Familial Factors

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. 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, the mutated gene for which 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.

Screening

It is common for couples to be screened for disorders that may occur in their ethnic group. People of Ashkenazi Jewish background may choose to be screened for heterozygosity for a panel of AR disorders, including Tay-Sachs disease, Niemann-Pick disease, Bloom syndrome, Canavan disease, Gaucher syndrome, cystic fibrosis, Fanconi anemia, and familial dysautonomia. People of African-American ancestry may choose to be screened for sickle cell anemia. People whose ancestors originated in the Mediterranean basin may be screened for thalassemia.

Maternal serum screening is offered to pregnant women during the first or second trimester of pregnancy (see Chapter 58) to assess the risk of both neural tube defects (NTDs) and fetal chromosomal abnormalities. Alpha-fetoprotein (AFP) is a protein secreted during fetal life by the liver, gastrointestinal tract, and yolk sac. If there is an open NTD, such as anencephaly or myelomeningocele, or any other defect in which the fetus’ skin is disrupted, such as an omphalocele, abnormally high levels of AFP will be found in the amniotic fluid. Some of the AFP crosses the placenta and enters the maternal circulation. Levels of AFP are highest during 14 to 18 weeks of gestation, but some level of AFP generally can be detected in maternal blood samples at almost any time during the pregnancy. If the fetus has an NTD, high levels of AFP generally are detected in the maternal serum, but there is overlap between normal levels and levels detected in fetuses with NTDs. About 80% of fetuses with NTDs can be detected in this manner.

Lower than normal levels of AFP may be associated with a fetal chromosomal defect. Approximately 50% of fetuses with autosomal trisomies (Down syndrome, trisomy 18, trisomy 13) will be detected by low maternal serum AFP levels. Three other proteins—unconjugated estriol (uE3), inhibin A, and human chorionic gonadotropin (HCG)—are added to the maternal serum screening to compose the quad screen. The addition of these compounds increases the detection rate to about 80%. There is an increased risk of Down syndrome (trisomy 21) when levels of uE3 and AFP are both low and there is an increased level of HCG. The risk of trisomy 18 is greatly increased when AFP, uE3, and HCG are low. Women with an abnormal maternal serum screen are offered genetic counseling, fetal sonography, and amniocentesis, which is the definitive test for identifying chromosomal abnormalities. A negative screening test does not eliminate the risk that the fetus has a chromosomal abnormality or an NTD.

It is common for pregnant women to have a screening sonogram at 18 weeks’ gestation. An anatomy scan is done to look for congenital anomalies. Brain, heart, kidneys, lungs, and spine are examined.

Maternal Factors

The presence of either acute or chronic maternal illness during pregnancy may lead to complications in the developing fetus. Chronic conditions may expose the fetus to maternal medications that are potentially teratogenic. Acute illnesses such as varicella, Lyme disease, and cytomegalovirus expose the fetus to infectious agents that may cause birth defects. Other factors, such as maternal smoking, alcohol use, and maternal exposure to radiation or chemicals, also may necessitate genetic counseling. Advanced maternal age is defined as a mother who is 35 years of age or older at the time of delivery. These women have an increased risk of a nondisjunctional event and are at risk for having an infant born with a trisomy.

Amniocentesis may be recommended for reasons other than advanced maternal age. Known chromosomal problems in the family, a family history of a NTD, a past history of multiple pregnancy losses, and a history of one or more family members with a known genetic disorder that requires biochemical or DNA testing for prenatal diagnosis are common reasons for referral for amniocentesis. The procedure typically is performed in the early midtrimester, between 15 and 18 weeks of gestation. Under ultrasound guidance, a needle is inserted transabdominally into the amniotic cavity, and 20 to 30 mL of amniotic fluid is withdrawn for diagnostic studies. Generally, cytogenetic studies are done on the amniotic cells, but biochemical or DNA testing also may be performed.

An alternative to amniocentesis is chorionic villus sampling (CVS). Also performed under ultrasound guidance, CVS can be performed either transabdominally or transcervically. A small sample of the chorionic villi is taken by needle biopsy. CVS can be performed earlier than amniocentesis, usually between 10 and 12 weeks of gestation; however, it introduces a greater risk of pregnancy loss than amniocentesis. CVS is associated with an approximately 1% risk of spontaneous pregnancy loss, whereas the risk inherent in amniocentesis is approximately 1 in 1000.

Postnatal—Newborn and Infant

Two to 4% of newborns have a genetic abnormality or birth defect. This broad definition of a birth defect includes not only a visible malformation but also functional defects that might not be apparent at birth.

