Rothmund Thomson Syndrome: Symptoms, Types, Causes and Treatment

Rothmund-Thomson Syndrome (RTS) is a rare genetic disorder that affects multiple body systems, most notably the skin, skeleton, and eyes. Its hallmark is a distinct skin rash starting in infancy, but the syndrome can also bring a host of other challenges, including growth problems, bone abnormalities, dental issues, and a heightened risk of cancer. In this article, we'll explore the symptoms, types, causes, and treatment of RTS using the latest research, making this complex condition clearer and more approachable for patients, families, and healthcare providers.

Symptoms of Rothmund Thomson Syndrome

RTS manifests in a variety of ways, often starting with skin changes in infancy and progressing to involve other systems over time. Recognizing these symptoms is crucial for early diagnosis and management, which can significantly improve quality of life and health outcomes for those affected.

Symptom	Description	Frequency/Notes	Source(s)
Poikiloderma	Patchy skin discoloration, atrophy, telangiectasia	Appears in infancy, persists for life	1 3 4 5
Short stature	Height below normal for age	Common, may be accompanied by low weight	1 2 4 5
Sparse hair	Scalp, eyelashes, eyebrows thinned or absent	Frequent, especially in early childhood	2 4 5
Skeletal defects	Radial ray, ulnar, patella, or other bone abnormalities	20–30% of cases, variable severity	1 4 5
Juvenile cataracts	Early-onset clouding of the lens	More common in Type 1, rare in Type 2	1 2 4 5 7
Sun sensitivity	Skin reacts to UV (especially UVA)	Can be marked, varies by individual	2 5
Dental anomalies	Microdontia, caries, delayed eruption	Often present, may require intervention	5 14
Cancer risk	Osteosarcoma, skin cancer, hematologic malignancies	Osteosarcoma in up to 30%, skin cancer <5%	1 4 5 11 12
Other features	GI, respiratory, anemia, hypogonadism, nail changes	Less common, variable presentation	1 2 4 5 14

Table 1: Key Symptoms

Skin Manifestations and Poikiloderma

The earliest and most consistent feature of RTS is a facial rash that appears between 3–6 months of age and later spreads to the limbs and buttocks, but typically spares the trunk. This rash evolves into poikiloderma—a combination of hypopigmentation, hyperpigmentation, telangiectasia (visible small blood vessels), and skin atrophy. These skin changes are lifelong and can be socially and cosmetically distressing 1 3 4 5.

Growth and Hair Abnormalities

Children with RTS usually exhibit short stature and low weight, often apparent from a young age. Sparse hair—including the scalp, eyelashes, and eyebrows—is another frequent finding. Some patients may have total alopecia, while others experience only mild thinning 2 4 5.

Skeletal and Dental Problems

Skeletal abnormalities, often involving the forearm (radial ray defects), patella, or other bones, are seen in a significant proportion of individuals. These can be overt (visible at birth) or subtle (detected only by X-ray). Dental issues—such as small or misshapen teeth (microdontia), delayed eruption, and a tendency to cavities—are also common and can affect nutrition and self-esteem 1 4 5 14.

Eye and Other Systemic Features

Juvenile cataracts (clouding of the lens at a young age) are more frequent in some RTS types and can cause vision impairment if not treated. Other less common features include sunlight sensitivity (especially to UVA), hypogonadism, anemia, GI or respiratory issues, and nail abnormalities 2 4 5.

Cancer Risk

Perhaps the most serious complication is an increased risk for osteosarcoma (a type of bone cancer), particularly in childhood, and, less frequently, skin cancers and hematologic malignancies 1 4 5 11 12. This cancer predisposition is linked to specific genetic mutations (see below).

Types of Rothmund Thomson Syndrome

RTS is not a one-size-fits-all condition. Researchers and clinicians now distinguish between two main types of RTS, based on clinical features and genetic findings. Understanding these differences is key for prognosis and management.

