What are ERCC2-related Disorders? ERCC2-related disorders are characterized by increased sensitivity to sunlight (photosensitivity), which leads to severe sunburns with minimal sun exposure. They are caused by harmful genetic changes (variants) in the ERCC2 gene. The ERCC2 gene plays an important role in regulating other genes in the body. It also helps repair DNA damage that regularly occurs throughout a person’s life. In individuals with ERCC2-related disorders, the ERCC2 gene cannot correctly perform these critical functions, which leads to symptoms. ERCC2-related disorders can include several forms: Xeroderma Pigmentosum (XP), Xeroderma Pigmentosum/Cockayne syndrome complex (XP/CS complex), Trichothiodystrophy (TTD), and Cerebro-oculofacial-skeletal syndrome (COFS). It is difficult to predict which form an individual will develop based on their specific genetic changes. Some individuals have features that overlap with multiple ERCC2-related disorders. Xeroderma Pigmentosum The name xeroderma pigmentosum (XP) comes from two of its common characteristics: dry skin (xeroderma) and skin color changes (pigmentosum). Extreme sun sensitivity is present from birth and causes people with XP to have a very high risk of skin cancer, which may arise in childhood. It may also result in eye abnormalities, such as vision loss, dry eyes, damage to the outer layer of the eye (cornea), light sensitivity (photophobia), cancerous and non-cancerous tumors, and loss of the eyelids. Individuals also have a higher than average risk of developing cancers elsewhere in the body, such as the tongue, thyroid, and nervous system. Approximately 25% of individuals with XP have neurologic issues, including learning issues, hearing loss, small head size (microcephaly), coordination issues (ataxia), and seizures. For some individuals, these neurological issues start during infancy, whereas in others, they will not develop until adulthood. Several genes can cause XP, and XP that is caused by genetic changes in the ERCC2 gene is referred to as Xeroderma Pigmentosum type D (XPD). Xeroderma Pigmentosum/Cockayne Syndrome Complex Rarely individuals can have symptoms of xeroderma pigmentosa and another disorder called Cockayne syndrome (CS). When this occurs, an individual is said to have xeroderma pigmentosum/Cockayne syndrome complex (XP/CS complex). Additional symptoms in these individuals can include distinct facial features, growth issues, intellectual disability, hearing loss, and brain abnormalities. Trichothiodystrophy Trichothiodystrophy (TTD) is characterized by brittle hair and skin abnormalities, such as dry, scaly skin and eczema. Other symptoms include distinct facial features, intellectual disability, poor growth, frequent infections, nail and eye abnormalities, tremor, and coordination issues. Babies are often born early, have low birth weight, and are small for gestational age. People with trichothiodystrophy are sensitive to the sun and may sunburn easily, but they do not have a significantly increased risk to develop skin cancer. Several genes can cause TTD. TTD caused by genetic changes in the ERCC2 gene is referred to as TTD type 1. Cerebro-oculofacial-skeletal Syndrome Cerebro-oculofacial-skeletal syndrome (COFS) is the most severe ERCC2-related disorder. It is characterized by having a small head size, intellectual disability, poor growth, and abnormalities of the brain, joints, and eyes. People with COFS are sensitive to the sun and may sunburn easily, but they do not have a significantly increased risk to develop skin cancer. Several genes can cause COFS. COFS caused by genetic changes in ERCC2 is called COFS type 2. Additional considerations for carriers Carriers of ERCC2-related disorders do not typically show symptoms of the disease. However, there is an increased risk of serious pregnancy complications, particularly in the third trimester, in individuals carrying a fetus affected with trichothiodystrophy. These complications can include high blood pressure (pre-eclampsia) and HELLP syndrome. These conditions can be life-threatening and may present with symptoms such as nausea, swelling, and vision changes. An individual whose pregnancy may be affected by an ERCC2-related disorder should speak with their physician for recommendations and may benefit from a consultation with a high-risk physician. How common are ERCC2-related Disorders? The incidence of all ERCC2-related disorders together is unknown. Several genes are known to cause XP, which has an incidence of 1 in 430,000 births. Approximately 15% of XP is caused by ERCC2. The incidence of XP due to genetic changes in ERCC2 is more common among individuals of Iraqi Jewish descent. Several genes are known to cause TTD, which has an incidence of 1 in 830,000. Between 30-60% of TTD is caused by ERCC2. Both XP/CS complex and COFS due to ERCC2 have been described in only a handful of families. How are ERCC2-related Disorders treated? There is no cure for ERCC2-related disorders. Treatment is directed at managing the specific symptoms an individual has and can differ depending on the form and severity of the ERCC2-related disorder. Individuals with ERCC2-related disorders often require care from several specialists, such as dermatologists, neurologists, ophthalmologists, and others. They may also benefit from receiving early intervention and other supportive services beginning at a young age. Management for individuals with sun sensitivity includes strictly avoiding sun and UV light, especially to the skin and eyes. Skin-covering clothing, sunscreen, and sunglasses with UV protection are strongly recommended. What is the prognosis for an individual with an ERCC2-related Disorder? The prognosis for ERCC2-related disorders depends on the specific form that an individual has, though all forms are associated with a shortened lifespan. The average life expectancy of an individual with XP is in the 20s-30s. Early death typically occurs due to the increased risk of skin cancers and neurologic issues. Prognosis may be improved for some individuals who practice strict sun avoidance. Many individuals with XP-CS complex die during their childhood or teenage years. Individuals with TTD often die before adulthood, sometimes as early as infancy, due to the high risk of developing infections. Most people with XP-CS complex and TTD have intellectual disability. Due to the severity of the condition, individuals with COFS usually die before age 5. Other names forERCC2-related disorders ICHTHYOSIFORM ERYTHRODERMA WITH HAIR ABNORMALITY AND MENTAL AND GROWTH RETARDATION ICHTHYOSIS, CONGENITAL, WITH TRICHOTHIODYSTROPHY PIBIDS SYNDROME TAY SYNDROME TRICHOTHIODYSTROPHY WITH CONGENITAL ICHTHYOSIS TRICHOTHIODYSTROPHY, PHOTOSENSITIVE XERODERMA PIGMENTOSUM IV Xeroderma pigmentosa Xeroderma pigmentosum group D References Baer et al., 2020, Clin Genet., 98(3):251-260, PMID: 32557569 Gregg et al., 2021, Genet Med, 23(10):1793-1806, PMID: 34285390 Kraemer et al., 2022, https://www.ncbi.nlm.nih.gov/books/NBK1397/ Lucero et al., 2022, In: StatPearls [Internet], PMID: 31855390 Natale et al., 2017, Orphanet J Rare Dis., 12(1):65, PMID 28376890 Randall et al., 2019, Br J Haematol., 185(4): 752–754, PMID: 30334570 Reunert et al., 2020, Am J Med Genet A., 185(3):930-936, PMID: 33369099 Schubert et al., 2019, In: Harper's Textbook of Pediatric Dermatology, 4th ed., https://doi.org/10.1002/9781119142812.ch138 Tamura et al., 2012, Eur J Hum Genet., 20(12):1308-1310, PMID: 22617342