Chapter 185. Genetic Evaluation of Developmental Delay/Mental Retardation

Medically, mental retardation (MR) or “intellectual disability” (ID, the currently preferred term) is a highly variable, heterogeneous manifestation of central nervous system dysfunction. According to the Diagnostic and Statistical Manual, 4th edition (DSM-IV) (1994), the diagnostic criteria are (1) onset before age 18; (2) an IQ of approximately 70 or below; and (3) concurrent deficits or impairments in two or more of the following areas: communication, self-care, home living, social and interpersonal skills, use of community resources, self-direction, functional academics, health and safety, and work and leisure.

MR or ID (for the purposes of this chapter we will use the traditional abbreviation, MR, recognizing that it likely will become outmoded in the future) is grouped into four degrees of severity by measure of tested IQ. Mild MR is defined as “educable”; patients possess an IQ level from 50 to approximately 70. Moderate MR is considered a “trainable” severity level and is seen in individuals with IQs of 35 to 55. In severe MR, the IQ level is 20 to 40, and profound MR is most frequently defined by an IQ level below 20 to 25. About 85% of individuals with MR function within the mild range, whereas about 10% function within the moderate range, and only 5% are severely to profoundly disabled. Recently, the American Association on Mental Retardation proposed that a different system, one that utilizes the intensity of the support needed by the individual, would better express the functional limitations of the individual and thus hold more practical use. Intensity of intervention is quantified as intermittent, limited, extensive, or pervasive. However, grouping by degrees of severity is still useful from the clinical point of view.

Mental retardation may become evident during infancy or early childhood as developmental delay (DD), which is a common clinical problem in pediatrics and is estimated to occur in approximately 2% to 10% of the population (see Chapter 91). However, recent data from the United States Department of Education indicate that the prevalence of MR among school-aged children (ages 6–17) is 1.14%. The different rates of prevalence of MR depend on definitions used, methods of ascertainment, and population studied. The individual’s cultural and socioeconomic environments should also be taken into consideration when testing procedures are applied. It is important to note that the prevalence of mild retardation varies inversely with socioeconomic status, whereas moderate to severe disability does not. The approach to the evaluation of developmental delay is further discussed in Chapters 91 and 547.

Etiology

Etiologic factors may be biological or socioenvironmental; in some cases, there may be combination of the two. The biological factors can be prenatal, perinatal, or postnatal. The prenatal factors can be further subdivided into preconceptional, embryonic, and fetal factors. Preconceptional factors include single gene abnormalities such as neurocutaneous disorders; malformation syndromes; inborn errors of metabolism; and chromosome aberrations, including trisomy syndromes and polygenic familial syndromes. In the embryonic phase, chromosome abnormalities, infections (eg, congenital cytomegalic virus syndrome), exposure to teratogens (eg, excessive alcohol), placental dysfunction, and central nervous system (CNS) malformations are considered factors that can result in developmental delay/mental retardation (DD/MR). Fetal factors include infection and certain exposures. Prematurity, hypoxia/ischemia, hypoglycemia, hyperbilirubinemia, and infections are perinatal conditions that can cause MR. Postnatal influences include infections, asphyxia, trauma, metabolic disorders, poisoning, and malnutrition.

McLaren and Bryson1 reviewed more than a dozen studies and found that causes of mental retardation could be divided into the following categories and associated prevalence: chromosomal, 30%; CNS malformations, 10% to 15%; multiple congenital anomaly (MCA) syndromes, 4% to 5%; metabolic, 3% to 5%; acquired causes, 15% to 20%; and unknown causation, 25% to 38%. A genetic etiology was present in almost 50% of the cases and explains the important role of the clinical geneticist in the diagnosis ans management of the child with DD/MR.

