CHILDREN WITH DOWN'S SYNDROME
George Capone (USA)

Background:

The first comprehensive description of this condition was provided by Dr. John Langdon Down in 1866. Down's syndrome most often results from complete trisomy of chromosome 21, due to non-dysjunction during gamete formation. In about 95% of cases of trisomy 21, the non-dysjunction is of maternal origin . Rarely, non-dysjunction will occur after fertilization is complete, resulting in two different cell lines. This condition is referred to as mosaicism because there exists one trisomic and one euploid cell line within the same embryo-fetus. A small number of cases result from either complete or partial translocation of chromosome 21 to another chromosome (usually in the G or D group). Some forms of translocation Down's syndrome are associated with a familial pattern of inheritance. Overall, 90-95% of cases of Down's syndrome result from full trisomy 21; 2-4% result from translocation; and 2-4% are the result of mosaicism.

Data collected by the Centers for Disease Control in the USA regarding the prevalence of Down's syndrome have been compiled in the U.S. from 17 states with population-based birth defects surveillance programs. During 1983 to 1990, the overall birth prevalence of Down's syndrome was 9.2 cases per 10,000 live born infants (> 20 weeks gestation). Rates differed significantly by racial/ethnic group for Hispanic (.12%), Caucasian (.09%), and Afro-American (.07%) infants. The prevalence rates increased with advancing maternal age in all racial/ethnic groups.

Diagnosis:

A presumptive diagnosis of Down's syndrome is made by the physician or hospital staff shortly after birth. In the newborn period, infants with Down's syndrome may be difficult to distinguish from infants with other chromosome anomalies. A karyotype performed on blood lymphocytes or skin fibroblasts is mandatory to confirm the diagnosis even in cases where the phenotypic appearance is obvious. For purposes of genetic counseling it is critical to distinguish complete trisomy 21 from trisomy 21/mosaicism or an unbalanced translocation. The ten most common physical features which may aid in diagnosis are given below [Table 28-1]. No single phenotypic finding is by itself diagnostically significant , but rather it is the association of three or more of these features together which warrants a high degree of suspicion.

Table 28-1
Diagnostic Features of Down's syndrome in the Newborn Period

Clinical Evaluation:

Once the diagnosis of Down's syndrome has been made the clinician will often be called upon for his/her opinion regarding a variety of issues. The most common inquiries have to do with 1) associated medical conditions, 2) neurodevelopmental status, and 3) behavioral or psychiatric conditions. Each of these areas will need to be addressed according to the age of the individual concerned and the degree of familiarity the clinician brings to bear on these issues.

MEDICAL CONDITIONS:

In addition to the well-recognized phenotypic features characteristic of this condition, it is paramount that physicians be aware of the variety of congenital and acquired medical problems associated with Down's syndrome. These are best categorized according to the individuals chronologic age. Management of specific medical conditions is generally no different in persons with Down's syndrome compared to individuals in the general population; however their presentation may present a diagnostic challenge. Because of the high incidence of certain medical conditions, screening of asymptomatic individuals at regular intervals is strongly recommended.

Newborn: (0-1 month)

A medical prognosis given during the neonatal period should be determined on an individual basis, according to the presence or absence of specific medical conditions and not soley upon the diagnosis of Down's syndrome.

Congenital heart disease (CHD) occurs in 40-60% of Down's syndrome newborns. The most common cardiac lesions are AV canal (60%); isolated VSD, ASD, or PDA (30%); and tetralogy of Fallot (7%). Cardiac defects are responsible for a significant degree of morbidity and mortality during the first two years of life. GI tract anomalies are seen in 6-12% of Down's syndrome newborns, and include: duodenal stenosis or atresia (2.5%), inperforatae anus (<1%), Hirshprung's Disease (<1%), tracheoesophageal fistula, esophageal atresia, bile duct atresia, malrotation and pyloric stenosis. Physiologic complications such as oral motor dysfunction or gastroesophageal reflux are also seen. Congenital cataracts are seen in about 2-4% of newborns with Down's syndrome which represents a ten-fold increase compared to the general population. There is also an increased incidence of congenital hypothyroidism due to absence or aplasia of the thyroid gland which occurs in about 1 to 2% of newborns.

