Definition
In the mid-1800s several physicians described groups of patients who had intellectual disability, short stature, and specific facial characteristics including upslanting palpebral fissures, epicanthal folds, flat nasal bridge, and protruding tongue.
Subsequently, J. Langdon Down, after whom Down syndrome (DS) was named, emphasized that affected individuals could be distinguished from the heterogeneous group of all those with intellectual disabilities based on their unique physical features.
Unlike other genetic conditions, individuals with DS are typically diagnosed in the newborn period based on these distinctive physical characteristics.
Clinical syndrome is phenotype of individuals with Trisomy 21.
Incidence
DS, or trisomy 21, is the most common genetic cause of intellectual disability, occurring in one in 691 live births.
DS occurs in all ethnic groups, socioeconomic levels, and geographic regions.
Once the medical complications at birth are appropriately treated, individuals with DS can live well into their 60s and beyond with productive lives if appropriate educational, medical, and societal resources are provided.
Pathophysiology
DS is described as the presence of an additional (third) copy of the genetic material located on the 21st chromosome.
The typical human karyotype is composed of 46 chromosomes, which group into 23 pairs. The first 22 pairs of chromosomes are known as the autosomes. The last pair, composed of the X chromosome and/or the Y chromosome, is known as the sex chromosomes. Females will have two X chromosomes, while males will have one X chromosome and one Y chromosome.
DS can occur in one of three ways.
Nondisjunction
DS due to nondisjunction, also known as standard trisomy 21, occurs when like chromosomes fail to separate during meiotic division. This results in the egg or sperm cell contributing two copies of chromosome 21, producing a child with three complete copies of the 21st chromosome.
Standard trisomy 21 is the most common form of DS, accounting for 95% of all known cases.
The recurrence risk for parents of a child with standard trisomy 21 is 1% or one in 100, until the maternal age–related risk for having a child with a chromosomal variation exceeds 1% (>38 y/o).
The karyotype for an individual with standard trisomy 21 will be 47,XY,+21 in males or 47,XX,+21 in females.
Robertsonian translocation
DS due to a Robertsonian translocation occurs when an individual inherits a complete copy of the 21st chromosome from each parent, as well as, a copy of the long arm of the 21st chromosome fused to the long arm of another acrocentric chromosome (chromosome 13, 14, 15, 21, or 22).
DS due to a Robertsonian translocation accounts for 3% to 4% of all known cases.
The recurrence risk for parents of a child with a Robertsonian translocation can vary between 0.5% and 100% depending on which parent is the carrier of the balanced translocation, as well as which acrocentric chromosome was involved. Thus, it is important that parental chromosome karyotype analysis be performed prior to providing a recurrence risk.
The karyotype for an individual with DS due to a Robertsonian translocation would be 46,XY,der(N;21)(q10;q10) or 46,XX,der(N;21)(q10;q10), where N can be any of the acrocentric chromosomes (chromosome 13, 14, 15, 21, or 22).
Mosaicism
Mosaic DS occurs when one chromosome fails to separate during any of the mitotic divisions of embryogenesis. The degree of mosaicism depends on how far into embryogenesis the mitotic division occurred. If nondisjunction occurred later in embryogenesis, an individual will have a greater number of typical cells (with 46 chromosomes) compared to cells with an additional copy of the 21st chromosome.
Mosaic DS is the rarest form of DS, accounting for only 1% of all known cases.
Parents of a child with mosaic DS have the same recurrence risk as that of standard trisomy 21.
The karyotype for an individual with mosaic DS will be 46,XY[N]/47,XY,+21 [N] in males or 46,XX[N]/47,XX,+21[N] in females, where N represents the number of cells counted that are composed of the specified chromosomal number.
Risk factors
Advanced maternal age is possibly the most significant factor related to chromosome 21 nondisjunction. Increased age of the mother at conception influences chromosome segregation in the eggs.
The incidence of DS increases with advancing maternal age is as follows: less than 1 in 464 (age <30 years), 1 in 415 (age 30), 1 in 238 (age 35), 1 in 175 (age 36), 1 in 133 (age 37), 1 in 100 (age 38), 1 in 75 (age 39), 1 in 56 (age 40), 1 in 32 (age 42), 1 in 18 (age 44), 1 in 10 (age 46), and 1 in 6 (age 48).
