Rothmund-Thomson syndrome
RTS; congenital poikiloderma; poikiloderma congenitale; "type 1" RTS (no RECQL4 mutation, no osteosarcoma) and "type 2" RTS (RECQL4-positive, osteosarcoma risk)
Rothmund-Thomson syndrome is a rare autosomal recessive RecQ-helicase deficiency syndrome — a sister disorder to Bloom and dyskeratosis congenita in the broader family of helicase / DNA repair / telomere biology disorders. The cardinal feature is a striking poikiloderma — atrophy, telangiectasias and reticulated hyperpigmentation / hypopigmentation — that develops on the face in infancy and progressively extends to the buttocks and extensor extremities, frequently sparing the trunk. The genetic defect is a biallelic loss-of-function mutation of RECQL4 on chromosome 8q24.3 in "type 2" RTS, defining a substantially elevated lifetime risk of osteosarcoma (~30%) and cutaneous squamous cell / basal cell carcinoma. "Type 1" RTS without RECQL4 mutation has poikiloderma and juvenile cataracts but no osteosarcoma risk. RECQL4 mutations also cause RAPADILINO and Baller-Gerold syndromes, which overlap clinically.
Genetics
- Biallelic loss-of-function mutations of RECQL4 on chromosome 8q24.3 in "type 2" RTS — encodes the RECQL4 helicase, a member of the RecQ family essential for DNA replication initiation, mitochondrial function and end-resection during DNA repair.
- Autosomal recessive.
- "Type 1" RTS — no RECQL4 mutation; clinically distinguished by absence of osteosarcoma risk and presence of juvenile cataracts; underlying gene unknown.
- RECQL4 mutations also cause:
- RAPADILINO syndrome — Radial defects, Patellar aplasia/hypoplasia, cleft Palate, Diarrhoea, Dislocated joints, Little stature, Limb malformations and slender Nose / Normal intelligence.
- Baller-Gerold syndrome — craniosynostosis + radial defects.
Clinical features
- Poikiloderma — develops on the face in the first year of life, then extends to the buttocks and extensor extremities; combination of atrophy, telangiectasias and reticulated hyperpigmentation / hypopigmentation; spares the trunk and chest in many patients (a clinical clue distinguishing from generalised photosensitive erythemas).
- Photosensitivity — present in infancy; sun-protection from early life essential.
- Skeletal abnormalities — short stature, radial-ray defects (absent / hypoplastic thumb), patellar abnormalities, brachymelia, congenital dislocations.
- Hair — sparse hair / alopecia; absent / sparse eyebrows and eyelashes; nail dystrophy.
- Dental — hypodontia, microdontia, malformed teeth.
- Eye — juvenile cataracts (more in "type 1" RTS).
- GI / endocrine — short stature, hypogonadism, diabetes.
- Cancer — see next section.
Cancer risk
- Osteosarcoma — ~30% lifetime risk (RECQL4-positive type 2 RTS only); median age at diagnosis 11–14 years (substantially younger than the sporadic peak); often multifocal at presentation.
- Cutaneous squamous cell carcinoma — ~5% lifetime risk; in poikilodermatous skin, particularly photo-exposed sites; younger age of onset than sporadic.
- Cutaneous basal cell carcinoma — increased risk.
- Lymphoma, myelodysplastic syndrome, AML — modestly increased risk.
Surveillance & management
- Multidisciplinary care — paediatric oncology, dermatology, ophthalmology, orthopaedics, ENT, clinical genetics; lifelong.
- Skin:
- Lifelong rigorous photoprotection (broad-spectrum SPF 50+, sun-protective clothing).
- Annual full skin examination; biopsy any new or changing lesion.
- Skeletal / osteosarcoma surveillance — clinical examination for bone pain or limp; some centres use plain radiography or whole-body MRI from age 5 in RECQL4-positive type 2 RTS, although evidence base is limited.
- Eye — annual ophthalmology from infancy; cataract surgery as needed.
- Dental — paediatric dentistry from infancy.
- Cancer treatment — markedly enhanced normal-tissue radiosensitivity and chemotherapy toxicity due to defective DNA repair; radiotherapy and DNA-damaging chemotherapy used cautiously.
- Genetic counselling and cascade testing of relatives.
References
- Wang LL et al. Rothmund-Thomson syndrome — clinical and molecular review. Am J Med Genet C Semin Med Genet; 2009.
- Larizza L et al. Rothmund-Thomson syndrome. Orphanet J Rare Dis; 2010.
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