Battaglia et al.2 conducted a retrospective analysis of the diagnostic yield of 120 patients with developmental delay or mental retardation referred to a university-based institute of child neuropsychiatry. Diagnostic studies, which included current MRI techniques and video-electroencephalogram (EEG) polygraphy, yielded a causal diagnosis in 41.6% and a pathogenetic categorization in 39.2% of the patients. Etiology remained unknown in 19.1% of the 120 patients. Causal categories included chromosomal abnormalities in 14 patients, fragile X syndromes in 4 patients, known MCA/MR syndromes in 19 patients, fetal environmental syndromes in 1 patient, neurometabolic disorders in 3 patients, neurocutaneous disorders in 3 patients, hypoxic/ischemic encephalopathy in 3 patients, other encephalopathy in 1 patient, and congenital bilateral perisylvian syndrome in 2 patients. Notably, this study marked the first time that appropriately different forms of CNS malformations were defined, resulting in a better etiologic yield.

In summary, although the impact of specific factors on prevalence varies among the cited studies, all the reports classify causes of MR into five major categories: MCA syndromes, CNS malformations, metabolic disorders, acquired conditions, and so-called pure or nonspecific (idiopathic) mental retardation.

In about 20% to 55% of individuals seen in clinical settings, no clear etiology of MR can be determined, despite extensive efforts. However, recent developments in diagnostic testing, including cytogenetic and molecular genetic techniques, for example, comparative genomal hybridization (CGH microarray) (see Chapter 174), neuroimaging, current metabolic screening, and detailed EEG studies, make it likely that the estimated percentage of idiopathic MR cases will decrease in the future. A better diagnostic yield will be obtained as an increasing number of patients originally diagnosed with DD/MR without a defined cause are actually found to have a newly recognized MCA/MR syndrome or a positive CGH study.

Clinical Features

The overwhelming majority of children with mental retardation (MR) are identified when age-appropriate expectations are not met. In fact, the cardinal symptom of MR is represented by delayed achievement of developmental milestones (see Chapter 91). Delay may be restricted to specific areas of development, as is often the case of the child with moderate to mild retardation. For example, a toddler or school-aged child may present with normal motor development but with delayed speech and language abilities.

The diagnosis of MR does not imply a constant state. Early intervention, social interaction, caregiving, and access to and provision of special education services have a significant impact on functioning of children with MR. The development of cognitive abilities requires not only the integrity and maturation of the nervous system but also an adequate motivation and a harmonic, well-balanced personality organization. Some early personality changes noted in the first months of life, if not properly addressed, may lead to a progressive lowering of cognitive abilities. In autistic conditions presenting in early childhood, evolution toward mental retardation is often observed. The quality of early reciprocal social interaction, particularly with the mother, is of the utmost importance for the adequate stimulation of cognitive abilities and for giving the child the interest and motivation to use them. Thus, the natural history of mental retardation is greatly variable and dependent on differences in etiology and associated disability as well as access to adequate educational and therapeutic experiences. However, children who lose previously attained developmental milestones have a progressive neurologic disorder and represent an important subgroup (Section 29, Part 7).

Diagnosis

When mental retardation (MR) is identified in a child, there is a shared sense of urgency to determine the causative factor. Given the potential impact of an MR diagnosis, and the hundreds of conditions known to cause mental retardation, any number of investigations may be initiated to establish a diagnosis. A emerging consensus, however, from the child neurology and medical genetics fields suggests an alternative to an extensive diagnostic approach. A more rational (focused) evaluation is a strategy that promises to provide significant benefits to the patient, family, and practitioner.

Traditionally, the primary care physician weighs a variety of factors when deciding which screening tests to perform on a specific patient. The seriousness of the condition being evaluated, the acceptability (including risk, safety, yield, sensitivity, and specificity) of the test, and how important it is to make a diagnosis are usually considered before the testing proceeds. Rational evaluation is an expansion and extension of this approach specific to MR (Fig. 185-1). Rational evaluation is based on two premises: (1) Making a diagnosis is important, and (2) clinical signs, coupled with individual family needs, will drive the evaluation. Making a diagnosis is essential to the individual and the family, who want to know not only why and how MR occurred in their child but also the chance of it happening again. A specific diagnosis helps with predicting recurrence chances in genetic counseling and in planning medical management. In addition, an early diagnosis may help avoid costly and invasive tests.

