Xeroderma pigmentosum (XP) is an autosomal recessively inherited disease characterized by exquisite sensitivity to ultraviolet (UV) radiation. Mutations in eight genes (XPA to XPG and XPV), which correspond to complementation groups that assist in DNA repair, have been identified. The repair rate of damaged DNA depends on the specific mutation, resulting in a range of severity in disease presentations. The incidence of disease ranges from 2.3 per million in Western Europe to 1 per 20,000 in Japan and depends on the demographic of the population [23].

There are two main clinical presentations of XP, which include extreme photosensitivity with secondary changes including vesicles, bullae, and conjunctivitis, or disproportionate numbers of lentigines that appear in sun-exposed areas. The onset of these cutaneous manifestations is typically at 1–2 years of age [24]. Chronic cutaneous changes include severe xerosis and premature aging of the skin, with telangiectasias, atrophy, hypopigmentation, and hyperpigmentation. Furthermore, these patients have an increased risk of both NMSCs and melanoma in sun-exposed areas, especially in the head and neck region. These cancers can have an aggressive course, with a tendency to grow rapidly and metastasize early [25]. The median age for NMSC diagnosis is 8 years and median age for melanoma diagnosis is 19–22 years [26, 27]. The overall risk of NMSC is 10,000× normal, and the risk of melanoma is 2,000× normal in patients with XP [27]. Ocular tissue involvement also occurs in almost half of all these patients, resulting in changes like conjunctivitis, ectropion, corneal opacities, and neoplasms [24]. Important extracutaneous findings include progressive neuronal deterioration, which occurs in 20–25% of patients [24, 27]. In the past, diagnosis was made on the basis of clinical features and observations of defective DNA repair, but there is increased utilization of genetic testing, including whole exome sequencing [28].

Management of these patients requires rigorous photoprotection, both when the patient is indoors and outdoors. Measures like UV-resistant films on all windows in a patient’s home and school environments and protective headgear, gloves, and clothing to cover all body surfaces when going outdoors are imperative, given the extraordinary risk of skin cancer in XP patients. High-dose oral isotretinoin has a chemoprophylactic effect and significantly reduces the rate of skin cancer formation during treatment, but the skin cancer formation rate increases again to the pretreatment rate once the medication is stopped [29]. Novel treatments, including a bacterial DNA repair enzyme delivered in a liposomal lotion and gene therapy, are currently under investigation [30]. Regular visits to the dermatologist and ophthalmologist for cancer surveillance are the standard of care. The most common cause of death in XP patients is skin cancer, followed by neurologic decline and internal cancers.

Rothmund-Thomson (RT) is another exceedingly rare autosomal recessively inherited genodermatosis. There are about 300 cases of RT reported in the literature [31]. RT1 is a subset without a known causative gene, while RT2 has been linked to a mutation in RECQ4 and an increased risk for malignancy [32]. Mutations in the DNA helicase RecQ family of genes are responsible for Bloom, Werner, and RT, which have different clinical presentations, but share similar mutations that cause gene instability, resulting in a strong predisposition to malignancy [14]. The cutaneous findings usually manifest between 3 and 6 months of life and almost always before the first year of life, with erythema, edema, and blistering, on the cheeks and face, before spreading to the extremities and buttocks [33]. These skin changes can occur in response to ultraviolet light, but can also occur in the setting of minimal sun exposure [34]. This rash typically spares the trunk and abdomen. Chronic changes include atrophy, hyperpigmentation, hypopigmentation, and reticular telangiectasias that can persist throughout the patient’s lifetime. Other cutaneous findings that would support the diagnosis of RT include diffuse hypotrichosis on the scalp and eyebrows, nail dystrophy, and palmoplantar keratosis. Squamous cell carcinoma is the most common cutaneous tumor and represents an important manifestation of RT. Important extracutaneous clues to the diagnosis include cataracts, short stature, and skeletal abnormalities.

The diagnosis of RT is primarily based on characteristic clinical findings, as well as genetic testing for RECQL4 mutations , and treatment for these patients is mainly supportive. In terms of long-term management, it is important to know that patients with RT have increased susceptibility for both osteosarcoma (most common malignancy) and cutaneous SCC. Given these associations, there should be an emphasis on photoprotection and a low threshold for work-up of musculoskeletal complaints. NMSC, especially SCC, presents at a mean age of 34 years, but surveillance with complete skin examinations should begin in adolescence [35].