The total number of pregnancies in women ages <35 years is greater than women >35 years; thus, most newborns with DS are born to women <35 years despite having a lower chance of having a child with DS.
Clinical presentation
Signs and symptoms
The majority of newborns with DS will have hypotonia and distinct physical characteristics. Table 41-1 lists the 10 features that are typically present in the neonatal period.
A general examination may reveal other findings, although not all of these features need to be present to suspect a diagnosis of DS. The following physical findings may be noted (Figure 41-1):
Skull: Brachycephaly with flat occiput
Eyes: Epicanthal folds in addition to upslanting palprebral fissures, Brushfield spots of the iris (especially in babies with blue eyes)
Nose: Short, a low nasal bridge, small nares
Ears: Small, may be low set
Tongue: Protruding
Mouth: Downturned, small oral cavity
Extremities: Short hands, possible single palmar transverse crease, digital dermatoglyphics, fifth finger clinodactyly, and wide space between the first and second toes with vertical plantar creases
Condition variability
Development
Children with DS have global developmental delay in gross motor, fine motor, and language domains.
Motor skills are delayed due to low muscle tone and joint laxity. Motor milestones include rolling between 5 and 6 months, sitting independently between 8 and 11 months, crawling between 12 and 17 months, and walking independently between 15 and 74 months.
Language delay may be further affected by the low muscle tone, small mouth with protruding tongue, and open-mouth posture. Speech intelligibility may result due to difficulties in motor planning and coordinating movement of the tongue, lips, jaw, and palate.
Fine motor delays lead to challenges in self-help and/or academic skills, such as, feeding, writing, and dressing.
Cognitive
The degree of cognitive functioning in individuals with DS varies widely with IQ ranging from mild to moderate intellectual disability.
Children with DS between 6.5 and 8.0 years have IQ levels between 45 and 71 (mean 55.6) compared to adolescents with DS between 12.2 and 25.9 years with IQ levels between 28 and 47 (mean 37.6).
Performance strengths are noted on visual–spatial tasks compared to short-term memory auditory and verbal tasks.
Age-related decline in IQ is seen in individuals with DS, typically occurring in the third or fourth decades, which may or may not be impacted by dementia. The mean IQ level is 45 by adulthood with significant variability in the range of IQ levels. However, adaptive functioning improves into young adulthood, followed by a period of stability, and may subsequently decline in the mid-40s.
Behavioral
Individuals with DS are often described to be social and affectionate; however, they are at risk for certain maladaptive behavior.
During childhood, they may have externalizing behavioral problems (opposition, hyperactivity, impulsivity, and inattention) and propensity toward internalizing symptoms (shyness, withdrawal, anxiety) during late adolescence and adulthood.
The risk for psychopathologies may continue through adulthood and it is often difficult to determine if it is influenced by age-related cognitive decline or by clinical dementia of the Alzheimer type.
Co-occurrence of autism spectrum disorder or pervasive developmental disorders in DS may exist. The prevalence of autism among children with DS ranges from 1% to 13%, and overall function in individuals with DS and autism is significantly lower than those with DS.
Diagnosis
Chromosomal studies are indicated to confirm the clinical suspicion of DS and to determine the genotypic cause of DS (eg, standard trisomy 21, translocation, or mosaicism).
DS due to translocation will require parental chromosome studies to determine future recurrence risks.
Management
Medical
Individuals with DS require the same health care as outlined for the general population and also require additional health supervision specific for their needs. The Committee on Genetics of the American Academy of Pediatrics has developed these health supervision guidelines (2011) to assist pediatricians in providing medical care for children with DS.
Thyroid
Individuals with DS are at a higher risk for hypothyroidism than the general population. Thyroid screening should be performed as part of the newborn screening panel at birth. If the state newborn screening panel only tests for free thyroxine (T4), thyroid-stimulating hormone (TSH) should also be obtained.
Cardiac
Approximately 50% of infants with DS have congenital heart disease (CHD), with an atrioventricular septal defect being the most common type. An echocardiogram is required at birth, even in the absence of a murmur, and should be read by a pediatric cardiologist. Any abnormalities necessitate referral to a pediatric cardiologist. Infants with CHD should be evaluated for any symptoms of congestive heart failure, which include tachypnea, poor weight gain, and feeding difficulties.