Despite recent advances and continued intensive efforts directed at understanding the causes of MR, there remains a lack of uniformity concerning evaluation of patients. However, two professional groups have attempted to bring some clarity to the approach. In 1995, the American College of Medical Genetics (ACMG)3 published a consensus report that suggested that three-generation pedigrees, complete history and physical examination, serial evaluations of the patient, consideration of chromosome or fragile X DNA testing, neuroimaging in the presence of neurologic symptoms, and metabolic testing in children with appropriate symptomology were among the essential elements of the rational MR evaluation. In 2003 the Child Neurology Society4 produced a separate consensus report that comprehensively reviewed the evidence regarding the diagnostic evaluation of the child with DD/MR. This paper cited most of the previous literature and investigations on this topic. The summary of their findings was similar to the ACMG report, and this body did recommend consideration of chromosome analysis and DNA study for fragile X in all patients without a diagnosis and performance of neuroimaging and metabolic studies in selected patients.

The importance of a thorough clinical history cannot be overestimated. Prenatal, birth, and family history should be recorded. A careful, head-to-toe physical examination includes documentation of growth parameters (especially occipitofrontal circumference [OFC]), detection of minor anomalies, a neuromotor assessment, and a meticulous search for skin changes. Recognition of abnormal phenotypic findings and recording of measurements (eg, ear length), where indicated, are critical. Photographs and videos can prove very useful. Videotaping is an invaluable tool because it can document behavioral characteristics, gait, posture, and any movement disorders.

Determination of changes in occipitofrontal circumference (OFC), microcephaly or macrocephaly, are particularly important and represent a decision point in the algorithm (Fig 185-2). Microcephaly will be discussed in detail below. Macrocephaly, OFC more than 2 standard deviations above the mean or above the 97th percentile, is a potential sign of a number of conditions associated with DD/MR. It also can be an autosomal dominant trait, demonstrating the importance of comparing a child features to the parents. As in microcephaly, it is important to determine if the change in head size was present at birth and is proportionate or not with overall body size. The common syndromes associated with macrocephaly include the fragile X syndrome, the FG syndrome, neurofibromatosis type 1 (NF1) (see Chapter 182), Sotos syndrome (see eTable 185.1), and the PTEN-related conditions (see eTable 185.1). An MRI will often assist in the diagnostic process as many of these listed conditions have typical findings on the imaging study.

In the context of evaluation of the child with developmental delay, detection of microcephaly holds a paramount importance. Etymologically, microcephaly means a small head, but the term micrencephaly would be more appropriate to designate a small brain. A high correlation between the growth of the two structures exists. Tables of head circumference in fetuses and from birth to adulthood have been well established. Most investigators have defined microcephaly as an occipitofrontal circumference (OFC) of less than 3 standard deviations (SD) below the mean for age and sex. However, a surprising amount of controversy exists about whether 3 SD or 2 SD below the mean for age and sex is actually abnormal. Certainly, the broader definition of 2 SD below the mean includes some persons with a normal brain who have a small head. Study of the head size of healthy school-aged children will detect a few persons with head measurements of less than –2 SD, because the definition is based on a normal distribution. In this group, however, persons with measurements of less than –3 SD are extremely unusual, and therefore an OFC of that size usually indicates a pathologic abnormality of brain growth. Small head size that is proportionate to chest size and length in infants and to height in older children suggests proportionate small body size. However, in a child who is physically or neurologically abnormal, proportionate smallness should not be assumed. In addition, an individual whose height and OFC are both 3 SD below the mean usually has a generalized abnormality of growth affecting both the brain and linear growth rate and should be evaluated for a broad pattern of malformation. Because small head size can be a familial trait or a normal familial developmental pattern (as in macrocephaly), the OFC of the parents and siblings should be recorded and compared with the head measurement of the propositus.