Type	Main Features	Genetic Cause	Cancer Risk	Source(s)
RTS Type 1	Poikiloderma, cataracts, ectodermal dysplasia	ANAPC1 mutations (recently identified)	Low	4 5 7
RTS Type 2	Poikiloderma, skeletal defects, cancer risk	RECQL4 mutations	High (esp. osteosarcoma)	4 5 6 7 8 9 10

Table 2: RTS Types and Their Features

RTS Type 1

RTS Type 1 is characterized by classic skin changes (poikiloderma), juvenile cataracts, and features of ectodermal dysplasia (affecting hair, nails, and teeth). Skeletal abnormalities are less prominent, and these patients have not been shown to be at significantly increased risk for osteosarcoma or other cancers. The genetic cause was recently identified as mutations in the ANAPC1 gene, which is involved in cell cycle regulation 7.

RTS Type 2

RTS Type 2 presents with poikiloderma, but also includes a high frequency of congenital bone defects (such as radial ray anomalies), and, most notably, a markedly elevated risk of osteosarcoma (often in childhood) and other cancers. RTS Type 2 is caused by biallelic mutations in the RECQL4 gene, a DNA helicase crucial for DNA repair and stability. About 60–65% of RTS patients have identifiable RECQL4 mutations, most often in the gene's helicase domain 4 5 8 9 10.

Clinical Overlap and Heterogeneity

While these two types are distinct, there can be clinical overlap. Some patients have features of both types, and not all individuals with RECQL4 mutations develop cancer. Mild or atypical cases may also occur, possibly reflecting the specific mutation involved or the presence of modifying genetic or environmental factors 4 8.

Causes of Rothmund Thomson Syndrome

The root cause of RTS lies in the genes—specifically, mutations that disrupt essential processes in cell division, DNA repair, and maintenance of genomic stability. These gene defects are inherited in an autosomal recessive pattern, meaning both parents are usually carriers but unaffected themselves.

Gene	Function	Associated RTS Type	Consequences	Source(s)
RECQL4	DNA helicase, genome stability	Type 2	Bone defects, cancer risk	4 5 6 8 9 10
ANAPC1	Cell cycle regulation (APC/C)	Type 1	Cataracts, ectodermal features	5 7

Table 3: Genetic Causes of RTS

RECQL4 Mutations

The RECQL4 gene encodes a member of the RecQ helicase family, which is vital for DNA replication, repair, and chromosome stability. Mutations in RECQL4, particularly those affecting the helicase domain, result in defective DNA repair and increased genomic instability. This instability not only explains the skin and bone features (possibly due to abnormal cell turnover and development) but also the markedly increased cancer risk—especially for osteosarcoma 4 6 8 9 10.

• Frameshift, nonsense, and splice-site mutations are most common.
• Some mutations are "milder" and lead to less severe symptoms or lower cancer risk 8.

ANAPC1 Mutations

More recently, mutations in the ANAPC1 gene have been associated with RTS Type 1. ANAPC1 is part of the anaphase-promoting complex/cyclosome (APC/C), which regulates cell cycle progression and ensures proper division. Mutations here disrupt normal cell cycling, leading to features like cataracts and ectodermal dysplasia, but not the bone defects or cancer risk seen with RECQL4 mutations 7.

Inheritance and Genetic Counseling

RTS is inherited in an autosomal recessive manner:

• Each child of carrier parents has a 25% chance of being affected, 50% chance of being a carrier, and 25% chance of being unaffected.
• Genetic counseling, carrier testing, and prenatal diagnosis are available if the family mutations are known 5.

Pathophysiology: How Do These Mutations Cause Disease?

• Genomic instability is central to RTS, especially Type 2, due to impaired DNA repair and chromosome cohesion. This leads to developmental defects and predisposes cells to become cancerous 6 8 9.
• Features of premature aging (skin atrophy, cataracts, osteopenia) are thought to result from cumulative cellular damage and impaired tissue regeneration 10.

