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Genetic Evaluation Opens New Avenues of Diagnosis
Genetic testing is opening up new avenues of diagnosis for children born with developmental delays and mental retardation, helping pediatricians identify conditions that previously could not be diagnosed clinically.
In Sunday's session on "Genetic Evaluation of the Child With Global Developmental Delays and Mental Retardation," John B. Moeschler, MD, FAAP, professor of pediatrics at Dartmouth Medical School and director of clinical genetics at the Children's Hospital at Dartmouth, Hanover, NH, reviewed a clinical genetics evaluation process he uses to diagnose patients who present with signs of developmental delay or mental retardation.
After discussing a case study of a child with Noonan syndrome, Dr Moeschler defined global developmental delay as a significant delay in two or more developmental domains: gross or fine motor, speech/language, cognitive, social/personal, and activities of daily living. The term is usually reserved for children under 5 years of age.
He defined mental retardation as a disability characterized by significant limitations in intellectual functioning and in adaptive behavior as expressed in conceptual, social, and practical adaptive skills. This disability generally originates before age 18.
Benefits of Genetics
The benefits of a clinical genetics evaluation for these conditions include avoiding unnecessary testing and gaining information that will help pediatricians manage the complications of the disorder, Dr Moeschler said. Such an evaluation is also cost effective when compared with usual care by neurologists, a recent study found.
The diagnostic process he described starts with a clinical history, family history, dysmorphology examination, and neurologic exam. If these steps do not result in a clinical diagnosis of developmental delay or mental retardation, then the clinician should try genetic testing.
The genetic testing he discussed included standard karyotyping and fragile X molecular genetic testing. If the results of these tests are normal, then clinicians should try fluorescence in-situ hybridization (FISH) for submicroscopic subtelomere rearrangements.
Once a diagnosis is established with genetic tests, pediatricians can then either manage or refer the patient or apply genetic testing to family members, if necessary, to confirm the diagnosis. If the patient has dysmorphology, such as microcephaly or macrocephaly, then magnetic resonance imaging may be required.
However, the genetic tests currently available for developmental delays and mental retardation result in a diagnosis in an estimated 54 percent of patients. The rest may go undiagnosed until a better test comes along, Dr Moeschler said.
The Diagnostic Process
The family history should include three generations of medical histories, with special attention to mental retardation and developmental delays. About 15 percent of patients will have a family history of mental retardation.
Standard karyotyping examines more than 550 bands of chromosomes for abnormalities, he said. These cytogenic studies have a diagnosis rate of about 9.5 percent. Fragile X molecular genetics testing can increase that diagnostic rate. It is especially useful in patients with a family history of mental retardation and dysmorphic facial characteristics, such as a long, narrow face.
About half of all structural chromosomal rearrangements involve the telomeres (ends) of the chromosomes, and that's why subtelomeric testing is valuable. Many of these abnormalities are not detected by routine karyotyping, Dr Moeschler said.
FISH is a technology used to detect subtelomeric rearrangements. About 7.4 percent of all children with mental retardation and developmental delays have subtelomeric abnormalities, he added. However, many of the syndromes detected are unique or rare syndromes with little known about their management, and the test may produce some false-positive results.
Based on findings of metabolic risks or complications from a history and physical examination, metabolic studies may be used to detect rare causes of mental retardation and developmental delays. However, these studies have a diagnostic rate less than 1 percent and there is a lack of data and expert consensus on the proper management of these rare causes, he said.
A dysmorphic examination is by far the most useful diagnostic study in the evaluation of developmental delays and mental retardation, with a diagnostic rate ranging from 39 percent to 81 percent. Next in utility is a neurologic exam, with a diagnostic rate of about 42 percent. By comparison, FISH has a diagnostic rate of 4.4 percent, Dr Moeschler said.