What are genophotodermatoses (rare genetic disorders)?

Genophotodermatoses: Rare Genetic Disorders with Photosensitivity

Genophotodermatoses are hereditary skin disorders characterized by abnormal cutaneous reactions to ultraviolet radiation due to genetic defects in DNA repair mechanisms, metabolic pathways, or natural photoprotection systems. 1, 2

Classification and Key Disorders

Genophotodermatoses represent a distinct category of photodermatoses that are genetically determined, as opposed to immunologically-mediated or chemically-induced photosensitivity. 2, 3 The primary disorders in this category include:

DNA Repair-Deficient Disorders

Xeroderma Pigmentosum (XP) is the prototypical genophotodermatose, caused by autosomal recessive pathogenic variants in nucleotide excision repair genes (XPA, XPB/ERCC3, XPC, XPD/ERCC2, XPE/DDB2, XPF/ERCC4, XPG/ERCC5, ERCC1, and XPV/POLH). 4

Clinical manifestations include:

• Extreme sun sensitivity with severe sunburn reactions 4
• Significant skin freckling and poikiloderma 4
• Dramatically elevated cancer risk: patients under age 20 have 10,000-fold increased risk of nonmelanoma skin cancers and 2,000-fold increased risk of melanoma compared to the general population 4
• Median age of nonmelanoma skin cancer diagnosis is 9 years (range 1-32 years) 4
• Ocular complications including photophobia, conjunctival injection, keratitis, and lid atrophy 4
• Neurologic manifestations in approximately 25% of patients, including progressive sensorineural hearing loss, cognitive impairment, neuropathy, and contractures 4

Epidemiology varies by ancestry: 1 in 1,000 in the United States, 2.3 in 1,000 in Western Europe, and substantially higher in Japan (1 in 22,000), the Middle East, and North Africa. 4

Disorders of Cornification and Pigmentation

The following genodermatoses demonstrate photosensitivity due to deficient natural photoprotection: 1, 2

• Albinism: Lack of melanin pigment results in absent photoprotection 2
• Vitiligo: Depigmented areas lack melanocyte-mediated UV protection 2
• Poikiloderma syndromes: Including Rothmund-Thomson syndrome (RTS type 2), caused by biallelic pathogenic variants in RECQL4, characterized by poikiloderma and 30% prevalence of osteosarcoma 4

Metabolic Photodermatoses with Genetic Basis

Porphyrias result from enzymatic defects causing accumulation of photosensitizing porphyrins in the skin, representing congenital metabolic photodermatoses. 2

Critical Management Principles

UV Protection (Essential for All Genophotodermatoses)

Strict UV avoidance is the cornerstone of management and directly impacts morbidity and mortality. 4

Specific protective measures include:

• Limiting exposure to both UVA and UVB radiation from sunlight 4
• Evaluating indoor light sources with UV meters to identify and replace significant UV-emitting sources (particularly uncovered fluorescent lights) 4
• Using sunscreen with high sun protection factor 4
• Wearing UV-protective clothing, wide-brimmed hats, and UV-blocking sunglasses 4
• Installing UV-resistant films on windows 4

Surveillance Requirements for Xeroderma Pigmentosum

Multidisciplinary monitoring is mandatory given the extreme cancer risk and multisystem involvement: 4

• Dermatologic evaluations every 3 months to detect early skin cancers 4
• Ophthalmologic examinations at least twice yearly for ocular disease 4
• Oral examinations by specialists at least twice yearly for oral cancers 4
• Otolaryngology monitoring for progressive hearing loss 4
• Vitamin D supplementation due to sun avoidance 4

Special Considerations for Specific Genophotodermatoses

For Rothmund-Thomson syndrome (RECQL4-related): Annual dermatologic exams, eye screening, and awareness of osteosarcoma symptoms (bone pain and swelling) are critical, as the median age of osteosarcoma onset is 9-10 years with 50% probability by age 20. 4

Common Pitfalls to Avoid

Do not assume all photosensitive disorders are genophotodermatoses—the differential includes immunologically-mediated photodermatoses (polymorphic light eruption, solar urticaria), drug-induced photosensitivity, and photoaggravated dermatoses (lupus erythematosus, psoriasis). 2, 5, 3

Do not delay genetic testing when genophotodermatoses are suspected—early diagnosis enables appropriate cancer surveillance protocols that can reduce mortality, particularly in XP where skin cancers develop in early childhood. 4

Do not use standard myeloablative chemotherapy dosing in DNA repair disorders—these patients require dose-reduced regimens and avoidance of DNA-damaging agents due to extreme sensitivity. 4