CHAPTER 4

Once a child has been identified as having a developmental-behavioral disorder, the initial evaluation will characterize the descriptive nature of the developmental disorder as well as attempt to determine the underlying etiology (see Chapter 11, Making Developmental-Behavioral Diagnoses). This chapter will discuss the primary pediatric health care professional’s clinical evaluation including medical history, physical examination, and diagnostic medical testing with a focus on those aspects of the evaluation that may be most helpful in the determination of an etiological diagnosis underlying the descriptive developmental-behavioral disorder. Specific examples of disorders will be provided that best illustrate important concepts in the biological basis of disorders of development and behavior.

There are multiple reasons to diagnose the underlying etiology of a developmental-behavioral disorder rather than to simply characterize the descriptive nature of the disorder. The most important justification for determining an etiological diagnosis is to identify disorders that are treatable and for which timely intervention may improve the natural history of the disorder. Interventions may include pharmaceutical treatment, dietary modifications, or surveillance for known medical complications. Second, identification of a specific diagnosis may end the diagnostic odyssey, resolving detrimental uncertainty and anxiety for the family and preventing costly and invasive testing in the future. A specific diagnosis may also provide access to additional support services, to a community of similarly affected families, and to opportunities for participation in research. Third, medical professionals are likely to be able to provide a more accurate medical prognosis if the underlying etiology of the developmental disorder is known. Last, if a specific genetic etiology is identified, then genetic counseling can be provided to the family at risk for recurrence in future pregnancies within the nuclear or extended family.

Classical twin studies have shown that intelligence within the normal range is a heritable trait, likely as a function of the cumulative effect of many genetic variants that each have a small effect size. The focus of this chapter will not be the biological determinants of development and behavior that are prevalent in the population and of individually small effect size such as those identified using genome wide association studies in large cohorts. Rather, the focus will be on those rare determinants of development that have a large effect size and that may be identifiable as a discrete etiological diagnosis with clinically available testing or careful history taking and physical examination.

Pedigree analysis is a well-established technique that can provide clues to the underlying etiology of developmental-behavioral disorders. A thorough analysis of the pedigree will include brief medical histories of the parents, siblings, grandparents, aunts, uncles, and cousins of the child being evaluated, as well as determination of the ethnic background of the family and a specific inquiry into whether the parents of the child are consanguineous. While consanguineous unions are rare in the United States, there are areas of the world in which recent shared ancestry of the two parents is the norm.1 The presence of consanguinity would increase the likelihood that a developmental-behavioral disorder is the result of a recessive genetic condition. Similarly, even in the absence of consanguinity, if both parents are members of the same ethnic group, then the likelihood of recessive genetic disease is increased. Known founder effects in specific populations may allow the clinician to focus the diagnostic evaluation on those conditions. For example, the carrier status for Tay-Sachs, Canavan, and Niemann-Pick type A diseases are increased in the Ashkenazi Jewish population. There are multiple recessive genetic etiologies of developmental-behavioral disorders that are much more prevalent among the Amish and other endogamous religious communities. The absence of recent or remote shared ancestry between parents should not be considered reassuring against the possibility of a genetic diagnosis; it would simply moderately reduce the likelihood of a recessive genetic condition.

It is important to note that the specific presentation of a disorder may differ between a child with a specific developmental-behavioral disorder and previously affected generations in the family, a phenomenon known as variable expression. One relatively common genetic disorder that exemplifies variable expression is neurofibromatosis type 1 (NF1). While over 90% of those with NF1 will have the characteristic skin findings of café-au-lait macules and intertriginous freckling, about half will have learning disabilities and smaller percentages will have autism and intellectual disability.² This demonstrates the importance of a broad family history that addresses conditions beyond the realms of development and behavior.

Fragile X syndrome is another example of a condition with variable findings in the family history. In the case of fragile X, the unusual family history is due to genetic anticipation. The disorder is caused by an unstable trinucleotide repeat in the gene FMR1. The trinucleotide repeat may lengthen when inherited through the maternal germ line and result in more severe manifestations after the expansion, a circumstance called anticipation. Additionally, FMR1 is on the X chromosome, meaning that males with a mutation are hemizygous (have only that allele of the gene) whereas females are heterozygous (have a second normal allele of the gene). Thus, a boy with significant developmental delay due to FMR1 trinucleotide repeat expansion may have a mother with premature ovarian insufficiency but normal cognition due to a smaller repeat expansion in the gene (a premutation). Male and female premutation carriers (eg the maternal grandfather) may develop the fragile X–associated tremor and ataxia syndrome (FXTAS), an adult-onset movement disorder that does not manifest with developmental delays in childhood.3 For male patients with developmental delay, specific inquiry about the health and development of the maternal uncles and great-uncles is indicated to assess for fragile X and other causes of X-linked intellectual disability. For fragile X, like NF1, a family history of conditions other than atypical behavior and development may provide clues to the etiological diagnosis for the patient.

