Intellectual Disability 

Updated: Apr 19, 2016
Author: Ari S Zeldin, MD, FAAP, FAAN; Chief Editor: Amy Kao, MD 

Overview

Practice Essentials

Intellectual disability (ID), is a descriptive term for subaverage intelligence and impaired adaptive functioning arising in the developmental period (< 18 years).

Signs and symptoms

Patients with ID and developmental delays may demonstrate the following:

  • Language delay: One of the first signs of ID may be language delays, including delays in expressive language (speech) and receptive language (understanding)

  • Fine motor/adaptive delay: Significant delays in activities such as self-feeding, toileting, and dressing are typically reported in children with ID

  • Cognitive delay: Difficulties with memory, problem-solving, and logical reasoning

  • Social delays: Lack of interest in age-appropriate toys and delays in imaginative play and reciprocal play with age-matched peers

  • Gross motor developmental delays: Infrequently accompany the cognitive, language, and fine motor/adaptive delays associated with ID unless the underlying condition results in both ID and cerebral palsy.

  • Behavioral disturbances: Infants and toddlers may be more likely to have difficult temperaments, hyperactivity, disordered sleep, and colic; associated behaviors may include aggression, self-injury, defiance, inattention, hyperactivity, sleep disturbances, and stereotypic behaviors.

  • Neurologic and physical abnormalities: Prevalence of ID is increased among children with seizure disorders, microcephaly, macrocephaly, history of intrauterine or postnatal growth retardation, prematurity, and congenital anomalies

Evaluation of patients for ID can include the following examinations:

  • Head circumference: Microcephaly correlates highly with cognitive deficits; macrocephaly may indicate hydrocephalus, is associated with some inborn errors of metabolism, and may be seen early on in some children later diagnosed with autism[3, 4]

  • Height: Short stature may suggest a genetic disorder, fetal alcohol syndrome, or hypothyroidism; tall stature may suggest fragile X syndrome (FraX), Soto syndrome, or some other overgrowth syndrome associated with MR/ID

  • Neurologic: This examination should include assessments of head growth (for microcephaly/macrocephaly), muscle tone (for hypotonia or spasticity), strength and coordination, deep tendon reflexes, persistent primitive reflexes, ataxia, and other abnormal movements, such as dystonia or athetosis.

  • Sensory: Children with disabilities and ID are more likely than other children to have visual impairment and hearing deficits

  • Skin: Findings can include hyperpigmented and hypopigmented macules, such as café-au-lait macules (associated with neurofibromatosis type 1), as well as ash-leaf spots (associated with tuberous sclerosis), fibromas, and irregular pigmentation patterns

  • Extremities: Although ID with multiple congenital anomalies and major malformations accounts for only 5-10% of all cases, most of these affected individuals have 3-4 minor anomalies, especially involving the face and digits

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies

  • Array-based comparative genetic hybridization (CGH), or microarray

  • High-resolution karyotype

  • Fragile X testing

  • FISH probes

Imaging studies

  • Brain magnetic resonance imaging (MRI): Should be conducted in any child with global developmental delays or ID[5]

  • Head computed tomography (CT) scanning: Preferred imaging study for calcifications that may be identified with TORCH infections (ie, toxoplasmosis, other infections, rubella, cytomegalovirus [CMV], herpes simplex) or when tuberous sclerosis is suspected or craniosynostosis is a concern

  • Skeletal films: Assist with phenotypic description, syndrome characterization, and assessment of growth

Additional tests

Detailed assessment by a licensed professional is necessary to confirm the diagnosis of ID. Some of the most commonly used tests in children include the following:

  • Bayley Scales of Infant Development

  • Stanford-Binet Intelligence Scale

  • Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R)

  • Wechsler Intelligence Scale for Children–IV (WISC-IV)

  • Vineland Adaptive Behavior Scales-II

See Workup for more detail.

Management

The mainstay of ID treatment is the development of a comprehensive management plan for the condition. The complex habilitation plan for the individual requires input from care providers from multiple disciplines, including special educators, language therapists, behavioral therapists, occupational therapists, and community services that provide social support and respite care for families affected by ID.

Neuropathic pain due to dysautonomia or motor spasms may create chronic disturbances. Treatment should be prompt and include the following:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild pain

  • Tramadol or equivalent for moderate pain

  • Opioids for severe pain as indicated

  • Management of sources of pain

No specific pharmacologic treatment is available for cognitive impairment in the developing child or adult with ID.[6] Medications, when prescribed, are targeted to specific comorbid psychiatric disease or behavioral disturbances.

The psychostimulant class of drugs is commonly prescribed in individuals with ID, because of the diagnosis of attention deficit with or without hyperactivity disorder (ADHD/ADD) in 6-80% of these patients. However, few studies on stimulants in people with MR/ID are available. The studies that do exist indicate that benefits vary, and significant adverse events, such as severe social withdrawal, increased crying, drowsiness, and irritability, have been noted, especially at higher doses of methylphenidate (0.6 mg/kg).[7]

The neuroleptic drugs are the most frequently prescribed agents for targeting behaviors such as aggression, self-injury, and hyperactivity in people with MR/ID. These indications are generally off-label for ID and caution is advised.

See Treatment and Medication for more detail.

Background

Intellectual disability (ID) is a descriptive term for subaverage intelligence and impaired adaptive functioning arising in the developmental period (< 18 y). ID and other neurodevelopmental disabilities are seen often in a general pediatric practice.

The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5), characterizes ID by deficits in general mental abilities, such as reasoning, problem solving, planning, abstract thinking, judgment, academic learning, and learning from experience. The deficits result in impairments to adaptive functioning, such that the individual fails to meet standards of personal independence and social responsibility in one or more aspects of daily life, including communication, social participation, academic or occupational functioning and personal independence at home or in community settings.[8]

Approximately 10% of children have some learning impairment, while as many as 3% manifest some degree of ID. The population prevalence of these combined disorders of learning rivals that of the common childhood disorder asthma.

ID originates during the developmental period (i.e., conception through age 18 years). ID is categorized as a neurodevelopmental disorder and is distinct from the neurocognitive disorders, which are characterized by a loss in cognitive functioning. Major neurocognitive disorder may occur with ID such as when an individual with Down syndrome develops Alzheimer's disease, for example. In a case like this, both ID and neurocognitive disorder would be diagnosed.