Microcephaly is a descriptive term that does not refer to a particular etiology and covers a wide range of heterogeneous cases caused by multiple mechanisms.5 Most malformed brains are small. However, microcephaly is a relatively common finding in a large number of constitutional and acquired conditions. Many of the common autosomal chromosome syndromes have prenatal microcephaly as one feature of their recognizable pattern, and most have postnatal microcephaly as a finding (see Chapters 174 and 176). Interruption of neuronal production or secondary destruction and/or faulty migration, caused by intrinsic or extrinsic factors, may cause microcephaly.

A child with disproportionately small head at birth is said to have primary or congenital microcephaly, and a child with normal birth OFC, whose head circumference falls below normal percentiles after birth, has secondary or postnatal microcephaly.

Some authors prefer to classify microcephaly as isolated or pure/nonsyndromic, and associated or syndromic. Isolated or pure/nonsyndromic microcephaly was described in the 1950s in adults with mental retardation and called microcephalia vera. The inheritance of so-called microcephalia vera is most often autosomal recessive, whereas autosomal dominant and X-linked transmission have also been recorded. Recently, 6 different genetic loci for primary nonsyndromic microcephaly have been identified; four of them have had their particular gene identified (eg, microcephalin). Associated or syndromic microcephaly may be part of a distinct pattern of malformation (genetic, acquired, or of unknown origin).

Figure 185-2 presents a diagnostic approach to the child with microcephaly. This approach is designed to supplement the approach to DD/MR. The initial step in evaluating a child with microcephaly is to obtain the newborn head size and as many measurements on the OFC chart as possible. Congenital microcephaly implies an intrauterine onset of the abnormality of brain growth and has a different set of causes than does microcephaly with postnatal onset. The head measurement is then compared with linear growth and weight to determine whether the head size is disproportionately small for the body or if the subject has an overall pattern of growth deficiency. The head size can also be compared with chest size in infancy, because these two measurements are similar during the initial months after birth. Proportionate head circumference, chest size, and length in an otherwise normal individual with mild microcephaly would imply overall small size and not an abnormality of brain growth.

A complete pre- and perinatal history together with an extensive family pedigree (three-generation), including consanguinity, and measurements of parents’ head sizes constitute an essential second step. Physical examination, including a careful search for dysmorphic features or structural defects, should follow to determine whether the child may have a malformation syndrome. Signs of prenatal abnormalities, such as frontal bone recession or absence of flexion creases on the fingers, are especially important. A thorough neurologic examination should be performed to ascertain the presence of any abnormal finding, such as alteration of tone and reflexes, and presence of abnormal movements, posture, gait, and behavior. The presence of seizures should be carefully documented. In the presence of the aforementioned findings and features, the small head almost certainly indicates an abnormal brain. A complete ophthalmologic evaluation with pupillary dilation is mandatory in all children with an abnormal head size, because the detection of chorioretinitis, optic nerve hypoplasia, optic atrophy, cataracts, retinal folds, or macular abnormalities may lead to a specific diagnosis or suggest a pathologic process.

Historical and physical/neurologic findings determine laboratory evaluation of the child with microcephaly (Fig. 185-2). If the child is dysmorphic or has multiple malformations and does not fit a recognizable syndrome, a karyotype should be performed; in case of normal results, other possible pathways are illustrated in the algorithm. If the child does fit a recognizable syndrome (eg, Smith-Lemli-Opitz), then the most appropriate tests to define that syndrome should be undertaken. If the child shows no major/minor anomalies but has a history of seizures, an accurate waking/sleep electroencephalogram (possibly with videopolygraphy) and neuroimaging should be carried out. Neuroimaging is also recommended in the child with pre- or postnatal microcephaly, with no specific diagnosis, in search of possible intracranial calcifications or structural defects. A metabolic screening is performed whenever signs of metabolic disorders are present. Appropriate microbiologic cultures and titers are suggested in the infant with signs of intrauterine infection syndromes or with no obvious diagnosis. eTable 185.2 outlines the recognizable causes and common syndromes of microcephaly.

