The Burden of Genetic Disorders in Childhood

Genetic disorders can appear at any age, but some of the most obvious and severe diseases begin in childhood. It has been estimated that 53/1,000 children and young adults can be expected to have diseases with an important genetic component. If congenital anomalies are included, the rate increases to 79/1,000. In 1978 it was estimated that just over half of admissions to pediatric hospitals were for a genetically determined condition. By 1996, owing to changes in health care delivery and a greater understanding of the genetic basis of many disorders, that percentage rose to 71% in one large pediatric hospital in the USA, and 96% of chronic disorders leading to admission had an obvious genetic component or were influenced by genetic susceptibility. Major categories of genetic disorders include single-gene, genomic, chromosomal, and multifactorial conditions.

Individually, single-gene disorders are rare, but collectively they represent an important contribution to childhood disease. The hallmark of a single-gene disorder is that the phenotype is overwhelmingly determined by changes that affect an individual gene. The phenotypes associated with single-gene disorders can vary from one patient to another based on the severity of the change affecting the gene and additional modifications caused by genetic, environmental, and/or stochastic factors. This feature of genetic disease is termed variable expressivity. Common single-gene disorders include sickle cell anemia and cystic fibrosis.

Single-gene disorders tend to occur when changes in a gene have a profound effect on the function of the gene product. Such effects can include insufficient product (structural protein, enzyme, metabolites), loss of function, or a harmful gain of function. Testing for single-gene disorders typically involves searching for mutations most often by directly sequencing the gene and, in some cases, looking for small deletions and/or duplications that might affect the causative gene. Single-gene disorders can occur sporadically, owing to occurrence of de novo mutations (mainly true for dominant disorders), but they can also be caused by inherited changes.

The risk of having a child with a single gene disorder can vary from one population to another. In some cases this is due to the founder effect, in which a specific change affecting the causative gene achieves relatively high frequency in a population derived from a small number of founders. This frequency is maintained because of restricted interbreeding with persons outside of that population. This is the case for Tay-Sachs disease in Ashkenazi Jews and French Canadians. Other changes may be subject to positive selection when found in the heterozygous carrier state, such as hemoglobin mutations that confer relative resistance to malaria.

Genomic disorders are a group of diseases caused by rearrangements of the genome including deletions (loss of a copy of DNA), duplications (addition of a new copy of DNA), and inversions (altered organization of DNA). When these disorders are caused by rearrangements that affect several adjacent genes that contribute to a specific phenotype they are sometimes referred to as contiguous gene disorders. DiGeorge syndrome, which is caused by deletions of genes located on chromosome 22q11, is a common example. Some genomic disorders are associated with distinctive phenotypes that can be recognized clinically, and others produce nondescript phenotypes of developmental impairment with variable effects on intellect as well as growth and physical appearance. Genomic disorders are often identified by fluorescent in situ hybridization (FISH) or by array comparative genome hybridization (aCGH) technologies. Larger changes may be seen on a chromosome (cytogenetic) analysis.

Deletions, duplications, and inversions that affect whole chromosomes, or large portions of a chromosome, are commonly referred to as chromosomal disorders. One of the most common chromosomal disorders is Down syndrome, which is most commonly associated with the presence of an extra copy, or trisomy, of an entire chromosome 21. When all or a part of a chromosome is missing the disorder is referred to as monosomy. In some cases, only a portion of cells that make up a person’s body carry the chromosomal defect. This is referred to as mosaicism. Translocations are another common type of chromosomal anomaly, in which a piece of one chromosome breaks off and becomes attached to a different, nonhomologous chromosome. Translocations can be balanced, meaning that although there has been a rearrangement, no material has been lost or gained; they can also be unbalanced, when some material (often at the breakpoint connecting DNA from different chromosomes) is deleted or duplicated compared to normal. Chromosomal disorders are typically identified on a chromosome analysis but may also be detected by FISH or aCGH.

Multifactorial disorders are caused by the action of multiple genes and/or gene-environmental effects. Spina bifida and isolated cleft lip or palate are common pediatric disorders that display multifactorial inheritance patterns. These traits can cluster in families but do not have a mendelian pattern of inheritance (Chapter 75). In most cases the causative genes are unknown, and genetic counseling is based on empirical data. The concept of multifactorial inheritance extends to common pediatric disorders, such as asthma and diabetes mellitus.

The Changing Paradigm of Genetics in Medicine

Although specific treatments are not available for most genetic disorders, there are some important exceptions. Inborn errors of metabolism were the first genetic disorders to be recognized, and many are amenable to treatment by dietary manipulation (Chapter 78). These conditions result from genetically determined deficiency of specific enzymes, leading to the buildup of toxic substrates and/or deficiency of critical end products.

Individual metabolic disorders tend to be very rare, but their combined impact on the pediatric population is significant. Tandem mass spectrometry has made it relatively inexpensive to screen for a large number of these disorders in the newborn period. Use of this technology not only dramatically increases the number of metabolic disorders identified within a population but also allows treatment to be initiated at a much earlier stage in development (Chapters 72 and 78).

An area where most progress has been made regarding genetic therapies has been the lysosomal storage disorders. These are a group of metabolic diseases caused by defects in lysosomal function. Lysosomes are cellular organelles that contain specific digestive enzymes. Some of these disorders that were lethal or associated with intractable chronic illness can now be treated using specially modified enzymes that are administered by intravenous infusion. These enzymes are then taken up by cells and incorporated into lysosomes. Conditions such as Gaucher disease and Fabry disease are routinely treated using enzyme replacement, and similar therapies are being developed for other lysosomal disorders.