ID also can be categorized as syndromic, if associated with dysmorphic features, or nonsyndromic, if not associated with dysmorphisms or malformations. The understanding of specific ID syndromes is expanding with recent molecular genetic advances. More than 800 recognized syndromes listed in the Online Mendelian Inheritance in Man (OMIM) database are associated with ID, reflecting clinical diagnostic advances in the field. The most common associated chromosomal abnormality is trisomy 21, or Down syndrome. The most common X-linked abnormality associated with MR/ID is fragile X syndrome. However, for most cases of MR/ID, no specific genetic abnormalities are found.

Some forms of MR/ID are due to nongenetic factors and may be identifiable by their associated dysmorphisms and clinical presentation. Examples include prenatal exposure to teratogens (e.g., anticonvulsants, warfarin, alcohol) or prenatal thyroid dysfunction. Prenatal and postnatal exposure to lead and the associated decrement in IQ may increase an individual's chance of functioning in the MR/ID range. ID may result from an acquired infection or injury during the developmental period from, for example, a severe head injury or meningitis or encephalitis infection

Diagnostic criteria (DSM-5)

Intellectual disability (intellectual developmental disorder) is a disorder with onset during the developmental period that includes both intellectual and adaptive functioning deficits in conceptual, social and practical domains. According to the DSM-5, the following three criteria must be met[8] :

  • Deficits in intellectual functions, such as reasoning, problem solving, planning, abstract thinking, judgment, academic learning, and learning from experience, confirmed by both clinical assessment and individualized, standardized intelligence testing.

  • Deficits in adaptive function that results in failure to meet developmental and sociocultural standards for personal independence and social responsibility. Without ongoing support, the adaptive deficits limit functioning in one or more activities of daily life, such as communication, social participation, and independent living, across multiple environments, such as home, school, work, and community.

  • Onset of intellectual and adaptive deficits during the developmental period.

Severity is specified as mild, moderate, severe, or profound based on the level of impairment in adaptive functioning, and not IQ scores, because it is adaptive functioning that determines the level of support required. The three domains of adaptive functioning are conceptual, social, and practical.

In addition to severity, the specifier “associated with a known medical or genetic condition or environmental factor” may be given. Examples include genetic disorders, such as fragile X syndrome, tuberous sclerosis, and Rett syndrome; and environmental factors including fetal alcohol exposure (even in the absence of fetal alcohol syndrome).

Pathophysiology

MR/ID is the end result of many disorders of CNS function. Most individuals with significant intellectual impairment have no discernible structural abnormalities of the brain. CNS malformations, a visual correlate of the disorders, are diagnosed in 10-15% of cases; dysfunction is localized primarily to the cortical structures, including the hippocampus and the medial temporal cortex. The most common malformations consist of neural tube defects, hydranencephaly, and microcephaly. Less commonly, CNS malformations include disorders of migration (the lissencephalies) and agenesis of the corpus callosum.

Multiple congenital anomaly syndromes with malformations confined to nonneurologic organ systems may be present in 5% of all patients with MR/ID. Between 3% and 7% of cases may be associated with a wide array of inborn errors of metabolism complicated by multiorgan system disease. Alcohol exposure in utero may account for as many as 8% of those with mild MR/ID.

Most individuals with mild MR/ID and other learning disorders do not have other neurologic complications, CNS malformations, or dysmorphisms. They are more likely, however, to be born into families of low socioeconomic status, low IQ, and little education. The etiologic contribution of poverty to their poor cognitive function remains unclear. Clearly, however, poor cognitive functioning and MR are correlated positively with a life of poverty.

Frequency

United States

The frequency of MR/ID of all degrees ranges from 1-3% of the population. ID has an overall general population prevalence of approximately 1% and prevalence rates vary by age. Prevalence for severe intellectual disability is approximately 6 per 1,000.[8]

International

A study with excellent ascertainment conducted in Aberdeen, Scotland, yielded a prevalence of 1 in 300 for severe MR and 1 in 77 for mild MR. Among those with severe MR were more boys than girls (male-to-female ratio 1.2:1), and among those with IQ >70, in the mild range of deficiency, boys exceeded girls by a ratio of 2.2:1.[9]

Although prevalence rates vary from country to country, the variance in prevalence may be attributed to ascertainment bias, the standardization methods employed from study to study, and a generalized upward drift in IQ scores over time. Even so, the greatest variance in statistics of prevalence is most likely to fall within the category of mild MR, a group for which the ascertainment bias is large.

Race-, sex-, and age-related differences in incidence

Consistent racial differences in prevalence of MR/ID and associated mortality rates are not known to exist.

The gender ratios for mortality and morbidity do not differ from the gender ratio noted in the severe/profound ranges of intellectual disability (ie, male-to-female ratio, 1.2:1).

MR/ID refers to intellectual impairment that develops prior to the age of 18 years.

Certain syndromes associated with MR/ID, such as Down syndrome, are associated with shorter life expectancy than the general population. In a comparison of those with MR/ID with and without Down syndrome from the California Department of Developmental Services cohort, excess mortality in the Down syndrome group tended to decrease with advancing age up to 35-39 years but increased thereafter. The increase in death rate from age 40 years was steeper in patients with Down syndrome than in those without Down syndrome.[10]

Mortality/Morbidity

MR/ID itself is not necessarily associated with an increased premature death rate. However, individuals with severe to profound MR/ID experience a decreased life expectancy related to the underlying etiology or additional complicating neurologic disorders, such as epilepsy. Neurologic dysfunction resulting in immobility, significant oral motor incoordination, dysphagia, and aspiration confers a greater risk of premature death than MR/ID itself. When significant neurologic dysfunction is associated with other organ system anomalies, an individual's life expectancy is shortened further.

Respiratory disease is the most prevalent cause of death among individuals with profound MR/ID. In particular, respiratory infections were the leading cause of death among a Finnish cohort of children with MR/ID.[11] For those affected by mild MR/ID, life expectancy does not differ from that of the general population.

Comorbid psychiatric conditions are diagnosed more frequently in those with intellectual disabilities than in the general population. Even so, psychiatric disorders probably are underappreciated in this population.

  • Attention deficit/hyperactivity disorder (ADHD) is diagnosed in 8-15% of children and 17-52% of adults with MR.

  • Self-injurious behaviors require treatment in 3-15%, particularly in the severe range of MR/ID.

