Genetics and Congenital Anoma... Health Article

Genetic profile

Of all major congenital malformations, 60% have an undetermined cause, and 20% are attributed to multifactorial inheritance. The remaining 20% are divided roughly equally between single-gene disorders, chromosomal syndromes, and teratogenic causes. Considering that inclusion in the multifactorial group does not imply a specifically determined cause in any particular case, about 80% of all major malformations have no readily identifiable cause. The most frequently malformed organs are the brain, heart, and urinary tract (kidneys, ureters, bladder, and urethra). Deformations and disruptions most often affect the extremities (hands and feet), limbs (arms and legs), skull, and face.

Multifactorial inheritance is assumed for most isolated congenital anomalies, with a risk for recurrence in subsequent pregnancies of 3–5%. Single-gene (e.g., autosomal dominant, autosomal recessive, sex-linked, etc.) and chromosomal syndromes present a broad range of recurrence risks, but most often are 1–3% for chromosomal syndromes, and 25% or 50% for single-gene disorders.

Demographics

Considered individually, most anomalies and genetic syndromes are uncommon, and some are quite rare. As a group, however, they are quite common. Major congenital anomalies are the leading cause of death for children less than one year old, and the second and third most frequent cause for those less than five and 15 years old, respectively. Approximately 40% of all pediatric hospital admissions are related to congenital anomalies.

As already noted, malformations may be isolated or multiple, with minor or major clinical significance. Of all newborns, about 14% have a single minor malformation, 3% have a single major malformation, and up to 0.7% have multiple major malformations. The frequency of major malformations is even higher at conception, estimated at 10–15%, but most of these result in spontaneous pregnancy loss. About 2% of newborns are found to have a disruption of some type. In the presence of a major congenital malformation, especially if it affects the central nervous system or urinary tract, there is an 8% risk that a deformation will also occur. Skeletal dysplasias have an overall incidence of about 0.5%, with diagnosis of some of the milder forms often delayed until childhood. Ectodermal dysplasias occur in about 0.7% of individuals, but only several types associated with major malformations are usually diagnosed at birth. Other forms of congenital dysplasias are rare.

Diagnosis

Many anomalies are now detected/diagnosed prenatally, either through testing chosen because of a known or suspected risk factor, as a coincidental finding during testing chosen for another purpose, or as a chance finding by routine prenatal evaluations. Prenatal testing is done either through imaging studies, most often routine (level I) or detailed (level II) obstetric ultrasound, or through direct biochemical or genetic testing of the fetus using chorionic villus sampling (CVS) or amniocentesis.

Fetal echocardiography is sometimes used to confirm heart defects, and some rare conditions might require x rays or magnetic resonance imaging (MRI) of the fetus (via the mother), while a few others can only be diagnosed by a fetal skin biopsy. Some tests are designed only to screen for certain anomalies or syndromes (increase or decrease the likelihood).

Evaluating congenital anomalies postnatally usually involves attempts to confirm the suspected or most likely diagnosis, while at the same time excluding other possible diagnoses. Major external anomalies are easily detected, but those affecting internal organs require recognition of the signs and symptoms they produce (e.g., a baby with breathing difficulty who turns blue (cyanotic) while crying may have a heart defect), which could be subtle and/or not appear until well after birth.

Any child with an apparently isolated congenital anomaly should have this confirmed (i.e., exclude subtle or hidden signs of an association or syndrome). Multiple congenital anomalies are best evaluated by a geneticist, if possible, even in cases involving an obvious diagnosis, such as a common condition like Down syndrome. The family may wish to have a consultation in a genetics clinic, where a comprehensive approach helps to ensure that a thorough evaluation and explanation of the condition are provided. In addition, psychosocial issues are addressed, appropriate referrals can be made (e.g., other specialists, support groups, or more extensive psychological assistance as needed), and the most complete and current information on testing and other options are available. In cases with an unusual presentation of symptoms, or rare syndromes, geneticists have the best chance of establishing a diagnosis, often in consultation with colleagues who specialize in a particular syndrome or class of disorders. In other situations, a geneticist might suggest periodic revaluations if a diagnosis is unclear initially, since some children grow into a syndrome (i.e., the defining characteristics only become apparent as the child grows). Unfortunately, all too often a diagnosis is never established, regardless of effort expended or specialists consulted. Even in these cases, a geneticist may be able to offer a reasonable estimation as to a cause and recurrence risk, based on a process of eliminating some factors, making others more likely, and applying any available empirical data from similar cases.

Regardless of situation, a genetics evaluation includes as many of the following as possible:

• a complete physical examination of the affected child
• a review of medical records
• evaluation of the pregnancy history
• a consultation to obtain and evaluate the medical history of the immediate and extended family

Based on these evaluations, one or more of a wide variety of possible medical tests could be suggested. If a hereditary syndrome is suspected, physical examination, medical record review, and testing might also be requested of one or more family members to help establish a diagnosis. The importance of making a diagnosis rests in the ability it provides to answer other questions parents inevitably have. The diagnostic process also attempts to determining how a malformation, deformation, disruption, dysplasia, or some combination, occurred.