A 24-year-old woman comes to the office at 12 weeks gestation for prenatal counseling. She is 120 cm (3 ft 11 in) tall with short upper and lower extremities but normal torso length. Physical examination is also significant for depression of the nasal bridge and a bulging forehead. Her husband is phenotypically normal and has no medical problems. The patient knows that there is a 50% chance of passing on her condition to the fetus. An abnormality involving which of the following cells is most likely responsible for this patient's features?

Question

A 24-year-old woman comes to the office at 12 weeks gestation for prenatal counseling.  She is 120 cm (3 ft 11 in) tall with short upper and lower extremities but normal torso length.  Physical examination is also significant for depression of the nasal bridge and a bulging forehead.  Her husband is phenotypically normal and has no medical problems.  The patient knows that there is a 50% chance of passing on her condition to the fetus.  An abnormality involving which of the following cells is most likely responsible for this patient's features?

Quizplus · Accepted Answer

11ec160b_3b60_977f_9249_0f58dfd37e35_MD0001_00 This patient's limb shortening with normal torso length, specific craniofacial features (frontal bossing, midface hypoplasia), and risk of passing the condition to her offspring (50%) are characteristic of achondroplasia. The condition is caused by an autosomal dominant point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene; 90% are de novo (unaffected parents) and 10% are inherited. Because the mutation is autosomal dominant, the fetus of an affected and an unaffected parent has a 50% chance of inheriting the mutation. Achondroplasia affects endochondral ossification, the process that makes long bones (eg, humerus, femur, phalanges) and portions of the skull and face. In endochondral bone formation, mesenchymal cells differentiate into chondrocytes that secrete cartilage matrix. These chondrocytes continue to proliferate through childhood, forming an elongating cartilage template that progressively becomes calcified and later invaded by osteoblasts, osteoclasts, and blood vessels originating from the periosteum. Deposition of osteoid matrix over the septa of calcified cartilage matrix forms woven bone, which then undergoes remodeling into compact bone. FGFR3 is normally responsible for limiting chondrocyte proliferation during endochondral ossification. In achondroplasia, FGFR3 becomes constitutively activated, causing exaggerated inhibition of chondrocyte proliferation that results in the characteristic bone shortening and craniofacial abnormalities. (Choices B and E) Hypothalamic neurosecretory cells produce growth hormone-releasing hormone and anterior pituitary somatotrophs produce growth hormone (GH). Hypothalamic or pituitary insults (eg, tumor, ischemia) can result in defective release of either hormone. GH deficiency can lead to proportional short stature (both long and flat bones affected) as opposed to the disproportionate short stature seen in achondroplasia (only long bones affected). (Choice C) The flat bones (eg, most of the skull, pelvis) grow primarily via intramembranous (not endochondral) ossification. In intramembranous ossification, mesenchymal cells differentiate directly into osteoblasts and begin osteoid matrix secretion without the formation of cartilaginous bones. As a result, most flat bones remain unaffected in achondroplasia. (Choice D) Osteoclasts are specialized macrophages that function to resorb bone. Paget disease, characterized by disordered bone mass, initially begins with excessive activity of abnormally large osteoclasts followed by osteoblastic activity and eventual sclerosis. Patients are usually elderly and can present with focal bone pain and pathologic fractures. Educational objective: Unlike the process of intramembranous ossification that forms flat bones, endochondral ossification proceeds along a cartilage template and is responsible for the formation of long bones. Achondroplasia is characterized by an exaggerated inhibition of chondrocyte proliferation in the growth plates of long bones and manifests with proximal limb shortening, midface hypoplasia, and macrocephaly. __________ References: Pediatric aspects of skeletal dysplasia. (http://www.ncbi.nlm.nih.gov/pubmed/23330244) Achondroplasia: from genotype to phenotype. (http://www.ncbi.nlm.nih.gov/pubmed/17950653)

A 24-Year-Old Woman Comes to the Office at 12 Weeks