  • Major depression, bipolar disorders, anxiety disorders, and other mood disorders are the most common psychiatric diagnoses in adults with MR/ID. Obsessive-compulsive disorder, conduct disorder, tic disorders, and other stereotypic behaviors are also diagnosed more commonly in those with MR/ID. Schizophrenia may have a prevalence of 3% in individuals with MR/ID, compared to 0.8% in the general population.

  • In the 1970 Isle of Wight study, as many as 30% of children with MR/ID exhibited an emotional or behavioral disorder, compared to 6% of children in the general population. MR compounded by epilepsy conferred a 56% risk of comorbid psychiatric disease in this study.[12]

  • Occult visual and auditory deficits occur in 50% of those with MR/ID, particularly when refractive errors are considered.

  • The rates of transmittable diseases, including sexually transmitted diseases (STDs), hepatitis B, and Helicobacter pylori infection, are increased significantly among individuals with MR/ID.

  • One in 5 individuals with MR/ID also has cerebral palsy (CP).

  • As many as 20% of individuals with MR/ID have seizures.

  • GI complications with MR/ID include feeding dysfunction, excess drooling, reflux esophagitis, and constipation.

  • GU complications with MR/ID include urinary incontinence and poor menstrual hygiene.

  • A profound social morbidity affects individuals with MR/ID and their families. This morbidity can be measured in lost wages, dependence on social services, impaired long-term relationships, and emotional suffering.

  • Individuals with a diagnosis of intellectual disability with co-occurring mental disorders are at risk for suicide. Screening for suicidal thoughts is essential in the assessment process.

 

Presentation

History

Presenting signs/symptoms

The presenting symptoms and signs of MR/ID typically include cognitive skills delays, language delay, and delays in adaptive skills. Developmental delays vary depending on the level of MR/ID and the etiology. For example, in mild nonsyndromic MR/ID, delays may not be notable until the preschool years, whereas with severe or profound MR associated with syndromes or extreme prematurity, for example, significant delays in milestones may be noted from birth.

  • Language delay: One of the first signs of MR/ID may be language delays, including expressive language (speech) and receptive language (understanding). Red flags include no mama/dada/babbling by 12 months, no 2-word phrases by age 2, and parents reporting they are concerned that the child may be deaf.

  • Fine motor/adaptive delay

    • Significant delays in activities such as self-feeding, toileting, and dressing are typically reported in children with MR/ID.

    • Prolonged, messy finger feeding and drooling are signs of oral-motor incoordination.

  • Cognitive delay: Children with MR/ID have difficulties with memory, problem-solving and logical reasoning. This may be expressed early on with preacademic difficulties or difficulty following directions (particularly multipart directions).

  • Social delays: Children with MR may display lack of interest in age-appropriate toys and delays in imaginative play and reciprocal play with age-matched peers. Rather than their chronological age, play reflects their developmental levels.

  • Gross motor

    • Delays in gross motor development infrequently accompany the cognitive, language, and fine motor/adaptive delays associated with MR/ID unless the underlying condition results in both MR/ID and cerebral palsy.

    • Subtle delays in gross motor acquisition, or clumsiness, may be identified in the developmental assessment.

  • Behavioral disturbances

    • Even before an age at which psychopathology can be identified, infants and toddlers who go on to have MR/ID may be more likely to have difficult temperaments, hyperactivity, disordered sleep, and colic.

    • Associated behaviors may include aggression, self-injury, defiance, inattention, hyperactivity, sleep disturbances, and stereotypic behaviors.

  • Neurologic and physical abnormalities

    • Prevalence of MR is increased among children with seizure disorders, microcephaly, macrocephaly, history of intrauterine or postnatal growth retardation, prematurity, and congenital anomalies.

    • In the process of addressing somatic problems, assessment of a child's cognitive abilities is often overlooked.

Diagnoses of MR/ID and autism frequently overlap. Approximately 50-75% of those with autism (autistic disorder) also have MR/ID.[13] Some literature has suggested diagnostic shifts from MR to autism for unknown reasons.[14]

Family history

Guidelines from the American Academy of Pediatrics recommend that the evaluation of a child with MR/ID includes an extensive family history, with particular attention to family members with MR, developmental delays, consanguinity, psychiatric diagnoses, congenital malformations, miscarriages, stillbirths, and early childhood deaths. The clinician should construct a pedigree of 3 generations or more.[15]

Physical

Developmental assessment

See the list below:

  • The American Academy of Pediatrics recommends developmental screening for all children at regular intervals. Methods include several parental surveys, such as the Parents' Evaluation of Developmental Status (PEDS), Ages and Stages Questionnaires (ASQ) and Child Development Inventories (CDI). Other instruments require direct observation, such as the Bayley Infant Neurodevelopmental Screener, Battelle Developmental Inventory, Early Language Milestone Scale, and Brigance Screens.

  • Key behavioral observations should focus on the child's communicative intent, social skills, eye contact, compliance, attention span, impulsivity, and style of play.

  • For the diagnoses of developmental delay and MR/ID, an expanded neurodevelopmental and psychological examination is required. Various tests can be administered to assess language comprehension, language expression, nonverbal cognitive abilities, fine motor and adaptive abilities, attention span, memory, gross motor skills, and adaptive behaviors. The most common psychological tests for children include the Bayley Scales of Infant Development-III, the Stanford-Binet Intelligence Scale, the Wechsler Intelligence Scale for Children-IV, the Wechsler Preschool and Primary Scale of Intelligence-Revised, and the Vineland Adaptive Behavior Scales-II.

Physical examination

See the list below:

  • Head circumference: Measurement of all growth parameters must include head circumference. Microcephaly correlates highly with cognitive deficits. Macrocephaly may indicate hydrocephalus and is associated with some inborn errors of metabolism and may also be seen early on in some children later diagnosed with autism.[3, 4]

  • Height: Short stature may suggest a genetic disorder, fetal alcohol syndrome, or hypothyroidism. Tall stature may suggest fragile X syndrome (FraX), Soto syndrome, or other overgrowth syndrome associated with MR/ID.

  • Neurologic: This examination should include assessments of head growth (for micro/macrocephaly), muscle tone (for hypotonia or spasticity), strength and coordination, deep tendon reflexes, persistent primitive reflexes, ataxia, and other abnormal movements such as dystonia or athetosis.

