A married couple comes to the physician for routine prenatal counseling. The husband is 120 cm (3 ft 11 in) tall with disproportionately short upper and lower extremities, a large head, and a prominent forehead. He is unable to provide a biological family history as he was adopted. His spouse is of average height with normal constitutional features, and her family history is insignificant. They are concerned about their unborn child's height. Which of the following is the best response to their concerns?

Question

A married couple comes to the physician for routine prenatal counseling.  The husband is 120 cm (3 ft 11 in) tall with disproportionately short upper and lower extremities, a large head, and a prominent forehead.  He is unable to provide a biological family history as he was adopted.  His spouse is of average height with normal constitutional features, and her family history is insignificant.  They are concerned about their unborn child's height.  Which of the following is the best response to their concerns?

Quizplus · Accepted Answer

11ec160b_375c_c31a_9249_7758f795928a_MD0001_00 The husband's short stature and morphologic features are suggestive of achondroplasia. Achondroplasia is the most common form of short-limbed dwarfism and is caused by a mutation that results in constitutive activation of fibroblast growth factor receptor 3 (FGFR3). Achondroplasia occurs as a sporadic mutation (due to advanced paternal age) in 85% of cases. However, once a mutation occurs, it can be transmitted as an autosomal dominant trait (responsible for the remaining 15% of cases) (Choice A). Only 1 mutant copy of the FGFR3 gene is sufficient to cause the disorder; 2 copies of the mutant gene (ie, homozygosity) are lethal. As a result, the husband must be heterozygous for the achondroplasia mutation. A heterozygous parent has a 50% chance of transmitting an autosomal dominant mutation. Therefore, the unborn child has a 50% chance of inheriting achondroplasia. Because achondroplasia is a rare condition, the chance of the unborn child having a sporadic (de novo) mutation does not significantly add to the 50% risk of inheriting the disease. (Choice B) In sex-linked disorders, the responsible gene is located on a sex chromosome (either X or Y). Most sex-linked disorders are X-linked recessive (XLR). In XLR disorders, women with a copy of the defective gene will not have the disorder but will be carriers; men who inherit the defective gene will be affected. In X-linked dominant disorders, both males and females are affected following inheritance of the defective gene. (Choice C) Inheritance of an AD trait does not always result in the disease phenotype in conditions with incomplete penetrance. However, achondroplasia is a fully penetrant genetic disorder; if the mother carried the trait, she would have short stature. (Choice D) About 25% of children are affected in autosomal recessive (AR) disorders if both parents carry 1 copy of the defective gene (most common scenario). Many AR disorders are the result of enzymatic deficiencies (eg, phenylketonuria) that require both copies of the gene to be knocked out, as 1 functional copy usually provides sufficient activity to prevent occurrence of the disease. Educational objective: Achondroplasia is an autosomal dominant (AD) disorder that results in a gain-of-function mutation in the FGFR3 gene. Most individuals affected by AD disorders are heterozygous and have a 50% chance of transmitting the mutation to their offspring. __________ References: Achondroplasia (http://www.ncbi.nlm.nih.gov/pubmed/18328977) Achondroplasia: from genotype to phenotype. (http://www.ncbi.nlm.nih.gov/pubmed/17950653)

A Married Couple Comes to the Physician for Routine Prenatal