Rothmund-Thomson
Syndrome
CLINICAL FEATURES
The hallmark of RTS, a rare, autosomal recessive disorder, is poikiloderma with variegated cutaneous pigmentation, atrophy, and telangiectasias beginning in infancy. RTS patients are photosensitive and develop prominent erythema and facial swelling on sun exposure early in life, which may be accompanied by blister formation. They often have sparse scalp hair, eyebrows, and eyelashes. Other clinical features include juvenile cataracts, stunted growth, skeletal abnormalities including radial bone defects, and a predisposition for cancer, in particular for osteosarcomas (32 percent of patients). Five percent of RTS patients also develop non-melanoma skin cancer.
GENE DEFECT, PATHOGENESIS, AND LABORATORY ABNORMALITIES
Mutations in the helicase RecQL4 have been identified in a majority of patients with RTS. Cells from RTS patients have been reported with an increased sensitivity to ionizing radiation with increased formation of chromosome gaps and breaks, suggesting a role of RECQL4 in maintaining chromosome stability. This, however, was not confirmed in other patients, possibly reflecting heterogeneity in this disease. The exact function of the RECQL4 helicase remains unclear. Cells from one patient had reduced DNA repair after exposure to UVC. One RTS patient had increased acute toxicity after high-dose radiotherapy after surgery and subsequent palliative chemotherapy. However, another RTS patient was reported to have a normal acute response to radiation therapy for a squamous cell carcinoma of his tongue. He died 2 years later with extensive squamous cell carcinoma in the thorax, but no tumor in the oral cavity.
Fanconi Anemia
FA is an autosomal recessive disease characterized by progressive pancytopenia, growth retardation, various congenital abnormalities of the heart, kidney, and limbs, and a predisposition to cancer. More than 1200 patients have been reported to the International Fanconi Anemia Registry.
CLINICAL FEATURES
Cutaneous abnormalities are present in almost 80 percent of patients (Fig. 140-8A-D). Hyperpigmentation is present from birth or early childhood and is diffuse and accentuated over the neck, joints, and trunk. Café-au-lait spots and achromic lesions are also present.
Hematopoietic manifestations usually have their onset before age 10 years and most commonly lead pediatricians to make the diagnosis of FA. These consist of a hypocellular bone marrow with progressive
decrease in the number of circulating platelets, granulocytes, and erythrocytes. Skeletal malformations are common and often include aplasia or hypoplasia of the thumb, metacarpals, or radius. Short stature, renal deformities, strabismus, microphthalmia, hypogonadism, and central nervous system abnormalities, including hyperreflexia and mild mental retardation, are also observed. The frequency of acute myelogenous leukemia has been reported to be elevated 15,000-fold. If patients survive aplastic anemia and/or leukemia (e.g., as a result of bone marrow transplantation) they often develop solid tumors by the fifth decade of life, mostly squamous cell carcinomas of the head and neck and the anogenital area.
ENE DEFECT, PATHOGENESIS, AND LABORATORY ABNORMALITIES
FA is genetically heterogeneous with at least twelve complementation groups (FANCA to FANCM), all of which, except FANCI, have been cloned. Most of the FA proteins have been shown to act in a common DNA damage response signaling pathway, which also involves BRCA1 and BRCA2 (these genes are mutated in hereditary breast cancer; see Chap. 109). Activation of this FA/BRCA pathway is thought to mediate DNA recombination to repair DNA strand breaks and DNA cross-links, generated, e.g., by ionizing radiation or DNA cross-linking agents.
TESTING
Central to the FA/BRCA pathway is the mono-ubiquitination of the FANCD2 protein. The inability of FA cells to ubiquitinate the FANCD2 protein, as shown in Western blots after, for example, exposure to DNA cross-linking agents, is currently used as a screening tool to confirm the diagnosis of FA.