  • Sensory: Vision and hearing should always be tested in suspected cases of MR/ID. Children with disabilities and MR/ID are more likely than other children to have visual impairment (refractive errors, strabismus, amblyopia, cataracts, abnormal retinal pigmentation, and cortical blindness) and hearing deficits, particularly among those with severe impairments.

  • Skin: Cutaneous findings of etiologic interest include hyperpigmented and hypopigmented macules, such as café-au-lait macules (associated with neurofibromatosis type 1), and ash-leaf spots (associated with tuberous sclerosis), fibromas, and irregular pigmentation patterns.

  • Extremities: Examine for dysmorphic features and organ system dysfunction indicative of syndromes. Although MR/ID with multiple congenital anomalies and major malformations accounts for only 5-10% of all cases, most of these affected individuals have 3-4 minor anomalies, especially involving the face and digits.

Causes

Prenatal conditions (genetic)

Trisomy 21 or Down syndrome

  • This disorder accounts for 25-50% of persons with severe MR; Down syndrome occurs in approximately 1 per 600-800 live births.

  • In infancy, this disorder is recognized by specific facial features, including flat facial profile, brachycephaly, up-slanted and narrow palpebral fissures, and anomalous auricles.

  • Hypotonia, joint hyperextensibility, neonatal jaundice, simian crease, shortened digits, and excess skin on the back of the neck contribute to the clinical features.

  • Congenital heart disease is present in approximately 40%. GI malformations are present in 5%. Congenital cataracts are found in 3%, and as many as 35% require treatment for strabismus or refractive error. Infantile spasms may develop in 5%.

  • The IQ score ranges from 25-50. Generally, verbal-linguistic skills lag behind visual-spatial skills and social performance is usually above the mental age.

  • In trisomy 21, gene expression of chromosome 21 is increased in a dosage-dependent fashion that varies by tissue type. While some trisomic 21 genes are not expressed at elevated levels, many are. Of those significantly increased, several encode proteins critical for mitochondrial function and for neurogenesis.

  • Other chromosomal abnormalities (eg, deletions, duplications, translocations) may be present in as many as 25% of individuals with severe MR.

    • The most commonly occurring abnormalities of this class, detectable at the 500 band level of chromosomal analysis, are 5p- (ie, Cri du chat syndrome) and 4p- (ie, Wolf-Hirschhorn syndrome).

    • Cryptic subtelomeric deletions are diagnosed with increasing frequency as fluorescently tagged molecular DNA probes allow detection of deletions below the microscopic resolution of a standard karyotype.

    • Cryptic subtelometric rearrangements now account for 5-6% of cases of idiopathic mental retardation.

    • Chromosomal analysis is undergoing further refinement with the application of gene array hybridization techniques that may detect abnormalities in up to 20% of cases of idiopathic mental retardation.

Fragile X syndrome

See the list below:

  • The population prevalence of this disorder is approximately 1 in 3500 males, giving a prevalence within the MR population of about 1 in 76. For males with severe MR, the prevalence rises to about 1 in 13. Other studies have found in populations of those with mental retardation positive fragile X studies in 5.9% of males and 0.3% of females.[16] About 1 in 2000 females carries the fragile X (FraX) gene. Current studies suggest that FraX is the most prevalent form of inherited MR.

  • Males with the full FMR1 trinucleotide repeat expansion (ie, the full mutation) usually function in the moderate to severe range of MR.[17] Other features include testicular enlargement in the postpubertal period and minor facial anomalies (eg, large forehead, elongated face, protuberant auricles, prominent chin).

  • Females with the full FMR1 trinucleotide repeat expansion may have no symptoms, although some have mild learning disabilities or even mild to moderate MR.

  • Mitral valve prolapse and seizures may occur.

  • Up to 20% of FraX males meet criteria for autism; autisticlike behaviors can be present in affected females as well.

  • Direct DNA analysis of the FMR-1 gene is the method of choice for diagnosing both affected individuals with the full trinucleotide repeat expansion (>200 repeats) and unaffected carriers with the premutation (60-200 repeats).

Contiguous gene deletion syndromes

Although less common, some of these syndromes can be readily identified clinically. The following syndromes often can be confirmed by utilizing a fluorescence in situ hybridization (FISH) probe to the deleted region in question.

Prader-Willi syndrome

  • The Prader-Willi syndrome (PWS) involves deletion at 15q11-q13 (deletion of the paternally derived region).

  • Classic clinical features include neonatal and infantile hypotonia, feeding problems or failure to thrive in infancy, excessive weight gain with hyperphagia beginning between ages 12 months and 6 years, food compulsions, hypogonadism, global developmental delay, almond-shaped eyes, thin upper lip, and down-turned corners of the mouth.

  • The candidate gene within the Prader-Willi gene region is SNRPN, which encodes a ribonucleoprotein involved in mRNA splicing. How SNRPN contributes to the hypothalamic dysfunction that defines many clinical features of PWS is unclear.

  • It is the first known human disorder of genomic imprinting, leading to revolutionary changes in the field of molecular genetics and the understanding of uniparental disomy.

  • Negative FISH results in PWS may be due to maternal uniparental disomy (UPD) of chromosome 15 (2 number 15 chromosomes from the mother) and can be confirmed with molecular studies.

Angelman syndrome

  • The Angelman syndrome (AS) also involves deletion at 15q11-q13 (deletion of the maternal copy of the gene region).

  • MR, absent speech, microcephaly, seizures, puppetlike ataxic movements, inappropriate laughter, and facial dysmorphisms characterize AS.

  • The candidate genes within the AS critical region include UBE3A, whose protein product is important in the posttranslational modification of proteins by ubiquitination, and GABRA3, a subunit of the GABAa receptor.

  • Negative FISH results in AS may be due to paternal UPD of chromosome 15 (2 number 15 chromosomes from the father) and can be confirmed with molecular studies.

  • Point mutations occasionally are found in AS with negative results on FISH and UPD studies.

Smith-Magenis syndrome

  • Smith-Magenis syndrome (SMS) involves deletion at 17p11.2.

  • MR, short stature, brachydactyly, minor skeletal and facial anomalies, sleep disturbance, self-injurious behaviors, and other organ system malformations characterize this contiguous gene deletion syndrome.[18]

  • Although as many as 100 genes may be deleted in SMS, the physical characteristics are subtle.

CATCH 22 syndrome

  • The CATCH 22 syndrome, which comprises DiGeorge Syndrome (DGS) and velocardiofacial syndrome (VCF), involves deletion at 22q11.

