome instability disorder | Martins 2023, *Frontiers in Aging* (pqac-00000001, pqac-00000027); Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005) | https://doi.org/10.3389/fragi.2023.1296409 ; https://doi.org/10.1186/1750-1172-5-2 | GO: DNA replication, DNA repair, genome stability |
| Mechanism / omics | RTS osteoblast metabolic signature | Patient-derived iPSC osteoblasts showed defective osteogenic differentiation, increased mitochondrial respiratory complex I function, increased OXPHOS/ATP, and sensitivity to complex I inhibitor IACS-010759 | Jewell 2021, *PLOS Genetics* (pqac-00000016, pqac-00000014) | https://doi.org/10.1371/journal.pgen.1009971 | GO: oxidative phosphorylation; cell type: osteoblast CL term suggestion |
| Recent development (2023) | DNA2-related RTS spectrum | 8 individuals (6 Brazilian probands + 2 Swiss/Portuguese siblings) with poikiloderma, congenital cataracts, severe growth failure; biallelic DNA2 variants with shared deep intronic founder-like allele; reduced DNA2 protein and impaired DSB repair | Filho 2023, *Journal of Medical Genetics* (pqac-00000029, pqac-00000028, pqac-00000031) | https://doi.org/10.1136/jmg-2022-109119 | HPO: congenital cataract, short stature, poikiloderma; GO: double-strand break repair |
| Recent development (2023) | CRIPT-related RTS-like syndrome | Biallelic CRIPT variants linked to RTS-like phenotype with neurologic involvement; in Martins summary, 6 individuals had developmental delay/severe speech compromise, frequent seizures, osteopenia/metaphyseal striations, sparse hair, pigmentary skin changes | Martins 2023, *Frontiers in Aging* (pqac-00000025, pqac-00000026) | https://doi.org/10.3389/fragi.2023.1296409 | Helps expand differential diagnosis for RECQL4-negative RTS presentations |
| Diagnostics | Clinical diagnosis | Poikiloderma plus additional findings used clinically; Martins cites diagnostic guidance requiring poikiloderma plus ≥2 features (e.g., cataracts, dental, GI, hyperkeratosis, cancer, nail/skeletal abnormalities, small stature, sparse hair) | Martins 2023, *Frontiers in Aging* (pqac-00000001) | https://doi.org/10.3389/fragi.2023.1296409 | HPO-driven phenotyping helpful |
| Diagnostics | Molecular testing strategy | RECQL4 sequencing remains central for RTS2; exome/WGS helped identify ANAPC1, DNA2, and CRIPT in RECQL4-negative cases; transcript analysis may be needed to detect intronic/splicing defects | Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005); Zirn 2021, *Skin Health and Disease* (pqac-00000004); Martins 2023, *Frontiers in Aging* (pqac-00000003, pqac-00000025) | https://doi.org/10.1186/1750-1172-5-2 ; https://doi.org/10.1002/ski2.12 ; https://doi.org/10.3389/fragi.2023.1296409 | Consider gene panels, WES/WGS, RNA studies |
| Management / implementation | Surveillance and multidisciplinary care | Cancer surveillance recommended for RTS2; subtype-specific care includes ophthalmologic surveillance for RTS1 and multidisciplinary long-term follow-up | Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000005); Zirn 2021, *Skin Health and Disease* (pqac-00000004) | https://doi.org/10.1186/1750-1172-5-2 ; https://doi.org/10.1002/ski2.12 | MAXO suggestions: ophthalmologic monitoring, cancer surveillance, genetic counseling |
| Management / implementation | Bone health measures | Baseline DXA at diagnosis, maintain fracture history, calcium/vitamin D per guidelines, bisphosphonates may be considered for multiple/serious fractures; avoid teriparatide because of osteosarcoma risk | Cao 2017, *Human Molecular Genetics* (pqac-00000013) | https://doi.org/10.1093/hmg/ddx178 | MAXO: bone density assessment, calcium supplementation, vitamin D supplementation |
| Clinical research | RTS-specific / related studies | NCT01304407 studied calcium absorption/bone mineral density in RTS (completed; 29 participants). NCT03898817 used patient-derived hiPS cells to study RecQ helicase disorders including RTS (terminated after planned inclusion). NCT03050268 includes RTS in a childhood cancer predisposition registry | ClinicalTrials.gov records (pqac-00000010, pqac-00000008, pqac-00000009, pqac-00000011) | https://clinicaltrials.gov/study/NCT01304407 ; https://clinicaltrials.gov/study/NCT03898817 ; https://clinicaltrials.gov/study/NCT03050268 | Real-world implementation of natural history, mechanism, and predisposition research |
| Prognosis | Osteosarcoma outcome | Five-year survival for osteosarcoma reported as ~60–70%, similar in RTS and non-RTS patients in older review | Larizza 2010, *Orphanet Journal of Rare Diseases* (pqac-00000002, pqac-00000005) | https://doi.org/10.1186/1750-1172-5-2 | Prognosis heavily influenced by cancer occurrence |


*Table: This table compiles key identifiers, genes, phenotypes, risks, and recent developments for Rothmund–Thomson syndrome using only currently available evidence snippets. It is useful as a compact, citation-linked reference for populating a disease knowledge base.*