Birth defects have a significant impact on childhood morbidity and mortality. Almost 11% of childhood deaths can be traced to a genetic cause. If contributing genetic factors related to childhood deaths are considered, this increases to almost 25%. Consultation with a geneticist for a newborn or infant may be prompted by many different findings, including the presence of a malformation, abnormal results on a routine newborn screening test, abnormalities in growth (e.g., failure to gain weight, increase in length, or abnormal head growth), developmental delay, blindness or deafness, and the knowledge of a family history of a genetic disorder or chromosomal abnormality or (as a result of prenatal testing) the presence of genetic disorder or chromosomal abnormality in the infant.

Adolescent and Adult

Adolescents and adults may be seen by a geneticist for evaluation of a genetic disorder that has late onset. Some neurodegenerative disorders, such as Huntington disease and adult-onset spinal muscular atrophy, present later in life. Some forms of hereditary blindness (retinal degenerative diseases) and deafness (Usher syndrome, neurofibromatosis type 2) may not show significant symptoms until adolescence or early adulthood. Genetic consultation also may be prompted for a known family history of a hereditary cancer syndrome (breast and ovarian cancer, hereditary nonpolyposis colon cancer). Individuals may wish to have testing done to determine if they carry a mutation for these syndromes and would be at risk for developing certain types of cancers. A known family history or personal history of a genetic disorder or chromosomal abnormality might prompt testing in anticipation of pregnancy planning.

Family History

A pedigree usually is drawn to help visualize various inheritance patterns. Answers to questions about the family help determine if there is an autosomal dominant (AD), AR, X-linked, or sporadic disorder. When a child is affected with the new onset of an AD disorder, it is necessary to closely examine the parents to check for the presence of manifestations. If the parents are unaffected, the child’s condition is most likely the result of a new mutation, and the risk of recurrence in the condition is extremely low (although not 0, because of the possibility of gonadal mosaicism in one of the parents). When one parent is affected (even mildly so due to varying penetrance), the recurrence risk rises to 50%. With X-linked disorders, the focus is on the maternal family history to determine if there is a significant enough risk to warrant testing.

Questions about the couple’s age are important to ascertain the risk related to advanced maternal age for chromosome abnormalities and increased paternal age for new mutations leading to AD and X-linked disorders. A history of more than two spontaneous abortions increases the risk that one of the parents has a balanced translocation and the spontaneous abortions are due to chromosomal abnormalities in the fetus.

Pregnancy

During a genetic consultation, it is important to gather information about the pregnancy (see Chapters 58, 59, and 60). A maternal history of a chronic medical condition, such as a seizure disorder or diabetes, has known consequences in the fetus. Medication used in pregnancy can be teratogenic; the pregnant woman’s exposure to toxic chemicals (work related) or use of alcohol, cigarettes, or drugs of abuse can have serious effects on the developing fetus. Maternal infection during pregnancy with varicella, Toxoplasma, cytomegalovirus, and parvovirus B19, among others, has been found to cause malformations in the fetus.

Follow-up is needed if an amniocentesis or CVS reveals abnormal results. A fetal ultrasound may have detected a malformation that needs follow-up when the infant is born. Often hydronephrosis is detected prenatally. These infants need a repeat ultrasound soon after birth.

Delivery and Birth

An infant born prematurely is likely to have more complications than a term infant. An infant can be small, appropriate, or large for his or her gestational age; each of these has implications for the child (see Chapters 58, 59, and 60). In general, the finding that an infant is small for gestational age is suggestive of exposure to a teratogen or the presence of a chromosomal abnormality.

Past Medical History

Children with inborn errors of metabolism who have intermittent symptoms often have a history of multiple hospitalizations for dehydration or vomiting. Neuromuscular disorders may have a normal period followed by increasing weakness or ataxia. Children with lysosomal storage diseases, such as the mucopolysaccharidoses, often have recurrent ear infections and can develop sleep apnea.

Development

Many genetic disorders are associated with developmental disabilities. However, the onset of the disability may not always be present from the newborn period; many inborn errors of metabolism, including storage disorders, cause developmental manifestations after a period of normal development (see Chapters 7 and 8). Some adult-onset disorders have no symptoms until the teens or later. Assessing school problems is important. The type of learning problem, age at onset, and whether there is improvement with intervention or continued decline all are important for proper assessment.

Physical Examination

A careful and thorough physical examination is necessary for all patients with signs, symptoms, or suspicion of genetic disease. Sometimes subtle clues may lead to an unsuspected diagnosis. Features suggestive of a syndrome are discussed in more detail in Chapter 50.

Laboratory Evaluation