  • Infants with classic DGS are identified readily by aplasia or hypoplasia of the thymus, T cell lymphopenia, conotruncal cardiac defects, oral-motor dysfunction, and facial dysmorphisms (eg, low-set malformed ears, small jaw, palatal defects, hypertelorism, antimongoloid palpebral slant).

  • Minor variants may meet clinical criteria for the VCF syndrome. With a prevalence of 1 in 4,000 people, it is the most common known microdeletion disorder.

  • The majority of individuals with CATCH 22 have learning disabilities or mild MR and comorbid psychiatric disorders including schizophrenia and mood disorders with psychosis.

Williams syndrome

  • The Williams syndrome involves deletion at 7q11.[19]

  • Characteristic facial features are described as "elfin." In the majority, valvular stenosis, poor growth, hypotonia, late-onset contractures, dental anomalies, infantile colic, oral-motor discoordination, and hyperacusis (ie, hypersensitivity to sound) are reported. Infantile hypercalcemia may be transient and is often subclinical.

  • Mild to moderate MR, relative preservation of language, and associated weakness in visual-spatial development are typical.

  • Elastin is the candidate gene presumed responsible for some of Williams syndrome features, including supravalvular aortic stenosis.

Wolf-Hirschhorn syndrome

  • The Wolf-Hirschhorn syndrome, also known as 4p- syndrome, involves deletion at 4p16.3.

  • Severe growth retardation, microcephaly, "Greek helmet" facies and orofacial clefts, and other midline fusion defects characterize this syndrome.

  • The region of deletion is gene dense, and an undefined number of genes may contribute to this phenotype.

Langer-Giedion syndrome

  • This syndrome, also known as trichorhinophalangeal syndrome type II, involves deletion at 8q24.1.

  • Learning disabilities and the presence of MR vary.

  • Facial dysmorphisms include microcephaly, large ears, bulbous nose, broad nasal bridge, elongated philtrum, and sparse scalp hair. Multiple nevi and skeletal anomalies may be present.

Miller-Dieker syndrome

  • The Miller-Dieker syndrome (MDS) involves deletion at 17p13.3.

  • Infants present with severe neurologic impairment, seizures, and hypotonia secondary to lissencephaly. The smooth cerebral cortex with absent or decreased gyral formation results from abnormal neuronal migration.

  • The identified gene LIS1 may function as a G protein subunit in cellular signal transduction that is important in telencephalon development.

  • Many contiguous gene deletion syndromes for which a FISH probe is not available have been recognized in association with MR. A comprehensive survey is beyond the scope of this article.

Single gene mutation syndromes

Tuberous sclerosis

  • Hypopigmented cutaneous macules (ie, ash-leaf spots), calcified intracranial cortical tubers with or without heterotopias, seizures, retinal hamartomas, and renal angiomyolipomas characterize this hamartomatous condition.

  • MR may or may not be seen in affected individuals; the presence of seizures is the factor most associated with poor cognitive outcome. Autism is a rather common finding in children with tuberous sclerosis associated with MR.

  • This is an autosomal-dominant inherited condition with about half of affected individuals resulting from a new mutation. Two genes have been identified, one at 9q34 (TSC1) and the other at 16p13 (TSC2). A variety of deletions, rearrangements, and point mutations have been implicated in tuberous sclerosis.

Rubinstein-Taybi syndrome

  • Broad terminal phalanges, beaked nose, down-slanting palpebral fissures, epicanthal folds, and microcephaly characterize this syndrome.

  • Behavioral aspects include variable degrees of impulsivity, distractibility, instability of mood, and stereotypies.[20]

  • This is an autosomal-dominant inherited condition, with the majority of cases representing new deletions or point mutations of the CREB-binding protein gene (16p13.3).

Coffin-Lowry syndrome

  • This syndrome is characterized by hypertelorism, down-slanting palpebral fissures, frontal prominence, thickened lips and nasal septum, as well as dental and skeletal anomalies.

  • It is an X-linked condition, with females having mild manifestations. The syndrome results from mutations in the RSK2 gene, which encodes a CREB kinase (Xp22.2-p22.1).[21]

Rett syndrome

  • Developmental stagnation then regression, progressive microcephaly, seizures, ataxia, and autisticlike behaviors are seen in affected females.

  • This X-linked dominant condition with presumed lethality for affected males is caused by mutations in MeCP2, a transcriptional repressor (Xq28).[22]

Smith-Lemli-Opitz syndrome

  • Malformations consistent with holoprosencephaly sequence, syndactyly of toes 2 and 3, micrognathia, cleft palate, and moderate to severe MR are seen.

  • This autosomal-recessive inherited condition results from increases in 7-dehydrocholesterol (7-DHC) due to mutations in the 7-DHC reductase gene (11q12-q13).

  • Treatment with an oral cholesterol "cocktail" has shown some promise in this syndrome.

Costello syndrome

  • Characteristic clinical features include polyhydramnios, failure to thrive, cardiac anomalies, and tumor predisposition.

  • Mean IQ is in the mild MR range, but the spectrum extends from severe MR to average intelligence. Affected males are lower functioning than females and have significantly more behavioral problems.[23]

  • Mutation in HRAS is identified, resulting in a gain of function of the encoded protein and increased activation of the cellular signaling pathway Ras-MAPK.[24]

Many other single-gene disorders are associated with MR with additional phenotypic and behavioral features including such problems as microcephaly, seizures, or short stature, with or without dysmorphic facies.

Recent advances in genetic linkage analysis techniques in families with multiple affected members have revealed more than 50 candidate genes along the X chromosome. In some kindreds with a pattern of X-linked nonsyndromic mild MR (XLMR), linkage analysis has identified candidate genes that code for interleukin receptors, G protein signaling factors, transcription factors, and transcriptional repressors.

Environmental causes

Fetal alcohol syndrome and fetal alcohol effect

Alcohol results in a wide range of teratogenic effects.[25] The most severely affected individuals meet criteria for fetal alcohol syndrome (FAS) by demonstrating short palpebral fissures, dental crowding, camptodactyly flattened philtrum, thin vermillion border, flattening of the maxillary area, microphthalmia, prenatal and postnatal growth deficiency, microcephaly, and developmental delay.