Families affected by mitochondrial disorders may also have pedigrees with distinctive characteristics. Mitochondrial DNA (mtDNA) is inherited exclusively from the mother, and specific attention to the health history of matrilineal relatives may reveal indications of mtDNA-mediated disease. Rather than the typical two copies of each gene encoded by nuclear DNA that are present, each cell will typically have thousands of copies of mtDNA. Mutations in mtDNA are not homozygous or heterozygous, but rather are present at levels of heteroplasmy that vary from zero to 100% (known as homoplasmy). The levels of heteroplasmy may vary between different tissues in the body and may change dramatically from generation to generation. A child presenting with developmental delay due to mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) due to high levels of heteroplasmy for the m.3243A>G mutation in mtDNA may have matrilineal relatives with normal development but who are affected by diabetes, hearing loss, or migraine headaches due to lower levels of heteroplasmy for the same mutation.⁴

The absence of a significant family history of illness should not be considered reassuring against the possibility of a genetic disease being the etiology of the developmental-behavioral disorder. Most patients with a recessively inherited condition will not have any affected family members, especially outside of endogamous communities. With extensive use of whole exome trio testing in recent years, it has become apparent that a significant proportion of genetic disease results from de novo mutations in the child being studied (proband) and not inherited mutations.

Conception

Specific questions about the conception of a child presenting with developmental delay may provide important information about an etiological diagnosis. A history of multiple miscarriages for the child’s mother may indicate that she or her partner could be a carrier for a balanced chromosomal translocation. Such chromosomal anomalies are present in about 5% of couples with recurrent miscarriages.⁵ A balanced translocation typically results in a normal gene complement and normal development for that individual. However, the chromosomes may become imbalanced in the germ cells, and the resulting conceptus may not be viable or may result in a child with gene dosage abnormalities that cause developmental delay. Recurrent miscarriage could also indicate the presence of a thrombophilic disorder for the mother. Thrombophilic disorders in either the mother or the fetus are a risk factor for ischemic stroke in the perinatal period that may lead to developmental delays.6

Use of assisted reproductive techniques such as in vitro fertilization (IVF) is not thought to result in significantly increased levels of developmental-behavioral disorders overall. However, there is likely an increased risk of disorders resulting from abnormal imprinting of DNA.⁷ Imprinting is the process of altering DNA methylation and other epigenetic factors that govern the expression of genes. A relevant example of an epigenetic disorder is Angelman syndrome, which results in severe developmental delay due to DNA methylation abnormalities that prevent expression of the maternal allele of the gene UBE3A. Children with Angelman syndrome have a characteristically happy demeanor with frequent laughing and smiling. Ataxia and tremulousness are prominent and epilepsy is frequently present.

Gestation

The fetal environment is a critical determinant of the future health and development of a child. The presence of diabetes in the mother during gestation increases the risk for structural brain anomalies and other malformations, and it also appears to more subtly impair development for those children born to mothers with diabetes.^8,9 Maternal undernutrition resulting in a small-for-gestational-age child is also clearly correlated with poorer developmental outcomes.¹⁰

Maternal use of recreational drugs during gestation is linked to abnormal development in the child. Maternal alcohol use may result in a broad spectrum of manifestations from mild behavioral concerns to children with severe growth restriction and multiple congenital anomalies, depending on the quantity of alcohol consumption and the timing in gestation.¹¹ Evaluation of the effects of gestational exposure to cocaine, marijuana, opiates, and other drugs of abuse is ongoing, and a diverse range of behavioral, developmental, and morphological abnormalities have been linked to different agents.¹² In utero prescription drug exposure may also impact development and should be documented in a developmental history. The teratogenic effects of warfarin, phenytoin, valproate, retinoic acid, and other prescription drugs are well recognized and may have characteristic findings on physical examination.

Prenatal infections can significantly alter the developmental trajectory of a child. Vaccination of the population against varicella and rubella has reduced the number of fetuses exposed to these infections, though prenatal cytomegalovirus (CMV) infection remains a major cause of developmental delays in children. Roughly 1 in 150 children will have congenital CMV infection, and about 10% of infected infants will have clinical manifestations of the infection. Developmental delays are present in about two-thirds of the affected children, hearing loss in one-third, and visual impairment in about one-third.¹³ Recently, prenatal Zika virus infection has been associated with microcephaly and developmental delays in affected children. The ultimate burden on the population of this newly recognized congenital infection remains to be seen.¹⁴ In some rare cases, maternal medical concerns during pregnancy may be an indication that the fetus is affected by a specific disorder. For example, acute fatty liver of pregnancy is far more common among women carrying a fetus affected by long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD), a fatty acid oxidation disorder.