Without a specific diagnosis to explain the alteration or abnormality in brain growth, ultimate mental development cannot be predicted accurately. If the infant has an OFC of less than 3 SD below the mean and has abnormal neurologic signs, however, the probability of developmental retardation is high. With milder degree of decreased head size and no specific diagnosis, one must be cautious in predicting cognitive ability.

Genetic counseling regarding the risk of recurrence in a situation of undiagnosed sporadic microcephaly is not clear-cut. A child with severe nonsyndromic microcephaly whose parents are not consanguineous and who is the only affected person in the family may represent sporadic microcephaly caused by an autosomal or X-linked gene, or the child may have abnormal head size because of an unrecognized environmental cause. Without a specific physical or biochemical marker, these possibilities cannot be separated. Therefore, empirical recurrence risk figures must be used in this situation.

Laboratory and Radiographic Evaluation

The information gleaned from the history and physical exam alone can help in determining a diagnosis in a number of cases or in postulating a provisional diagnosis for appropriate testing (Fig. 185-2). For example, a patient presenting with DD, severe MR, absent speech, epileptic seizures, microbrachycephaly, ataxia, and jerky arm movements is likely to have Angelman syndrome. The priority testing, then, would be methylation analysis, molecular cytogenetics evaluation for Angelman syndrome (15q11 microdeletion) (see Chapters 173 and 174) and an EEG for the exact definition of the seizures and movement disorder. Test results would thus guide the therapy modality; the first choice in this case would most likely be drug treatment. In another example, a floppy infant with no progress in motor functions, little or no reaction to environmental stimuli, characteristic minor anomalies, and epileptic seizures should undergo a metabolic workup, searching for a peroxisomal disorder (eg, Zellweger syndrome); EEG and brain MRI would be the second-line investigation. Another illustrative case would be a child with “coarse facies,” macrocephaly, liver and spleen enlargement, deafness, DD, behavioral problems, and poor motor performance, who could have a lysosomal storage disorder; appropriate biochemical studies should be the first step toward the diagnosis. A child with distinct craniofacial features, large or late-closing anterior fontanel, generalized hypotonia, noncompaction cardiomyopathy, seizures, and developmental delay is likely to have the del 1p36 syndrome. Subtelomeric analysis with at least two region-specific fluorescence in situ hybridization (FISH) probes or high-resolution comparative genomic hybridization (CGH) array are the most appropriate laboratory investigations for confirmation of diagnosis. Last, a girl with apparently normal psychomotor development during the first 6 to 18 months of life, followed by developmental stagnation and then by rapid regression in language and motor skills, with loss of purposeful hand use, and postnatal deceleration of head growth, is likely to have Rett syndrome. Molecular testing of the MECP2 gene is the most rational approach toward confirmation of the diagnosis (see Fig. 185-2).

When to order cytogenetic studies and what particular test to perform in the evaluation of the child with DD can be an ongoing quandary. Reduced family resemblance may be one of the most sensitive indicators for the presence of chromosomal abnormalities. Minor anomalies observed in the infant or child but not seen in relatives may signal the necessity for cytogenetic evaluation (see Chapter 173). Most individuals with chromosome syndromes have patterns of minor anomalies and characteristic phenotypic findings often allowing for clinical recognition (eg, Down syndrome, Wolf-Hirschhorn syndrome). Conversely, it is worth noting that a number of MR patients thought to be nonsyndromic on physical examination were later found to demonstrate aneuploidy or fragile X. Thus, chromosome analysis or CGH and DNA for fragile X testing should always be considered (as recommended by the ACMG and the Child Neurology Society) with the highest yield in those with dysmorphic signs.

In recent years the advances in technology in molecular cytogenetics have been remarkable. CGH microarray detects deletions and duplications with much more accuracy than the standard karyotyping of the past including high resolution banding (see Chapter 173). Currently most clinical geneticists recommend CGH microarray as the first-line test in the evaluation of the child with DD/MR who has no obvious diagnosis and in whom a chromosome study is being considered. However, in a child with the clinical signs of Down syndrome or trisomy 18, standard cytogenetics would still be the initial step; in the child with velocardiofacial syndrome or the characteristic presentation of Prader-Willi syndrome, targeted FISH would be the first option in testing.

