Dermatological Manifestations of Inherited Cancer Syndromes in Children

A. Karalis; M. Tischkowitz; G.W.M. Millington


The British Journal of Dermatology. 2011;164(2):245-256. 

In This Article

Double Strand Break Repair Defects

Rothmund–Thomson Syndrome

Rothmund–Thomson syndrome (RTS; autosomal recessive) is caused by mutations in the DNA helicase gene, RECQL4.[19] Erythema, swelling and blistering of the face occur at around 3–6 months and the rash extends to include the extensor surfaces of the extremities, trunk, abdomen and buttocks.[20] Over the first year of life, poikiloderma develops and approximately one-third of individuals develop plantar hyperkeratotic lesions.[20] Hair is typically sparse and total alopecia can occur; other features include cataracts and skeletal dysplasia.[21] RTS is associated with an increased risk of osteosarcoma, BCC and SCC.[20]

Fanconi Anaemia

Fanconi anaemia (FA; predominately autosomal recessive with one rare X-linked form) comprises a triad of varied physical malformations, haematopoietic anomalies and cancer predisposition.[22,23] It is due to mutations in one of the FA complementation group genes, which code for proteins that are part of a nuclear multiprotein core complex involved in activating mono-ubiquitination of the FANCD2 protein during S phase of the growth cycle and after exposure to DNA cross-linking agents.[22] While a minority of individuals with FA develop no clinical features, most patients show hyperpigmented mottling, CALMs, small areas of hypopigmentation,[23,24] or pigmentation of the oral cavity.[25] These may be the only presenting feature in the early stages of FA.[23] Bone marrow failure typically occurs in the first decade[23] and there is an increased risk of certain solid tumours.[5,26,27]

One of the rarer FA genes, FANCD1, is, in fact, the BRCA2 gene and is therefore associated with early-onset breast and ovarian cancer,[5] as well as a possibly increased risk of melanoma in heterozygotes.[2] Similarly, there is a predisposition to breast cancer in heterozygous carriers of three other rare FA-related genes, FANCJ (also known as BRIP1), FANCN (also known as PALB2)[28,29] and RAD51C.[30,31] Thus, in a child with isolated pigmentation abnormalities, a family history of early-onset cancer may increase suspicion for FA.[23]

Ataxia Telangiectasia

The ATM gene encodes a member of the phosphatidylinositol 3-kinase family that responds to DNA damage by phosphorylating substrates involved in DNA repair and cell cycle control.[32] Clinically, its deficiency (autosomal recessive) produces ataxia telangiectasia (AT), a disorder defined by progressive cerebellar ataxia, oculocutaneous telangiectasias and immunodeficiency in the first few years of life, as well as marked radiation sensitivity and cancer susceptibility.[33] Elevated serum α-fetoprotein after the age of 2 years is a sensitive marker for AT, although the relation of this marker to the pathogenic mechanism is unclear.[34]

Pigmentary abnormalities are seen in most patients.[35] CALMs are common and may be seen in a dermatomal distribution.[34–36] Where they coexist with telangiectasias and cutaneous atrophy, they appear poikiloderma-like.[34] Occasionally vitiligo is found[36–38] and grey hair or skin atrophy can produce a progeroid appearance.[36,38] Seborrhoeic dermatitis is seen in most cases[36] while atopic and discoid eczema, follicular keratosis, dry skin and hirsutism may all occur as well.[36] Patients with AT have a 100-fold increase in the age-specific incidence rate for new cancers, most notably leukaemias or lymphomas,[39] with solid tumours appearing in adulthood.[37] Heterozygote carriers of ATM gene mutations have a two- to three-fold increased risk of developing breast cancer.[40,41]

Bloom Syndrome

Bloom syndrome (BS) has a higher prevalence within the Ashkenazi Jewish population (approximately 1% of Ashkenazi Jews are carriers of the BLMAsh mutation).[42] Homozygosity for BLM, which encodes a DNA helicase, results in short stature and predisposes to malignancy. The characteristic sun-sensitive rash in a 'butterfly distribution' appears on the face, as well as the dorsum of the hands and forearms.[42] CALMs and areas of hypopigmentation are common, large and numerous.[42] They are not usually seen in infancy, occurring in early childhood.[42] There is a significantly increased predisposition to early-onset haematological and solid malignancies.[43] Chronic lung disease and diabetes are also frequently encountered in patients with BS.[42]

Werner Syndrome

Werner syndrome is caused by homozygous mutations in the WRN gene (also known as RECQL2), a helicase involved in nonhomologous end-joining repair occurring at DNA double strand breaks.[44] The first symptom may be the absence of a pubertal growth spurt.[45] Characteristic cutaneous findings include scleroderma-like changes[45] and deep chronic ulcers around the ankles. The progeroid features include osteoporosis, subcutaneous fat loss, muscle wasting, bilateral cataracts and grey hair. Premature type 2 diabetes, hyperlipidaemia and atherosclerosis all occur at increased frequency.[45] The increased cancer risk includes sarcoma, osteosarcoma, thyroid carcinoma and melanoma (including acral lentiginous melanoma).[44,46]


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