Fetal alcohol effect (FAE) can be diagnosed only in the context of (1) maternal history of alcohol use and (2) a child with developmental and behavioral abnormalities that also manifests growth deficiency or the characteristic facial dysmorphisms.

The prevalence of FAS may be as high as 1.9 in 1000 live births and is the leading cause of MR in the western world. The impact of the milder FAE remains unknown. The teratogenic effects of alcohol may be responsible for as many as 8% of cases of mild MR. Alcohol's deleterious effects on cortical plasticity contribute to cognitive impairment.

Congenital hypothyroidism

Congenital hypothyroidism (known as cretinism in the past) is a neurologic syndrome that results from severe thyroid hormone deficiency during the fetal period. In the infant, the syndrome comprises deaf mutism, moderate to severe MR, spasticity, and strabismus.

Normal fetal brain development requires sufficient production of both maternal and fetal thyroid hormones. Normal glandular production of T4 and T3 requires sufficient dietary intake of iodine.

Iodine deficiency may affect an estimated 800 million people worldwide. It can result in endemic goiter, fetal wastage, milder degrees of developmental delay, and endemic congenital hypothyroidism.

Perinatal/postnatal conditions: These conditions are responsible for fewer than 10% of all MR cases.

Congenital cytomegalovirus (CMV)

Congenital rubella - No longer an important etiology in countries with high vaccination rates

Intraventricular hemorrhage related to extreme prematurity - An important cause only in societies with advanced neonatal care and survival of the premature

Hypoxic-ischemic encephalopathy - Always results in combined CP/MR

Traumatic brain injury - Shaken baby syndrome, closed head injury sustained in motor vehicle accidents

Meningitis - Decreasing in importance as the incidence of Haemophilus influenzae type B decreases in vaccinated populations

Trichomoniasis during pregnancy[26]

Neurodegenerative disorders

 

DDx

Diagnostic Considerations

CNS trauma

Environmental deprivation

Major sensory deficits (eg, deafness, blindness)

Malnutrition

Mitochondrial cytopathies

Neurodegenerative disorders

Differential Diagnoses

 

Workup

Laboratory Studies

The examiner must determine the nature and extent of the laboratory investigation following a history and physical examination. Recommendations have been made by both the American Academy of Pediatrics[27] and the American Academy of Neurology[5] .

Availability of genetic testing, and thus recommendations for work-up, are changing rapidly. Chromosomal microarray and new sequencing techniques have revolutionized genetic testing.[28]

Array-based comparative genetic hybridization (CGH) or "microarray" is increasingly used in the evaluation of MR/ID and should be considered in the work-up of all children with MR/ID either after or as first-line instead of high-resolution karyotype and fragile-X testing (see below). The yield may be as high as 20%; however, a high false-positive rate can also confound interpretation.[29, 30, 31, 28]

High-resolution karyotype (at the 650 band level of resolution at least) should be completed in all children with MR/ID.[27] Chromosomal abnormalities (trisomy 21 and others) may account for as many as 50% of those affected by severe to profound MR/ID.

Fragile X testing (ie, DNA analysis of the FraX promoter region) should be ordered in all children with MR/ID.[5] In the postpubertal period, the clinical manifestations of Fragile X syndrome are likely to be readily apparent, such that DNA analysis can be ordered with more selectivity in this population. Sex chromosome aneuploidy is seen in as many as 5% of children with mild MR/ID or learning disabilities.

FISH probes are ordered as clinically indicated, as follows:

  • Prader-Willi/Angelman syndrome

  • Smith-Magenis syndrome

  • CATCH 22

  • Williams syndrome

  • Wolf-Hirschhorn syndrome

  • Cri du chat syndrome

  • Langer-Giedion (trichorhinophalangeal) syndrome

  • Miller-Dieker syndrome

Given their low yield, metabolic labs are not routinely ordered unless clinically indicated or newborn metabolic screen was not done or results are not available.[5]

  • Plasma amino acids (aminoacidopathies)

  • Urinary organic acids (organic acidopathies)

  • Urinary mucopolysaccharides and oligosaccharides (mucopolysaccharidoses)

  • Plasma 7-DHC (Smith-Lemli-Opitz syndrome)

  • Thyroid function tests

  • Very-long-chain fatty acids (peroxisomal disorders)

  • Creatine kinase (in the assessment of profound central hypotonia versus myopathy)

Consider lead testing in children with risk factors.

Imaging Studies

See the list below:

  • Brain MRI

    • Brain imaging should be conducted in any child with global developmental delays or MR/ID. The yield will be higher in the setting of an abnormal neurologic examination (eg, microcephaly, focal neurologic finding and/or facial dysmorphisms).[5]

    • Brain MRI is generally preferred over CT scan because the former has greater resolution and enhanced detection of abnormalities in the progression and timing of myelination, demyelination, and heterotopic gray matter.

  • Head CT scan: This is the preferred imaging study for calcifications that may be identified with TORCH infections (ie, toxoplasmosis, other infections, rubella, CMV, herpes simplex), when tuberous sclerosis is suspected, or if craniosynostosis is a concern.

  • Skeletal films: These assist with the phenotypic description, syndrome characterization, and assessment of growth.

Other Tests

Detailed assessment by a licensed professional is necessary to confirm the diagnosis of MR/ID. Some of the most commonly used tests in children include the following:

  • Bayley Scales of Infant Development

    • Normalized for ages 2-49 months

    • Subtest scores for receptive and expressive language, gross motor, fine motor, cognitive/problem-solving ability, and sustained attention

  • Stanford-Binet Intelligence Scale

    • Normalized for ages 2 years to 23 years

    • Fifteen subtests for assessment of 4 key areas of cognitive proficiency: verbal reasoning, abstract/visual reasoning, quantitative memory, and short-term memory

  • Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R)

    • Normalized for ages 3 years to 7.25 years

    • Twelve subtests for assessment of verbal and nonverbal intelligence

  • Wechsler Intelligence Scale for Children–IV (WISC-IV)

    • For ages 6 years to 16 years, 11 months

    • Verbal and nonverbal intelligence scores derived from 12 subtests

  • Vineland Adaptive Behavior Scales-II

    • For neonates to adults

    • Measures ability to perform daily activities required for personal and social sufficiency; adaptive or functional behaviors rated by interviewing the patient or parent/caregiver

    • Deficiencies in at least 2 areas of adaptive skills required to meet the MR/ID diagnostic criteria

Electrophysiologic studies

  • Auditory evoked potentials in the context of audiologic assessment

  • Visual evoked potentials in cases of profound delay and suspected cortical blindness

  • EEG is not recommended as part of the routine work-up of MR/ID unless the history is suggestive of seizures or a specific epileptic syndrome.[5]

Histologic Findings

Pathologic analysis of cortical tissue by the Golgi method in the 1970s suggested that in cases of profound, unclassified MR, dendritic spines were decreased and/or had immature morphology. These findings have been confirmed in cortical autopsy material from individuals with Down syndrome and FraX. Dendritic spine morphology is related directly to the intradendritic microtubular components and their organization.