Therapeutic advances are extending to other nonmetabolic genetic disorders as well. Improvements in surgical treatment of congenital anomalies such as heart defects are extending the survival of children with birth defects or conditions such as Down syndrome. The life expectancy of those with cystic fibrosis has steadily increased, largely owing to improvements in antibiotic therapy as well as the management of chronic pulmonary disease and malabsorption. A major consequence of these advances is that an increasing percentage of affected patients are surviving into adulthood, creating a need to transition care from pediatric to adult providers.

Gene-replacement therapies have long been anticipated. However, it has proved difficult to develop safe and effective approaches for inserting genes into diseased tissues in a way that allows physiologically meaningful levels of gene expression to be maintained over long periods. The advent of therapeutics based on stem cells also offers the possibility of treatment for previously intractable disorders.

Long-standing and highly successful carrier screening programs have existed for disorders such as Tay-Sachs disease and many other rare single-gene disorders that are prevalent in specific populations. Couples are commonly offered screening for a variety of conditions, in part based on ancestry (Tay-Sachs disease, hemoglobinopathies, cystic fibrosis). Couples found to be at risk can be offered prepregnancy or prenatal testing, which is based on genetic tests aimed at detecting specific mutations.

Prenatal testing is also offered for chromosomal disorders such as Down syndrome; an increasing number of affected pregnancies are being recognized by noninvasive screening tests of maternal serum in the first and second trimester and by fetal ultrasound. Approaches to noninvasive prenatal diagnosis by sampling of fetal cells or fetal DNA in maternal blood are also being developed. In many cases, prenatal diagnosis can be confirmed by chorionic villus sampling at 10-12 wk or by amniocentesis at 16-18 wk of gestation. When a couple is at risk for a specific genetic defect, preimplantation genetic diagnosis (PGD) can sometimes be used to select unaffected early embryos, which are then implanted as part of an in vitro fertilization procedure. It is important that couples understand that although these approaches can be useful in detecting and, in the case of PGD, avoiding affected pregnancies, each has their limitations and none can guarantee the birth of a healthy child.

Genetic testing is increasingly available for a wide variety of both rare and relatively common genetic disorders. Genetic testing is commonly used in pediatric medicine to resolve uncertainty regarding diagnosis and provide a basis for genetic counseling; in some instances, it can serve as a prelude for specific treatment. In the future, predictive testing for predisposition to disease could become more common. It is likely that the expansion of such testing will depend, at least in part, on the extent to which such testing can be linked to strategies to prevent disease or improve outcome (Chapter 72).

It is possible that genetic tests will come to underlie a high proportion of all medical decisions and will be seamlessly incorporated into routine medical care. One of the areas in which genetic testing is likely to make a significant impact is on individualized drug treatment. It has long been known that genetic variation in the enzymes involved in drug metabolism underlies differences in the therapeutic effect and toxicity of some drugs. As the genetic changes that underlie these variations are identified, new genetic tests may be developed that will allow physicians to tailor treatments based on individual variations in drug metabolism, responsiveness, and susceptibility to toxicity. Such advances may help to usher in a new era of personalized medical treatment.

Genetics and Pediatric Practice

Pediatricians play a critical role in providing and coordinating medical services for families affected by genetic disorders. In this role, pediatricians are likely to come in contact with, or be served by, a variety of genetics professionals. Each of these professionals has undergone a program of training and certification consistent with their clinical role (Table 73-2). In most cases, pediatricians refer children with presumed genetic disorders to a clinical geneticist. Clinical geneticists are physicians who have completed a residency in genetics and are certified by the American Board of Medical Genetics. They can provide expertise in achieving a correct diagnosis, counseling the family regarding natural history and management of the disorder as well as recurrence risk, and implementing a management and treatment plan.

As the number of identifiable genetic disorders and the scope of genetic testing increase, pediatricians and clinical geneticists will be expected to recognize children affected by relatively rare disorders and asymptomatic children who are at risk for genetic disease. Some disorders for which early treatment is critical may be added to newborn or early childhood screening panels; others will be the subject of clinical practice guidelines. It is likely that physicians will come to rely on advances in technology to help them keep pace. Such advances may include the development of computer programs that can aid in the diagnosis of rare disorders and testing panels that can help identify the etiology of genetically heterogeneous disorders—disorders with more than one genetic cause. The usefulness of simple office-based practices such as obtaining an accurate family history should not be underestimated.

Ethics Issues

Like all medical care, genetic testing, diagnosis, and treatment should be performed confidentially. Nothing is as personal as one’s genetic information, and all efforts should be made to avoid any stigma for the patient. Many people fear that results of genetic testing will put them, or their child, at risk for genetic discrimination. Genetic discrimination occurs when people are treated unfairly because of a difference in their DNA that suggests that they have a genetic disorder or are at an increased risk of developing a certain disease. In the USA, the Genetic Information Nondiscrimination Act of 2008 protects individuals from genetic discrimination at the hands of health insurers and employers but does not extend protection against discrimination from providers of life, disability, or long-term care insurance.

Like all medical decision making, the decisions about genetic testing should be based on a careful evaluation of the potential benefits and risks. In the pediatric setting, these decisions may be more difficult because physicians and parents are often called to make decisions for a child who cannot directly participate in discussions about the testing. Molecular diagnostic tests are often used to diagnose malformation syndromes, mental retardation, or other disabilities wherein there is a clear benefit to the child. In other cases, such as genetic testing for susceptibility to adult-onset diseases, it is appropriate to wait until the child or adolescent is mature enough to weigh the pros and cons and make his or her own decisions about genetic testing.

Policies regarding genetic testing of children have been issued jointly by the American Society of Human Genetics and American College of Medical Genetics (Am J Hum Genet 57:1233-1241, 1995) and by the American Academy of Pediatrics (AAP) (Pediatr 2001;107:1451-1455, 2001). The AAP recommendations include the following: