Rothmund–Thomson syndrome

Overview

Rothmund–Thomson syndrome (RTS) is a rare genetic disorder that affects multiple systems in the body, primarily the skin, skeletal system, and eyes. It is a type of poikiloderma syndrome, meaning it is characterized by skin changes including discoloration, thinning, and telangiectasia (visible small blood vessels). RTS is also associated with growth retardation, sparse hair, cataracts, skeletal abnormalities, and an increased risk of certain cancers, particularly osteosarcoma (bone cancer).

The condition typically begins in infancy, with the appearance of a distinctive rash. As the child grows, additional symptoms emerge. RTS is inherited in an autosomal recessive manner and has been linked to mutations in the RECQL4 gene, which is involved in DNA repair. Early diagnosis and multidisciplinary care are essential for managing complications and improving quality of life.

Causes

Rothmund–Thomson syndrome is caused by mutations in the RECQL4 gene located on chromosome 8q24.3. This gene encodes a DNA helicase enzyme that plays a critical role in DNA replication and repair. Defective DNA repair leads to genomic instability, which is believed to underlie many of the clinical features of RTS, including cancer predisposition.

Genetic Inheritance:

• Autosomal recessive inheritance: Affected individuals inherit one defective copy of the RECQL4 gene from each parent.

• Parents of affected children are usually asymptomatic carriers.

Genotype-Phenotype Correlation:

• Mutations in RECQL4 are more commonly associated with RTS type II, which includes an increased risk of osteosarcoma.

• RTS type I may involve skin and eye changes without a confirmed genetic cause in some cases.

Symptoms

The clinical features of RTS vary widely but often begin within the first few months of life. Symptoms may affect the skin, bones, eyes, hair, teeth, and increase the risk of malignancy.

Cutaneous Features:

• Poikiloderma: A combination of skin atrophy, telangiectasia, and pigmentation changes that appear as a facial rash during infancy and later spread to the limbs and buttocks.

• Photosensitivity: Skin reacts abnormally to sun exposure, especially in early life.

Hair, Nails, and Teeth:

• Sparse scalp hair, eyelashes, and eyebrows

• Small or malformed teeth

• Nail dystrophy: Thin, brittle, or ridged nails

Ocular Features:

• Bilateral juvenile cataracts: Clouding of the lens often occurring in the first or second decade of life

• Photophobia (light sensitivity)

Skeletal and Growth Abnormalities:

• Short stature

• Skeletal dysplasia: Abnormal bone development, including absent or malformed thumbs or radius bones

• Delayed bone age

Increased Cancer Risk:

• Osteosarcoma: The most common malignancy in RTS, often diagnosed in childhood or adolescence

• Skin cancer: Increased risk of squamous cell carcinoma and basal cell carcinoma, especially in sun-exposed areas

Diagnosis

Diagnosis of Rothmund–Thomson syndrome is based on clinical findings, family history, and confirmed by genetic testing. Early signs like poikiloderma and growth abnormalities prompt further evaluation.

Clinical Evaluation:

• History of early-onset rash and photosensitivity

• Physical examination for skin, hair, skeletal, and ocular anomalies

Genetic Testing:

• RECQL4 gene sequencing: Confirms the diagnosis in most type II cases

• Carrier testing for at-risk family members

Imaging and Laboratory Studies:

• X-rays: To detect skeletal abnormalities and bone age

• Eye exams: To assess for cataracts or other visual impairments

• Bone scans or MRIs: To detect or monitor for osteosarcoma

Differential Diagnosis:

• Bloom syndrome

• Werner syndrome

• Kindler syndrome

• Xeroderma pigmentosum

Treatment

There is no cure for Rothmund–Thomson syndrome, so treatment is supportive and focused on managing symptoms, preventing complications, and early detection of cancer. A multidisciplinary team is essential for long-term care.

1. Dermatologic Care:

• Strict sun protection: sunscreen, protective clothing, and UV-blocking glasses

• Regular skin exams to monitor for precancerous lesions or skin cancer

2. Ophthalmologic Care:

• Routine eye exams to monitor for cataracts

• Surgical cataract removal when vision is impaired

3. Orthopedic and Growth Management:

• Monitoring of skeletal development and bone health

• Physical therapy for mobility and strength

• Growth hormone therapy in selected cases with endocrinology consultation

4. Oncologic Surveillance:

• Routine imaging and blood work to screen for osteosarcoma in childhood and adolescence

• Prompt evaluation of bone pain or swelling

• Skin checks every 6–12 months for signs of malignancy

5. Dental and Nutritional Support:

• Early dental care for malformed or missing teeth

• Nutritional counseling to support healthy growth and immune function

Prognosis

The prognosis for individuals with Rothmund–Thomson syndrome depends largely on the severity of associated complications, particularly the risk and management of osteosarcoma and other cancers. With appropriate medical support and cancer surveillance, many individuals can live into adulthood, though growth and cosmetic differences may persist.

Early intervention, cancer screening, and a coordinated care team can significantly improve outcomes. Life expectancy may be reduced in individuals who develop aggressive malignancies, especially if not detected early. However, with advances in genetic testing and supportive care, the outlook for patients with RTS continues to improve.