Microtubules in dendrites of cortical neurons often are fragmented or in disarray in cases of developmental failure. In contrast, in some neuronal storage diseases associated with impaired cognition, dendritic spines are sprouted exuberantly beyond the developmental period and in ectopic locations. A relationship is implied, then, between dendritic spine morphology and number and cognitive development in the human.

 

Treatment

Medical Care

See the list below:

  • Early identification of children with developmental delays is necessary to begin receiving early intervention services for children from birth to 3 years of age and early childhood education services for children aged 3-5 years, which are known to improve outcomes.

  • The mainstay of treatment of MR/ID is developing a comprehensive management plan for the condition. The complex habilitation plan for the individual requires input from care providers from multiple disciplines, including special educators, language therapists, behavioral therapists, occupational therapists, and community services that provide social support and respite care for families affected by MR/ID.

  • Preventive care: Unfortunately, routine preventive care for children and adults with MR/ID is lacking. Adaptive equipment (eg, for nonambulatory patients) and extra time (eg, double time slots) may be required to accommodate such patients. In addition, family members or other support persons may be helpful. Written plans (such as the Massachusetts Department of Developmental Services Annual Health Screening Recommendations and Health Record) are helpful for interdisciplinary team communication.

  • Physical activity and obesity are major contributors to disease in MR/ID. Very few programs exist that target healthy lifestyles (nutrition/diet, exercise, self-care, stress reduction) in those with MR/ID. Annual counseling and referral on these issues to community agencies and programs is recommended.[32] Medications (eg, antipsychotics) should be titrated to reduce the risk of obesity and metabolic issues.

  • Pain

    • Manifestations of pain in people with severe to profound MR/ID include crying, screaming, grimacing, protective postures (eg, arching, fetal position), rocking, and aggression. Parent/caregiver input is key to interpretation of these behaviors, though validated tools have been used as adjuncts (such as the Pediatric Pain Profile).

    • Common causes of acute pain include dental caries/abscesses, GERD, constipation, UTI, spasticity (when MR/ID is associated with cerebral palsy), pressure sores, and fractures.

    • In addition, neuropathic pain due to dysautonomia or motor spasms may create chronic disturbances. Treatment should be prompt and include NSAIDs or acetaminophen for mild pain, tramadol or equivalent for moderate pain, and opioids for severe pain as indicated, and management of sources of pain. Some suggest use of gabapentin for neuropathic pain if no sources are identified and there is a history of surgery, symptoms suggesting visceral hyperalgesia (eg, associated with feedings or bowel movements), or symptoms of autonomic dysfunction and spasticity.

  • Written, verbal and pictoral forms of communication as well as gestures and demonstrations are helpful for those with MR/ID to ensure mutual understanding and improve treatment adherence.

  • Sedation/anesthesia: Patients with MR/ID requiring anesthesia may have different reactions than the general population, such as paradoxical reactions to benzodiazepines, and care should be taken to use the lowest dose and titrate slowly.

  • Sexuality/abuse: A significantly higher proportion of children and adults with MR/ID have experienced some form of abuse, with some estimates of up to 70%, which contributes to mental health issues. This should be addressed at each medical visit and especially in the setting of changes in behaviors, such as increased aggression.

  • No treatments are available specifically for cognitive deficiency. Although the pharmacologic enhancement of cognition (eg, use of donepezil in patients with Down syndrome[33] ) is an area of interest, research on such nootropic (ie, knowledge-enhancing) compounds is limited. Such drugs have not become part of the routine or even experimental clinical management of this population.

Other concerns

See the list below:

  • Individuals in the United States older than 18 years are no longer under the guardianship of their biological parents. No exceptions are made for children with MR/ID. Most of these individuals, particularly those in the range of mild MR, are capable of making appropriate legal and medical decisions when adequately and appropriately informed of the decision outcomes.

  • Physicians have the duty to ascertain whether patients with MR/ID have the capacity to consent for medical treatments. This may be challenging and outside information and supports (eg, family, caregivers, social workers) may be required to confirm the patients' understanding of the risks, benefits and alternatives to the procedure.

  • Some individuals may not be capable of comprehending the implications of the medical or legal matter at hand. In such cases, the decision is best made by a member of the biological family. The family member may obtain guardianship status for power of attorney over these matters. If a family member is unavailable to serve as guardian, then a guardian ad litum can be assigned by the court for assistance in such legal and medical matters. If a patient with MR/ID does not have the capacity to consent, then the patient's assent should be sought if possible.

  • Subsequent to the long history of forced sterilization of girls/women with MR/ID, varied federal, state, and local laws regulate sterilization of individuals with MR/ID. The American College of Obstetrician/Gynecologists provides guidance on informed consent for sterilization procedures in patients with ID/MR.[34]

  • Complex decisions, particularly those involving end of life, are perhaps best handled with the assistance of the ethics committee of the involved medical institution.

  • Failure to identify a genetic cause of MR/ID with risks to other family members or risks to the patient for future medical complications are potential medical/legal pitfalls.

  • Perhaps 1 in 8 convicts on death row in the United States has MR/ID. Many persons cannot fully comprehend the Miranda Rights and other critical concepts necessary to maneuver through the criminal justice system.

Consultations

See the list below:

  • Developmental pediatrician or psychologist

  • Geneticist and counselor

  • Psychiatrist

  • Dentist

  • Podiatrist

  • Special education/educational therapist

  • Occupational, speech and/or physical therapist

  • Behaviorist

  • Pharmacist

  • Durable medical equipment providers

  • Social services agencies/social workers

Diet

Nutritional supplements are of no proven benefit.

