Random Dermatology MCQ - Rothmund Thomson Syndrome

A 3-year-old child develops a persistent, reticulated, red rash on the cheeks that later spreads to the extremities, eventually evolving into areas of poikiloderma (atrophy, telangiectasias, and hypo- and hyperpigmentation). The child has sparse hair, short stature, and bilateral cataracts. What is the most likely genetic defect and the most significant long-term oncologic risk associated with this syndrome?

A. Mutation in the BLM gene (RecQL3 helicase); high risk of osteosarcoma and skin cancer.
B. Mutation in the RECQL4 gene (RecQL4 helicase); high risk of osteosarcoma and skin cancer (SCC).
C. Mutation in the WRN gene (RecQL2 helicase); high risk of sarcomas and premature aging.
D. Mutation in the LMNA gene; high risk of cardiomyopathy and muscular dystrophy.
E. Mutation in the FBN1 gene; high risk of aortic dissection.

Correct Answer: B. Mutation in the RECQL4 gene (RecQL4 helicase); high risk of osteosarcoma and skin cancer (SCC).

Answer and Explanation

The correct answer is B. This question describes the classic presentation of Rothmund-Thomson syndrome (RTS) Type II. The key clues are the early onset of the characteristic poikilodermatous rash (starting on face and spreading), associated with short stature, sparse hair (scalp, eyebrows, eyelashes), and juvenile cataracts. The most common genetic cause, associated with the highest cancer risk, is biallelic mutations in the RECQL4 gene, which encodes a DNA helicase involved in genome stability. Patients with RECQL4 mutations have a significantly increased risk of osteosarcoma (most common malignancy) and squamous cell carcinoma (SCC) of the skin.

Why the Other Options are Incorrect:

• A. Mutation in the BLM gene (RecQL3 helicase): This causes Bloom syndrome, characterized by growth deficiency, sun-sensitive facial rash, and a high risk of various cancers (leukemia, lymphoma, GI cancers), but not poikiloderma or cataracts. The rash in Bloom is erythematous and telangiectatic, not truly poikilodermatous.

• C. Mutation in the WRN gene (RecQL2 helicase): This causes Werner syndrome, a progeroid disorder of young adults, featuring premature aging, scleroderma-like skin, and increased cancer risk, not a childhood poikiloderma.

• D. Mutation in the LMNA gene: This causes a spectrum of disorders including Hutchinson-Gilford progeria (severe premature aging in children) and other laminopathies, not the specific triad of poikiloderma, cataracts, and skeletal anomalies seen in RTS.

• E. Mutation in the FBN1 gene: This causes Marfan syndrome, characterized by tall stature, ectopia lentis, and aortic dilatation, none of which are present here.

Additional High-Yield Information for Exams:

• Clinical Features (RTS Type II - RECQL4-associated):

  • Skin: The poikiloderma typically begins between 3-6 months of age as an erythematous, edematous rash on the cheeks, spreading to extremities. It evolves into the classic atrophic, telangiectatic, and mottled pigmented patches.

  • Hair/Eyes: Sparse or absent eyelashes/eyebrows, alopecia. Juvenile bilateral cataracts develop in approximately 50% of patients.

  • Skeletal: Short stature, radial ray defects (hypoplastic thumbs), osteopenia, and predisposition to osteosarcoma.

• Genetics: Autosomal recessive. Two types:

  • RTS Type I: Poikiloderma, cataracts, no RECQL4 mutation, lower cancer risk.

  • RTS Type II: Poikiloderma, RECQL4 mutations, high risk of osteosarcoma and SCC.

• Differential Diagnosis: Other childhood poikiloderma syndromes:

  • Dyskeratosis Congenita: Features poikiloderma, nail dystrophy, oral leukoplakia, and bone marrow failure (pancytopenia).

  • Hereditary Sclerosing Poikiloderma (Weary-Kindler): Poikiloderma with sclerotic bands.

  • Bloom Syndrome: As above.

• Associated Conditions & Prognosis:

  • Osteosarcoma: The most common malignancy, with a peak incidence in childhood/adolescence. Any bone pain or swelling warrants urgent evaluation.

  • Skin Cancer: Increased risk of SCC, often within areas of poikiloderma. Also increased risk of BCC and melanoma.

  • Prognosis: Variable. Cancer is the leading cause of premature death. With vigilant surveillance, early detection and treatment of malignancies can improve outcomes.

• Management & Rationale:

  • Rationale: The cornerstone of management is aggressive cancer surveillance and sun protection to reduce skin cancer risk.

  • First-line/Obligatory Surveillance:

    • Oncologic: Annual whole-body skin exam by a dermatologist. Prompt evaluation of any bone pain or swelling with X-ray/MRI to rule out osteosarcoma.

    • Ophthalmologic: Regular eye exams for cataract detection and management.

  • Prevention: Strict, lifelong sun protection (sunscreen, protective clothing) is mandatory to reduce UV-induced DNA damage and skin cancer risk.

  • Supportive: Dental care (hypodontia common), monitoring for endocrine deficiencies (hypogonadism), and management of skeletal issues.