Infancy: (1-12 months)

Transient myeloproliferative disorder (TMD) is sometimes seen in the first few months of life. Elevated peripheral blood leukocyte count with a predominance of "blasts" forms may make this condition difficult to distinguish from true congenital leukemia. Newborns with TMD are at increased risk for developing acute non-lymphocytic leukemia (ANLL) before the age of 5 years. Infants with Down's syndrome are susceptible to both viral and bacterial infections of the respiratory tract. Recurrent otitis media, sinusitis, and rhinitis are frequent problems as are bronchiolitis and pneumonia. Lower respiratory tract infections may be a significant cause of morbidity during infancy particularly in those with uncorrected cardiac disease.

Respiratory infections tend to become less common with age and growth of craniofacial and respiratory structures. A number of ophthalmologic conditions may present during the first year of life including: strabismus (23-44%), refractive errors (35-40%), nystagmus (5-30%), astigmatism (18-25%), amblyopia (10-12%), blepharitis (9-32%), keratoconus (5-8%), ptosis (5%), nasolacrimal duct obstruction (4-6%). Guidelines for preventive medical screening and health maintenence can be found in Table 28-2:

Table 28-2.

Childhood: (1-12 years)

Disorders of thyroid function are particularly common in children with Down's syndrome. There is a trend for TSH values to increase and T4 to decrease with advancing chronologic age. Acquired hypothyroidism is seen in 2-7% of children. Both compensated (elevated TSH/normal T4) and uncompensated (elevated TSH/decreased T4) hypothyroidism are seen. Transient elevation in TSH sometimes noted in infants and children under two years of age may be due to hypothalamic-pituitary dysregulation. This condition often resolves without treatment. There is a high incidence of transient, conductive hearing loss (>50%) among children with this condition which is usually the result of otitis media, middle ear effusions, or impacted cerumen. Sensorineural and mixed hearing loss may be seen in up to 15-20% of children.

Obstructive sleep apnea (OSA) is noted in > 30% of children with Down's syndrome. Symptoms of OSA may include snoring, restless sleep, unusual sleep position, excessive mouth breathing, daytime somnolence, or behavioral changes. Factors which predispose Down's syndrome children to OSA include: a small oral cavity with relative macroglossia, narrowing of the upper airway, hypotonia of the pharyngeal muscles, chronic rhinitis, obesity and enlarged tonsils or adenoids.

Down's syndrome is associated with approximately 2% of all cases of acute leukemia in children. ANLL is most common in children under three years, while ALL is more common in children over three years of age. Within the ANLL group, there is a remarkable increase in the incidence of acute megakaryocytic leukemia in those children with a history of TMD.

Children with Down's syndrome are susceptible to subluxation of the hips, patella, and C-spine. Up to 15% of children show x-ray evidence of asymptomatic C-1/C-2 instability, determined by measuring the atlanto-dens interval (ADI) on lateral neck Xray (ADI = 3-5 mm.). Less than 1% of children demonstrate neurologic symptoms which may require treatment. Symptomatic children usually have an ADI > 8 mm. Symptoms may include: brisk deep tendon reflexes with upgoing plantar response, stumbling gait or inability to walk, loss of bowel or bladder control and torticollis. In addition to C-1/C-2 instability, a higher incidence of atlanto-occipital instability and congenital anomalies of the cranio-vertebral junction and cervical spine have been reported. Guidelines for preventive medical screening and health maintenence can be found in Table 28-3:

Table 28-3
Health Maintenence Guidelines During Childhood (1-12 years)

Children and adolescents with Down's syndrome demonstrate a reduction in linear growth rates, with heights 2-4 SD below the mean for the general population. The adolescent growth spurt usually occurs later compared to the general population. There is also a tendency toward excessive weight gain relative to height throughout childhood and adolescence in some individuals. Final adult heights for men range between 140 and 160 cm. while the typical range for adult women is between 135 and 155 cm.

The onset and progress of puberty is the same or only slightly delayed for adolescent boys with Down's syndrome. Reports of reduced sperm counts, and lack of mature sperm have led to the conclusion that most men with Down's syndrome are infertile. The onset of menses and duration of menstral cycles is about the same for women with Down's syndrome compared to other women in the general population. Women of childbearing age should be considered fertile and will require educational instruction about menstrual care and reproduction, and access to routine gynecological care. Guidelines for preventive medical screening and health maintenence can be found in Table 28-4:

Table 28-4
Health Maintenence Guidelines During Adolescence (12 to 18 years)

NEURODEVELOPMENT:

Newborn: (0-1 month)

Neuromotor dysfunction (generalized hypotonia with diminished primitive- and deep tendon-reflexes) is characteristic of most newborns with Down's syndrome.

