In female premutation carriers, an expansion in the number of repeats from the premutation to the full mutation range may occur during gametogenesis. The cause of this expansion is not understood. Although these females do not have symptoms and signs of FRAX, premutation carriers may manifest premature ovarian failure and/or a neurologic condition known as fragile X tremor/ataxia syndrome later in life.
Approximately 6.5% of all birth defects are attributed toteratogens—chemical, physical, or biologic agents that have the potential to damage embryonic tissue and result in congenital malformations. Agents known to be teratogenic include drugs (prescription and nonprescription); intrauterine infections (rubella); maternal diseases, such as diabetes mellitus; and environmental substances, such as alcohol and heavy metals. Knowledge of teratogenic agents and their effect on the developing fetus is important, because limiting exposure to these agents is an effective way to prevent birth defects (see Chapters 58, 59, and 60).
Rubella was the first maternal infection known to cause a pattern of malformations in fetuses affected in utero. Cytomegalovirus, Toxoplasma gondii, herpes simplex, and varicella are additional potentially teratogenic in utero infections (see Chapter 66).
Maternal diabetes mellitus and maternal phenylketonuria can result in congenital anomalies in the fetus. Strict control of these disorders before and during pregnancy protects the developing child (see Chapter 59).
Fetal alcohol spectrum disorder, which occurs in 10 to 20 per 1000 children, may be the most common teratogenic syndrome. Features include prenatal and postnatal growth deficiency, developmental disabilities, microcephaly, skeletal and cardiac anomalies, and a characteristic facial appearance. To cause the full-blown fetal alcohol syndrome, pregnant women must drink alcohol throughout the pregnancy. Lesser consumption during all or part of the gestation will lead to milder symptoms.
Warfarin, retinoic acid, and phenytoin are additional teratogenic agents (see Chapter 59).
High-dose radiation exposure during pregnancy in Hiroshima and Nagasaki, Japan, was shown to increase the rate of spontaneous abortion and result in children born with microcephaly, mental retardation, and skeletal malformations. Estimates of exposure to cause these effects were approximately 25 rad. The dose from routine radiologic diagnostic examinations is in the millirad range.
Individuals referred to a geneticist because of suspicion of a genetic disorder are called probands; individuals who come for genetic counseling are consultands. Referral for genetic evaluation may be made for a wide variety of reasons and at different stages of life (fetus, neonate, childhood, pregnancy).
Families with relatives affected with genetic disorders may have questions about how a disorder is inherited. The inheritance pattern and the risk of having an affected child can be discussed with a geneticist.
In some cultures, it is common for relatives to mate. This relatedness or consanguinity does not increase the likelihood of offspring having any particular single genetic disorder, but it may increase the chance that a child will be born with a rare autosomal recessive (AR) condition, as the mutated gene segregates through that family. Generally, the closer the relation between the partners, the greater the chance that the couple shares one or more mutated genes in common, increasing the risk that offspring will have an AR disorder. The risk of first cousins producing a child with an AR disorder is 1 in 64. In evaluating these couples, it is important to determine which ethnic group they belong to and to test for conditions commonly found in that group.