Bloom syndrome is an autosomal recessive disease found frequently in the Ashkenazi Jewish population and associated with a mutation in the BLM gene at chromosome 15q26.1 that encodes RECQL3 helicase [36, 37]. The DNA in lymphocytes, which lack this important helicase in affected patients, demonstrate an increase in sister chromatid exchanges and therefore DNA instability [38]. Several hundred cases have been reported in the literature. Erythema of the cheeks in a butterfly distribution after sun exposure is often the earliest cutaneous manifestation appearing within the first few weeks of life. The rash can spread over the face, but tends to spare the extremities and trunk. Photosensitivity resulting in blistering, erythema, and bleeding is commonly seen in any region exposed to UV radiation [36]. These cutaneous changes evolve into chronic changes that include mottled hypo- and hyperpigmentation, telangiectasias, atrophy, and scarring. Other important cutaneous manifestations are café au lait macules and hypopigmented macules, especially over the dorsum of the hands and forearms [39]. The most distinctive extracutaneous feature of Bloom syndrome is proportionate small stature. Other suggestive extracutaneous findings include a characteristic birdlike appearance due to lack of subcutaneous fat, recurrent bacterial infections with associated hypogammaglobulinemia, and impaired fertility in men and women. Diagnosis is ultimately made through karyotype or genetic mutation analysis [40].

The range of malignancies associated with Bloom syndrome is similar to the spectrum seen in the general population, but affects patients with an increased frequency and at a younger age. In the first decade, rare cases of Wilms tumor and osteosarcoma have been reported. In the second decade, hematologic malignancies and skin cancer become more common, and the risk of all other carcinomas, especially colon and breast cancer, increases thereafter [41]. Of note, pulmonary complications like bronchiectasis, while not malignant processes, contribute significantly to the mortality rate and are the second-leading cause of death after malignancy in these patients [41]. Dermatologic care should include photoprotection and frequent monitoring to detect skin cancers. Management can be very difficult because Bloom syndrome patients are susceptible to such a wide spectrum of malignancies, but avoidance of unnecessary radiation and early screening for the common malignancies like breast and colon cancer have been recommended [42].

Kindler syndrome , or congenital bullous poikiloderma , is a rare subtype of epidermolysis bullosa with an autosomal recessive inheritance pattern. It is caused by a mutation in the FERMT1 gene encoding kindlin-1, resulting in dysfunctional actin cytoskeleton-extracellular matrix interaction at multiple intra- and subepidermal levels [43]. To date, there have only been 250 cases of this blistering disease reported [44]. Patients typically present at birth with severe skin fragility and new blisters forming after exposure to trauma or sunlight. Chronic changes including sclerosing features and diffuse cutaneous atrophy affecting the dorsal aspects of the hands (Fig. 5.3) increase with age [45]. Other cutaneous findings include webbing of hands and feet, hyperkeratosis of palms and soles, nail dystrophy, ectropion, gingivitis, and periodontitis leading to premature loss of teeth. Furthermore, patients develop actinic keratoses or SCCs in the third and fourth decade of life, especially on the acral surfaces and oral mucosa, most likely due to ultraviolet-induced DNA damage and chronic inflammation [45]. Extracutaneous findings include esophageal, urethral, and vaginal stenosis and colitis secondary to mucosal inflammation [46]. Given the overlap with other blistering disorders, the gold standard of diagnosis is molecular genetic mutation testing for loss of function mutations in FERMT1 and supportive histological and immunofluorescence studies.

In terms of treatment, a multidisciplinary team is essential to minimize complications from strictures and scarring that can affect all mucosal surfaces. Regular dental care is necessary to monitor for and treat the gingivitis. Patients with severe dysphagia secondary to esophageal strictures may require repeat dilatations of the esophagus. Patients with severe colitis, urethral, or vaginal strictures may require surgical intervention. Photoprotection and proper wound care are the mainstays of dermatologic care. Monitoring for skin cancer with regular skin exams at least every 6–12 months, with careful attention to the oral mucosa and areas of chronic ulceration or leukoplakia, should begin at the age of 20 years [47].

Oculocutaneous albinism (OCA) is a disease entity with autosomal recessive transmission that is caused by a defect in melanin biosynthesis and affects about 1 in 17,000 individuals in the United States [48]. There are at least seven subtypes of OCA, but OCA1 and OCA2 are the most common forms.

The clinical presentation of OCA includes hypopigmentation of the skin, hair, and eyes due to an absence or reduction in melanin biosynthesis, despite normal number of melanocytes. Reduced melanin biosynthesis results in increased sensitivity to UV radiation and a propensity for cutaneous malignancies, especially SCC and BCC. Patients develop signs of early actinic damage, as well as amelanotic or pigmented melanocytic nevi. Cutaneous malignancies develop as early as childhood and present at a mean age of the third and fourth decade of life [49]. The true incidence of melanoma in this population is controversial, but appears to be low [50, 51]. The lack of ocular pigmentation is associated with abnormal optic projections of fibers from the retina to the optic cortex. Patients present with translucency of the iris, reduced visual acuity, photophobia, nystagmus, and strabismus. Treatment should include sun avoidance and ophthalmologic care.