Activity

Because obesity is more prevalent in those with MR/ID, regular physical activity should be included in the management plan[35] . Adaptive exercise programs for those with concomitant physical disabilities should be recommended as needed.[32]

 

Medication

Medication Summary

No specific pharmacologic treatment is available for cognitive impairment in the developing child or adult with MR/ID.[6] Medications, when prescribed, are targeted to specific comorbid psychiatric disease or behavioral disturbances.

Development of nootropic drugs that may alter cognitive processes positively has been of interest to researchers. Medications currently prescribed for dementia, such as acetylcholinesterase inhibitors, are not accepted treatments for MR/ID, and clinical trials have not been conducted in children. Phosphodiesterase inhibitors enhance cortical plasticity in an animal model of fetal alcohol syndrome.

Although vitamin and mineral therapies have gained popularity, their efficacy has not been established in clinical trials. A randomized controlled study of antioxidants and/or folinic acid for 18 months in 156 infants with Down syndrome found no evidence to support the use of these supplements in this population.[36]

CNS stimulants

Class Summary

The most common class of drugs prescribed in this population is the psychostimulants because of the diagnosis of attention deficit with or without hyperactivity disorder (ADHD/ADD) in 6-80%. Few studies are available on stimulants in people with MR/ID and, in many studies, those with MR/ID have been specifically excluded. Available studies indicate that benefits vary and significant adverse events, such as severe social withdrawal, increased crying, drowsiness, and irritability have been noted, especially at higher doses of methylphenidate (0.6 mg/kg).[7]

Methylphenidate hydrochloride (Ritalin, Metadate ER)

Stimulates cerebral cortex and subcortical structures.

Dextroamphetamine sulfate (Dexedrine) and racemic amphetamine (Adderall)

Increase amount of circulating dopamine and norepinephrine in cerebral cortex by blocking reuptake of norepinephrine or dopamine from synapse.

Alpha-adrenergic agonists

Class Summary

These agents are used commonly to modulate hyperactivity, aggression, tics, and dyssomnias. None of these drugs has an FDA-approved indication for MR/ID.

Clonidine hydrochloride (Catapres)

Agonist at presynaptic alpha2-adrenergic receptors within brain stem. Clonidine reduces norepinephrine release at these sites, reducing sympathetic outflow and enhancing parasympathetic outflow. May reduce aggression by increasing release of GABA in frontal cortex and other brain regions.

Guanfacine (Tenex)

Presynaptic alpha2-adrenergic receptor agonist that stimulates alpha2-adrenergic receptors in brain stem, activating an inhibitory neuron, which in turn decreases vasomotor tone and heart rate. Similar reduction in potentially negative impact on academic performance and cognitive function.

Neuroleptic drugs (antipsychotics)

Class Summary

The neuroleptic drugs are the most frequently prescribed agents for targeting behaviors such as aggression, self-injury, and hyperactivity in people with MR/ID. These indications are generally off-label for MR/ID and caution is advised. Increasingly, they are more likely to be reserved for the older child or adult in whom intensive behavioral intervention has failed. Likewise, the prevalence of comorbid psychiatric disorders in MR/ID increases with age. Neuroleptics interact with receptors for a variety of brain neurotransmitters, including dopamine, serotonin, acetylcholine, histamine, and norepinephrine. Their ability to antagonize dopamine receptors appears to correlate with the efficacy of these drugs and imparts their antipsychotic properties. Likewise, antidopaminergic activity evokes extrapyramidal symptoms. Rarely, neuroleptic malignant syndrome may occur.

Risperidone (Risperdal)

Atypical antipsychotic with fewer adverse neurologic effects and less propensity for extrapyramidal movements (eg, pseudoparkinsonism, akathisia, acute dystonias, tardive dyskinesia).

Aripiprazole (Abilify)

A newer atypical antipsychotic, aripiprazole is indicated in acute bipolar mania and schizophrenia.

 

Follow-up

Further Outpatient Care

See the list below:

  • Children with MR/ID should be evaluated regulalry by a neurologist or neurodevelopmental pediatrician with a special interest in the etiology and management of cognitive disorders. The physician should have adequate knowledge of the educational, social, and support services available in the community; assessing the appropriateness of the patient's individualized habilitation is important.

  • To maximize the individual's functional independence, the following areas should be addressed by the physician at least annually:

    • Treatment of associated impairments

    • Pharmacotherapy

    • Behavior management

    • Educational services

    • Recreational needs

    • Family counseling

  • The annual visit requires routine preventive medicine and coordination of specialized services such as dental and gynecologic care under sedation. Supplemental vaccines, including the influenza and hepatitis B vaccines, are particularly prudent for those in residential placements. A careful behavioral history is important to identify newly emerging maladaptive behaviors that may be treated effectively with behavior management. Examples of health care guidelines for individuals with MR/ID include the Massachusetts Department of Mental Retardation checklist.[37]

  • If patients have coexisting motor impairments, the physician should monitor for secondary orthopedic disease. Advanced knowledge in the pharmacologic management of spasticity and rigidity allows the clinician to refer the patient for botulinum toxin injections or baclofen pump insertion when appropriate. Arthroplasty for progressive hip dislocation and/or tendon releases for progressive contractures due to spasticity may be required.

  • The health maintenance schedule for individuals with Down syndrome is well recognized. The American Academy of Pediatrics and American Academy of Family Practice have provided practice guidelines on the preventive care of children and adults with Down syndrome.[38] Ongoing vision and audiologic evaluation, thyroid function tests, and screening for atlantoaxial instability and obstructive sleep apnea are some important components.

  • The American Academy of Pediatrics has recently provided practice guidelines for the health maintenance of children with Prader-Willi syndrome[39] .

Prognosis

Individuals with MR/ID fare better today than at any other recorded time in world history.

Patient Education

Family support and education around the issues of MR can be obtained from the following:

  • The Arc (formerly known as the Association for Retarded Citizens)

  • Membership Department

  • 1010 Wayne Ave., Suite 650

  • Silver Spring, MD 20910

  • American Association on Intellectual and Developmental Disabilities

  • 501 3rd Street, NW

  • Suite 200

  • Washington, DC 20001

  • 800-424-3688

  • Exceptional Parent Magazine

  • P.O. Box 2078

  • Department EP

  • Marion, OH 43305-2178

  • National Organization for Rare Disorders (NORD)

  • National Organization for Rare Disorders

  • 55 Kenosia Avenue

  • PO Box 1968

  • Danbury, CT 06813-1968

  • For excellent patient education resources, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education article Down Syndrome.