Gastrointestinal
Duodenal or anal atresia/stenosis: Infants with DS are at risk for duodenal or anal stenosis, or duodenal or anal atresia (30%), which should be diagnosed through physical examination and/or history.
Feeding difficulties: The combination of low muscle tone, a small oral cavity, and narrow nares can lead to difficulties with swallowing, choking with feedings, slow feedings, recurrent respiratory symptoms, and failure to thrive in infants with DS. In these instances, a speech/feeding evaluation is recommended and radiographic swallowing assessment should be considered.
Growth
All children with DS should have their growth monitored on the standard regular growth charts and should include use of weight for height and BMI.
Hematologic abnormalities
Transient myeloproliferative disease (TMD)
It is necessary to perform a complete blood count at birth due to the risk of TMD, which is present in 10% of infants with DS. TMD usually spontaneously resolves by 3 months of age, but 10% to 30% of infants with TMD later develop leukemia. Polycythemia is also common in infants with DS and may require medical management. If an infant has TMD, parents need to be aware of signs that could indicate leukemia, such as easy bruising, fatigue, petechiae, or appetite changes.
Hearing
Hearing should be evaluated during the birth hospitalization via a brainstem auditory evoked response or otoacoustic emission according to the universal newborn hearing guidelines.
Vision
An evaluation for cataracts should be performed at birth by visualizing the red reflex.
Surgical
Surgical repair is typically required for infants with duodenal or anal atresia or stenosis. A history of chronic constipation refractory to diet changes or laxatives may indicate Hirschprung disease. If Hirschprung disease is confirmed via biopsy, surgical removal of the affected region of the colon is required. Cardiac surgery is typically required for CHDs, such as atrioventricular septal defects.
Developmental/therapeutic interventions
Physical therapy
Physical therapy should begin shortly after birth. The goal of physical therapy is to ensure that the child avoids developing abnormal compensatory movement for the physical limitations (eg, short arms and legs relative to the trunk, ligamentous laxity, hypotonia, and decreased strength). Key areas that may be addressed during physical therapy sessions include improvement in tone, strength, and coordination.
Occupational therapy
In infancy, the occupational therapist may work closely with the speech therapist to address feeding difficulties and emphasize oral-motor exercises. As the child gets older, the occupational therapist will focus on self-care skills that will help the child become more independent, such as feeding, dressing, and playing. Fine motor skills in children with DS may be delayed due to hypotonia, ligamentous laxity, and decreased strength. In school-aged children, occupational therapies will often involve skills such as handwriting, typing, and using scissors. It is helpful for children to have experience with occupational therapy both in the classroom and home environment to emphasize learning of a variety of skills.
Speech therapy
Feeding: Speech therapy should be started in infancy if the infant has feeding problems.
Early language
Speech therapy during infancy is also important as prelanguage and prespeech skills can be addressed before the child is able to start forming words.
Children with DS often have speech delay, which is further impacted by their small oral cavity, protruding tongue, low muscle tone, and open-mouthed posture. Additionally, problems with motor planning and coordinating rapid movements of the tongue, lips, jaw, and palate can lead to speech that is less intelligible, which can be a major barrier to daily activities and social functioning.
In children with DS, expressive language is more delayed than receptive language.
Intensive intervention in a one-on-one format is most effective. Speech therapy in a group setting may help address pragmatic communication skills.
Parents should be highly involved to enable them to learn to respond to their children’s verbalizations and gestures, and learn how to encourage language skills from their child.
Depending on degree of language delay, speech therapists may consider using augmentative or alternative communication approaches, which include unaided approaches such as sign language or gesturing, or aided approaches with external symbol systems such as pictures or graphics.
Phonological awareness skills and phonics-based instruction can be particularly useful in teaching a child with DS to communicate and read. This type of instruction helps strengthen the reading of words not directly taught and increases comprehension and fluency. When teaching phonological awareness skills to a child with DS, visual support such as pictures should be provided and initially a smaller number of sounds (phonemes) should be used.
Prognosis
The quality of lives for individuals with DS continues to improve due to advancements in research, medical management, community support, and educational resources. Thus, it is important to look toward their future and offer anticipatory guidance throughout childhood and adolescence, as well as, during transitioning to adulthood.
By having appropriate interventional therapies, educational assistance, parental and societal support, and other therapies to address specific communicative or behavioral concerns, individuals with DS are capable of leading productive lives within the context of the society in which they live.
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