Infancy: (1-12 months)

Brain size is often normal throughout gestation and the first six months of postnatal life before decelerating during the latter half of the first year. Dysgenesis of the cerebral cortex and cerebellum, as well as delays in myelination during the first years of life probably constitute the primary neurologic substrate of neuromotor dysfunction which is characteristic of all infants with this condition. Seizures, particularly infantile spasms, may occur in up to 5% of infants during the first year.

Delay in the acquisition of gross motor milestones is usually obvious to physicians and parents during the first year. There is, however, considerable individual variation in the attainment of early motor milestones. Particularly severe neuromotor dysfunction may be associated with specific medical conditions such as infantile spasms or uncorrected CHD. Delays in prelinguistic, visual-perceptual and visual-motor milestones are also usually apparent by the end of the first year; however, delays in these areas often go unnoticed by parents and professionals who may tend to focus more on motor skill acheivement during this time. Reasonable restraint should be exercised in issuing an overly positive or negative developmental prognosis early in life because of the wide individual variation in all aspects of developmental function. Parents should be encouraged to enroll their child in an early intervention program. Guidelines for developmental intervention can be found in Table 28-5:

Table 28-5
Developmental Intervention During Infancy

Childhood: (1-12 years)

Dysplasia of the brain is probably best reflected by changes in brain growth and head circumference during the first few years of life. Detailed neuropathologic studies reveal a generalized hypocellularity of the brain. Reduction in neuronal number and density have been demonstrated for most regions examined. Ultrastructural studies of pyramidal neurons from the cerebral cortex reveal abnormalities of dendritic arborization and reduced numbers of post-synaptic spines. Surviving spines are often abnormally long, thin, or irregular in contour and appearance. Decreased myelination is noted throughout the cerebral hemispheres, basal ganglia, cerebellum, and brain stem during the first year of life.

Significant neuromotor dysfunction persists throughout the first few years of life, but tends to improve with increasing chronological age and rarely presents a serious limitation for older children. Many children however, will demonstrate difficulty with tasks requiring motor coordination and sequencing.

As expectations for language and cognitive growth increase during the second year of life, delays usually become apparent to both parents and professionals alike. As a group, children with Down's syndrome demonstrate greater deficits in verbal-linguistic skills relative to visual-spatial skills. A non-linear rate of cognitive development is often seen during the first decade of life, which manifests as slowing in the rate of cognitive growth with age. Most children with Down's syndrome test in the low-mild to moderate range of intellectual disabilities by the time they enter elementry school at 5-6 years of age. There are large individual differences in the onset and complexity of spoken language. Asynchrony of language development has been well documented in this population. Typically, language comprehension and production develop at significantly different rates with production skills showing the greatest delays. Poor speech articulation may further contribute to communication difficulties during childhood.

Most children will make steady developmental progress, so is important to document and comment upon the positive developmental gains made during this time. Children are usually receiving several types of developmental intervention during the preschool and school-age years. Parents who are eager to maximize developmental therapies on behalf of their child should not be discouraged or necessarily labeled as "in denial" provided the child accepts the efforts of the therapist without undue resistance. Many parents need to be sure that they are maximizing their child's chances of having a favorable outcome. In situations where a child becomes avoidant or oppositional toward therapy, some effort should be made to modify the program. Guidelines for developmental intervention can be found in Table 28-6.

Table 28-6
Developmental Intervention During Childhood

BEHAVIORAL AND PSYCHIATRIC:

Childhood: (1-12 years)

20-40% of children and adolescents with Down's syndrome may be diagnosed with a co-morbid behavioral or psychiatric disorder . Disruptive disorders (ADHD, conduct/oppositional and aggression) are seen in about 16%, while repetitive behaviors and autistic-spectrum disorders are seen in about 5%. The prevalence of ADHD (6-8%) in children with Down's syndrome is probably not different from the general population, but is lower than the prevalence observed in children with non-specific intellectual disabilities. Often these children come to the attention of the clinician because of behavioural concerns (sleep problems, non-compliance, running-off, or concerns about safety).

