A 5-year-old girl is brought to the office by her mother because she is concerned that her daughter "sunburns too easily." The mother says the patient's skin becomes red and scaly with only minimal sun exposure. She first noticed the problem when her daughter was 7 months old during a trip to the beach. The mother has since avoided exposing her child to excess sunlight, but finds it difficult now that the patient has begun kindergarten. Physical examination shows thin and hyperpigmented skin. She also has a few nevi on her hands that have been enlarging rapidly. This patient's disorder is most likely due to a primary defect involving which of the following processes?

Question

A 5-year-old girl is brought to the office by her mother because she is concerned that her daughter "sunburns too easily."  The mother says the patient's skin becomes red and scaly with only minimal sun exposure.  She first noticed the problem when her daughter was 7 months old during a trip to the beach.  The mother has since avoided exposing her child to excess sunlight, but finds it difficult now that the patient has begun kindergarten.  Physical examination shows thin and hyperpigmented skin.  She also has a few nevi on her hands that have been enlarging rapidly.  This patient's disorder is most likely due to a primary defect involving which of the following processes?

Quizplus · Accepted Answer

This patient likely has xeroderma pigmentosum, a rare autosomal recessive disorder that occurs due to defective nucleotide excision repair of DNA damaged by ultraviolet (UV) light. Normally, the regions of DNA damaged by UV radiation are excised and replaced by a series of DNA repair enzymes. In xeroderma pigmentosum, this process is impaired and leads to the accumulation of abnormal pyrimidine nucleotides and other carcinogenic adducts. The skin of affected individuals is normal at birth, but they present during the first year of life with severe sun sensitivity (eg, erythema, scaling) affecting light-exposed areas, especially the face. Later, the skin shows atrophy, telangiectasias, and intermingling areas of hypo- and hyperpigmentation due to chronic UV damage. Skin malignancies, including malignant melanoma and squamous and basal cell carcinoma, develop as early as ages 5-6. (Choice A) Abnormalities of genes responsible for DNA mismatch repair are found in patients with hereditary nonpolyposis colorectal cancer (HNPCC, or Lynch syndrome). These patients have a greater incidence of colorectal, endometrial, and ovarian cancer. (Choice C) Ras codes for a G protein that regulates growth factor signal transduction. Mutations that result in a constitutively activated Ras protein cause constant and unregulated cell proliferation, leading to malignancy (particularly pancreatic and colorectal cancer). (Choices D and E) p53 is a regulatory protein that halts cell cycle progression when DNA is damaged, allowing time for the DNA to be repaired. When the damage is irreversible, apoptosis is triggered. Acquired p53 mutations are found in the majority of spontaneous cancers, whereas inherited p53 mutations are responsible for Li-Fraumeni syndrome (which causes a wide range of malignancies at a young age). (Choice F) Fanconi anemia is an autosomal recessive condition caused by mutations in the genes responsible for the repair of interstrand DNA crosslinks. It is the most common inherited cause of aplastic anemia and presents with short stature, absent thumbs, and increased malignancy risk. Educational objective: Xeroderma pigmentosum develops due to a defect in nucleotide excision repair. This disease is characterized by increased sensitivity to ultraviolet radiation and a high incidence of cutaneous malignancy. __________ References: Xeroderma pigmentosum (http://www.ncbi.nlm.nih.gov/pubmed/26975629) Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect. (http://www.ncbi.nlm.nih.gov/pubmed/26884178)

A 5-Year-Old Girl Is Brought to the Office by Her