Interestingly, there is no known association between chromosome abnormalities and the level of MR. Although chromosome studies are performed less often on individuals with mild MR, individuals with moderate MR show no greater positive rate of chromosomal abnormalities than do those with profound MR.

Little is reported in the literature on the value of the EEG in MR patients, but a recent study by Battaglia et al. found that the diagnostic yield of EEG investigations was relatively high (8.3%).2,6 An EEG (waking and sleeping) polygraphy, together with an accurate clinical history of epileptic seizures, could allow the clinician to narrow the diagnosis as a definite epileptic syndrome. Other specific clinical presentations could justify an EEG exam, such as significant language impairment (Landau-Kleffner syndrome), Angelman syndrome, inv dup(15) syndrome, Wolf-Hirschhorn syndrome, and neuronal ceroid lipofuscinosis with both infantile and late-infantile onset. In all these conditions, the EEG may prove to be very helpful for diagnostic purposes and treatment.

It has been reported that neuroimaging can detect cerebral anomalies in 9% to 60% of individuals with MR. Many of these abnormalities are descriptive findings (agenesis or hypoplasia of the corpus callosum, ventricular enlargement) and have yet to add significantly to our knowledge of the causes of MR. However, when coupled with ongoing improvement in our knowledge surrounding the diverse brain malformation syndromes and sequences, the use of neuroimaging can undoubtedly complement the diagnostic process of the individual with MR.7

In several syndromes and conditions, (Prader-Willi, Angelman, Williams, velocardiofacial, fragile X), the recognizable physical and behavioral phenotype evolves over time; observation of these changes through systematic clinical follow-up can guide confirmation of a diagnosis (increasing the number of diagnoses by 5–20%), selection of a differential diagnosis, or elimination of a diagnosis. Serial clinical evaluations represent an important approach to the patient with MR with the potential to eventually lead to a definite diagnosis or even the characterization of a novel syndrome.

Treatment and Management

As with diagnosis, the first charge in the treatment and management of patients with MR is to recognize the individuality of each patient’s condition, environment, and prognosis. A few disorders associated with MR, such as phenylketonuria and hypothyroidism, can be treated with well-established regimens. Smith-Lemli-Opitz syndrome is an example of a malformation syndrome with DD/MR in which drug treatments are available (supplemental cholesterol) that may improve outcome. There remain a large number of conditions in which little can be done using standard pharmacological treatments, but clinical trials are being carried out in specific conditions (eg, statins for the learning disability of NF1). It is axiomatic that each patient has the inherent right to receive not just the ordinary care given to any child but also the extraordinary care necessary to the patient’s well-being, as prescribed by his or her singular situation.

Early intervention is key to a productive treatment plan. Intellectually disabled patients should receive a thorough “functional evaluation,” accomplished by an appropriate professional at the earliest possible juncture. Whenever possible, enrollment in a rehabilitation program, personalized to the individual’s function level, should occur. School placement at the appropriate time is considered mandatory. Vocational training, particularly when the child’s overall level of function allows for progression toward independent or semi-independent adult living, should be introduced in secondary school.

Beyond health surveillance and treatment, listening to the family’s primary concerns and addressing such concerns whenever possible are helpful. Referral to parent support groups or arrangement of a meeting with other parents of individuals with the same condition may be quite beneficial.

Prediction of chance of recurrence of the condition depends on the diagnosis. Genetic counseling referral is always indicated in the pediatric setting for the family who asks questions about diagnosis or recurrence risk. In the primary care practice or medical home, the pediatric clinician can anticipate such concerns and ask the parents (or child if appropriate) if they are interested in such a referral. Genetic consultation is now available in most medical centers in North America, Europe, Japan, Australia, and other parts of the world.