When evaluating a child with Down's syndrome for symptoms of hyperactivity and inattention clinicians need to consider the child's cognitive level, degree of communication impairment, educational expectations, family dynamics and associated medical conditions which may contribute to these symptoms (hearing loss, nighttime hypoxemia due to OSA, or medications). Stereotypic or repetitive motor behaviors (rocking, hand flapping, staring at fingers or lights, shaking objects) may be seen in children who are functioning in the severe or profound range of intellectual disabilities. The absence of well developed communication skills in these children may lead the clinician to consider a diagnosis of Autism. However, many of these children will fail to meet the diagnostic criteria for Autism because they have reasonably intact reciprocal social interaction skills. These children are more properly classified as having Stereotypic Movement Disorder (SMD). Children with either ADHD or SMD are generally readily distinguishable from their same age, Down's syndrome peers without these conditions.

Adolescence: (13-18 years)

Aggressive and disruptive behaviors are sometimes problematic as children get older and approach puberty. Concerns about difficult to control anger and/or hurting others usually brings this to the attention of the clinician. It is important to try to identify known precipitants which trigger the behavior and other environmental factors which maintain or reinforce it. Changes in the environment, educational program or a caretakers response to the behavior can then be made and their impact monitored. Occult sources of pain (headache, sinusitus, GE reflux, otitis media) as well as depression, mood disorders, anxiety disorders and premenstrual syndrome can also contribute to the development of these behaviors, and should be considered when evaluating a child or adolescent for aggressive or disruptive behavior.

DISCUSSION:

Children with Down's syndrome are living healthier lives than their peers born in previous decades. Social advocacy by parents and increased awareness of related medical conditions mean that persons with Down's syndrome are living longer, more productive lives. It was estimated that by the year 2000 well over 50% of individuals born with this condition will live beyond 60 years. Many individuals with Down's syndrome develop age-related medical disorders (cataracts, autoimmune thyroiditis, sensorineural hearing loss, Alzheimer's-type dementia) and certain psychiatric disorders (depression, obsessive-compulsive traits) at a higher frequency and earlier in life than members of the general population. Thus the need for regular medical care is lifelong.

SUGGESTED READING:

1. Rogers, P. Rozien, N. and Capone, G. Down syndrome, In Developmental Disabilities in Infancy and Childhood Vol II, 2nd Ed. (Capute, A. and Accardo, P. eds.) Paul H. Brookes, Baltimore 1996 p 221-244
2. Cooley, C. and Graham, J. Down Syndrome-An update and review for the primary pediatrician, Clinical Pediatrics 30(4): 233-253, 1991
3. Biomedical concerns in persons with Down Syndrome (Pueschel, S. and Pueschel, J. eds.)
   Paul H. Brookes, Baltimore 1992 pp 320
4. Wisnewski, K. Down Syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis, American Journal of Medical Genetics, Suppl. 7:274-281, 1990
5. Myers, B. and Pueschel, S. Psychiatric disorders in persons with Down Syndrome, Journal of Nervous and Mental Disease 179:609-613, 1991
6. Cohen, W. et al. Health care guidelines for individuals with Down Syndrome, Down Syndrome Quarterly 1(2) 1-10, 1996
7. Committee on Genetics, Health supervision for children with Down Syndrome, Pediatrics 93(5) 855-859, 1994

RESOURCES FOR FAMILIES AND PROFESSIONALS:

1. Down Syndrome Quarterly (Thios, S. ed.) The Nisonger Center, and Denison University Granville, Ohio 43023. Call for subscription rates Telephone 614-587-6338. Email:Thios@Denison.edu
2. National Down Syndrome Society, 666 Broadway, New York, NY. 10012 Telephone 212-460-9330 or toll free 1-800-221-4602. (http://www.ndss.org)
3. National Down Syndrome Congress, 1605 Chantilly Drive Suite 250, Atlanta, GA. 30324 Telephone 1-800-232-6372. (http://www.ndsccenter.org/old/ ) Email: ndsc@charitiesusa.com
   

This article was first published in Advances in Child Neurology in 1999.

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