An 18-year-old woman comes to the office for evaluation of graying hair. The patient has no other concerns and has otherwise been healthy. She reports that her mother had similar features at a young age and died of progressive pulmonary fibrosis. Examination shows diffuse gray hair. There are white patches on the surface of the tongue. Cardiopulmonary examination is unremarkable, and the abdomen is soft and nondistended. Skin examination shows areas of reticular hyperpigmentation on the neck and torso. The nails of the fingers and toes appear thin. Genetic testing reveals a loss-of-function mutation affecting the telomerase reverse transcriptase gene. Which of the following cell types is most likely to be affected by this mutation?

Question

An 18-year-old woman comes to the office for evaluation of graying hair.  The patient has no other concerns and has otherwise been healthy.  She reports that her mother had similar features at a young age and died of progressive pulmonary fibrosis.  Examination shows diffuse gray hair.  There are white patches on the surface of the tongue.  Cardiopulmonary examination is unremarkable, and the abdomen is soft and nondistended.  Skin examination shows areas of reticular hyperpigmentation on the neck and torso.  The nails of the fingers and toes appear thin.  Genetic testing reveals a loss-of-function mutation affecting the telomerase reverse transcriptase gene.  Which of the following cell types is most likely to be affected by this mutation?

Quizplus · Accepted Answer

11ec160b_375e_22ac_9249_0d05764b0675_MD0001_00 This patient has dyskeratosis congenita; a genetic disorder involving a mutation in the genes related to telomere maintenance (eg, telomerase reverse transcriptase) that results in short telomeres. Telomeres are a complex of protein (eg, shelterin) and DNA repeats (eg, TTAGGG) at the ends of chromosomes that prevent chromosomal degradation and fusion with neighboring chromosomes. With each cellular division telomeres progressively shorten, eventually reaching a critical length at which apoptosis or senescence is triggered. In cells with a high turnover rate (eg, epithelial cells, lymphocytes, hematopoietic stem cells), telomere length is maintained by telomerase. This complex, composed of an RNA template and a reverse transcriptase, adds DNA repeats to the end of telomeres as they are lost with cell division. Without normal telomerase activity, rapidly dividing cells cannot maintain chromosomal integrity, triggering premature cell death. In patients with short telomere disorders, loss of these cells can cause characteristic mucocutaneous changes (eg, oral leukoplakia, dystrophic nails), bone marrow failure (eg, pancytopenia), and pulmonary fibrosis (due to alveolar epithelial dysfunction). (Choices A, B, C, and F) Telomerase is inactivated in long-lived, differentiated cells such as cardiac myocytes, CNS neurons, compact bone osteocytes, and vascular endothelial cells; therefore, these cells are not likely to be affected by this patient's mutation. However, in cancer cells derived from differentiated cells, telomerase is reactivated, allowing continuous cellular division without loss of telomere length. (Choice E) Secondary oocytes are immature ova that form as a result of the division of a primary oocyte during meiosis I. They do not continue to divide and therefore are also not likely to be affected by this patient's mutation. Educational objective: Telomeres help maintain chromosomal integrity and are preserved in rapidly dividing cell lines (eg, epithelial cells, lymphocytes, hematopoietic stem cells) by telomerase. Disorders involving telomerase function (eg, dyskeratosis congenita) result in premature death of cells with high turnover, characteristically causing mucocutaneous changes (eg, oral leukoplakia, dystrophic nails), bone marrow failure, and pulmonary fibrosis. __________ References: Bone marrow failure and the telomeropathies. (http://www.ncbi.nlm.nih.gov/pubmed/25237198)

An 18-Year-Old Woman Comes to the Office for Evaluation of Graying