The majority of parents can report the birth weights and gestational ages of their children to clinicians, and many are aware of the Apgar scores that their children were assigned at delivery. These readily available pieces of data are a critical component of a developmental history. There is extensive literature on the developmental outcomes of children born prematurely, with more significant developmental delays in those children born earlier in gestation and at lower birth weight.15 Children born prematurely are at significantly higher risk for abnormalities on neuroimaging (such as hydrocephalus or periventricular leukomalacia) as well as other conditions associated with prematurity such as chronic lung disease.¹⁶ While there are likely many causes of adverse developmental outcomes among premature infants, recent research has found that there are characteristic epigenetic alterations associated with premature birth, raising the possibility that there are persistent abnormalities of gene expression throughout life.¹⁷ It should be noted that advances in the care of premature infants mean that developmental outcomes after premature birth are improving with time and that current premature infants likely have a better prognosis than infants born with the same degree of prematurity in previous decades. The literature on development after premature birth should be interpreted through this lens.

Apgar scoring, a systematic tool for assessing the status and response to resuscitation of neonates in the minutes after delivery, has been in use for decades, and lower Apgar scores at 5 minutes or longer have been consistently correlated with increased relative risk for poorer developmental outcomes later in life.¹⁸ However, most infants with low Apgar scores will not develop neurodevelopmental disability.¹⁸ The Apgar score is only one component of an assessment that an encephalopathic neonate has suffered a hypoxic-ischemic injury in the peripartum period. Laboratory testing for multisystem organ dysfuntion, electroencephalography, and brain imaging should be employed when hypoxic injury is suspected, and it has prognostic significance for developmental outcomes; for example, normal brain MRI scans convey a better prognosis and deep gray matter injury conveys a worse prognosis than injury limited to the cortex.¹⁹ Therapeutic hypothermia and high-dose erythropoietin appear to significantly improve the prognosis after perinatal hypoxic-ischemic brain injury, and the specific interventions that were employed in the neonatal period should also be documented if possible.²⁰

Medical History

Children with chronic medical conditions are known to be at risk for developmental delays. Congenital heart disease is a common condition affecting nearly 1% of the population, with about 1 in 300 individuals requiring a surgical repair in childhood. The congenital heart malformation itself may be causative of developmental delay due to impaired cerebral blood flow and oxygen delivery. Alternatively, many common genetic syndromes have both congenital heart disease and developmental delays as manifestations, including Down syndrome, Turner syndrome, Noonan syndrome, Williams syndrome, and the 22q11 deletion syndrome. Guidelines have been developed for appropriate developmental screening and interventions for children with congenital heart disease.21 Other chronic illnesses also impact development, such as the developmental delays seen in survivors of childhood cancers due to the effects of chemotherapy and radiation of the brain.²² Sickle cell disease is the most prevalent genetic disease in the African American population of the United States. Affected individuals may suffer cerebral infarctions that cause developmental delays.²³

Acute illnesses and accidents also have developmental consequences. Infections of the central nervous system, such as herpes simplex encephalitis or group B strep meningitis, result in developmental disorders in a significant proportion of affected children.²⁴ Traumatic brain injuries due to traffic accidents, falls, or abuse are a common occurrence for children, affecting up to 3% of all children. More severe acute brain injuries are associated with a larger impact on cognition later in life, with persistent developmental delays noted many years after initial injuries.²⁵

Dietary and Nutritional History

Inquiry into the diet of a child with developmental delays may provide important clues to the etiology of the disorder and potential treatment. Children with autism spectrum disorder may have very restrictive diets, resulting in micronutrient deficiencies that have secondary consequences for development and for general health. Malnutrition resulting in stunted growth has a clear impact on developmental outcome, and primary pediatric health care professionals should ask about the food security of a family if there are growth concerns. Causality may also run in the opposite direction: Developmental disorders may significantly impair the nutritional status of a child in the case of neurological dysfunction resulting in aspiration or dysphagia.²⁶

Specific dietary patterns could be indicative of an inborn error of metabolism. Ornithine carbamoyltransferase (OCT) deficiency is a disorder of the urea cycle resulting in hyperammonemia. There is a wide spectrum of severity for this disorder, from fatal neonatal encephalopathy to individuals that remain asymptomatic into adulthood. This is particularly true for females because the causative gene is on the X chromosome, so females with a mutation are mosaic for one functional copy of the gene. Some individuals with OCT deficiency may have chronic mild hyperammonemia resulting in developmental delays without overt episodes of significant encephalopathy. A characteristic dietary history in an individual with OCT deficiency is either avoidance of dietary protein sources, such as meat, or transient mild encephalopathy after protein intake.²⁷

Developmental Trajectory

In addition to documentation of the current level of development, attention should be paid to the skills of a patient relative to the typically developing child throughout the lifespan via a comprehensive developmental history (see Chapter 10

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