Treatment of Rothmund Thomson Syndrome

While there is currently no cure for RTS, a multidisciplinary approach can significantly improve symptoms, reduce complications, and enhance quality of life. Treatment focuses on symptom management, early detection and treatment of complications, and supportive care.

Manifestation	Management/Treatment Approach	Notes / Outcomes	Source(s)
Poikiloderma	Sun protection, pulsed dye laser for telangiectasia	Cosmetic improvement	4 5
Cataracts	Surgical removal	Restores vision	4 5
Skeletal issues	Orthopedic care, surgery as needed	Tailored to defect	4 5
Dental problems	Restorations, extractions, crowns, hygiene support	Ongoing dental follow-up	14
Osteosarcoma	Standard chemo/surgery; monitor toxicity	Similar outcomes to non-RTS	11 12 13
Skin cancer	Standard excision, dermatologic follow-up	Rare, but vigilance needed	1 4 5
Hematologic disease	Standard care, BMT for MDS/AML	Success in select cases	13
Surveillance	Annual exams, cancer vigilance, growth monitoring	Early detection is crucial	4 5

Table 4: Management Strategies in RTS

Skin and Sun Protection

• Strict sun protection is recommended due to photosensitivity and risk of skin changes.
• Pulsed dye laser therapy can be used to reduce the appearance of telangiectases (spider veins) for cosmetic reasons 4 5.

Eye and Dental Care

• Cataracts are managed surgically, with good outcomes if treated early.
• Dental issues require regular monitoring and intervention—fillings, crowns, extractions, and hygiene support can significantly enhance both health and self-esteem 14.

Orthopedic and Growth Management

• Orthopedic evaluation is essential for skeletal abnormalities; surgery or supportive devices may be needed.
• Growth hormone therapy is not recommended if growth hormone levels are normal 5.

Cancer Surveillance and Management

• Osteosarcoma: Standard chemotherapy and surgery are mainstays; some patients may need dose adjustments due to increased sensitivity, particularly with drugs like doxorubicin. Outcomes are similar to non-RTS patients if tumors are detected early 11 12.
• Skin cancer: Prompt dermatologic evaluation and excision.
• Hematologic malignancy: Standard therapies; bone marrow transplantation has been successful in rare cases 13.

Routine Monitoring and Multidisciplinary Care

• Annual physical, dermatologic, and ophthalmologic exams are crucial.
• Monitor for new or changing skin lesions, bone pain (suggestive of osteosarcoma), and growth/development.
• A multidisciplinary team (dermatology, genetics, orthopedics, oncology, dentistry) ensures comprehensive care and improves outcomes 4 5 14.

Genetic Counseling and Family Planning

• Families should receive genetic counseling about inheritance, recurrence risk, and options for prenatal or preimplantation diagnosis if family mutations are known 5.

Conclusion

Rothmund-Thomson Syndrome is a rare but impactful condition, touching many facets of health and daily life. Early recognition and proactive management can make a significant difference in the lives of those affected. Key points include:

• Characteristic poikiloderma and other skin changes are the hallmark, but RTS affects many systems, including bone, eyes, hair, and teeth.
• Two main types exist: Type 1 (ANAPC1 mutations, cataracts, lower cancer risk) and Type 2 (RECQL4 mutations, bone defects, high osteosarcoma risk).
• Inheritance is autosomal recessive, with important implications for families and genetic counseling.
• Cancer risk, especially for osteosarcoma, mandates vigilance and early intervention.
• Treatment is multidisciplinary, focusing on symptom relief, cancer surveillance, and supportive care to improve quality of life.

Summary of Main Points:

• RTS features skin, bone, hair, and eye abnormalities starting in infancy.
• Two forms exist, with different genetic causes and cancer risks.
• The syndrome is inherited in an autosomal recessive pattern.
• Management is supportive, preventive, and multidisciplinary.
• Early recognition and ongoing surveillance are vital for best outcomes.