PRENATAL DIAGNOSIS OF A GIRL WITH MUSCULAR DYSTROPHY CAUSED BY DE NOVO t(X;4) (p21;q35)

Abstract

In May, 1983 we obtained amniotic fluid for chromosome studies from a couple who were both 31 years old. The indication was parental anxiety because the mother worked closely with mentally retarded adults. The amniotic fluid cell karyotype was female with a balanced translocation: 46,X,t(X;4)(p21;q35) with the normal X preferentially inactivated. Alpha fetoprotein and detailed ultrasound examinations were normal. Chromosome studies of the parents were normal, so the translocation apparently arose as a new mutation.Two special circumstances complicated the counseling. First, a de novo rearrangement ascertained by amniocentesis carries roughly a 5% increased risk of birth defects over the general 3-5% population incidence of birth defects, but the available risk estimates do not appear to include the risk of mental retardation without malformation, since follow-up has been sporadic of such cases identified prospectively. Second, in a balanced X/autosome translocation the structurally normal X is genetically inactivated, which allows expression of any abnormal genes on the translocation X. There are at least 13 other girls with Duchenne muscular dystrophy who carry a de novo X/autosome translocation with a breakpoint at Xp21. In the absence of a family history of muscular dystrophy, these findings suggest a point mutation due to the break at Xp21.We advised the parents that the fetus was at some increased risk (of uncertain magnitude) for having malformations, retardation, or muscular dystrophy. The couple continued the pregnancy. At age 3 months, the infant has a normal appearance, developmental milestones and neurologic exam. However, at 24 hours of age her serum CPK was 21,450 IU/L. Subsequent values were 1,260 and 3,100 at 1 and 3 months, respectively. Such neonatal and infancy levels of CPK are strongly suggestive of Duchenne's muscular dystrophy.