ACH is caused by mutations in the FGFR3 gene. Early in development, FGFR3 is expressed during endochondral bone formation. More than 95% of cases of ACH are caused by one of two mutations in the same base pair (site 1138). This site, extremely active for mutations, is known as a mutational hot spot.
As they grow, children with ACH often develop associated medical and psychological problems. Hydrocephalus and central apnea may occur because of narrowing of the foramen magnum and compression of the brainstem and may present a life-threatening complication in infancy. Bowing of the legs may occur later in childhood because of unequal growth of the tibia and fibula. Dental malocclusion, obstructive apnea, and hearing loss due to middle ear dysfunction are common in later childhood. During later childhood and adolescence, the psychological effects of the short stature may manifest. In adulthood, further complications include compression of
Affected individual Individual with decreased penetrance
Figure 47-2 Pedigree showing decreased penetrance for an auto-somal dominant disorder. Proband (arrow) is affected. Maternal grandfather also is affected. The individual’s mother is presumed to be the carrier of the gene, even though she may show only slight symptoms of disease.
Each child of an affected parent has a one in two chance of being affected Males and females are equally affected Male-to-male transmission occurs Traits generally involve mutations in genes that code for regulatory nerve roots and sciatica. People with ACH have normal life spans and normal intelligence.
The diagnosis of ACH is made on the basis of clinical findings; characteristic x-ray abnormalities confirm the diagnosis. Molecular testing is available but is usually reserved for cases that are difficult to diagnose or those in which prenatal diagnosis is requested. Prenatal diagnosis is possible by molecular testing, using fetal cells obtained through amniocentesis or chorionic villus sampling.
One of the most common AD disorders, NF1 is estimated to be present in 1 in 3500 individuals. NF1 is caused by a mutation in the gene NF1, which codes for the protein neurofibromin.
Although the penetrance of NF1 is 100%, the expression is extremely variable. Many affected individuals have features so mild that they are never diagnosed.
SEE CHAPTER 186.
A condition that occurs in approximately 1 in 10,000 individuals, MFS shows pleiotropy, the condition in which abnormalities in multiple organ systems are caused by a mutation in asingle gene. Caused by a mutation in the FBN1 gene, clinical symptoms in MFS mostly involve three systems: cardiac, ophthalmologic, and skeletal. Skeletal findings include a tall, thinbody habitus (dolichostenomelia), spider-like fingers and toes(arachnodactyly), abnormalities of the sternum (pectus excavatum or carinatum), scoliosis, pes planus, and joint laxity.Eye findings include high myopia, which can lead to vitreoretinal degeneration; an abnormal suspensory ligament of thelens, which can lead to ectopia lentis (dislocation of the lens);and cataracts. Cardiac findings include progressive dilatationof the aortic root. Aortic insufficiency followed by aortic dissection is a common complication. Other clinical features of MFS include dural ectasia, abnormal pulmonary septation,and striae. Diagnostic criteria for MFS are summarized inTable 47-3.
New mutations in FBN1 account for 25% of cases of MFS. The gene is large and complex; more than 600 mutations have been identified in affected individuals. Many of the symptoms of MFS are caused not by the defect in the fibrillin protein itself but rather by an excess in transforming growth factor-beta (TGF-β), a protein usually bound by fibrillin. Losartan, an angiotensin II receptor antagonist that also lowers levels of TGF-β, may prevent aneurysms in patients with MFS.