Down syndrome

What is Down syndrome?

Down syndrome is one of the most common genetic conditions, and approximately 1 in every 700 babies born in the US is born with this syndrome. Researchers are still not able to identify the exact reasons the extra chromosome 21 develops, and there are possibly several factors at play. Maternal age is believed to be a significant risk factor, although more down syndrome babies are born to younger mothers, that is simply because the birth rate amongst younger mothers is higher.

Health conditions associated with Down syndrome include hypotonia, heart and thyroid disease, physical growth delays, mild to moderate intellectual delays and disorders, and very characteristic facial features.
Hypotonia (low muscle tone), flat facies, up slanted palpebral fissures, developmental delay, and single palm crease are some of the most frequent Down syndrome characteristics.

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What gene changes cause Down syndrome?

Down syndrome is a genetic disorder. It is caused by the addition of a full or partial copy of chromosome 21. The syndrome is also often referred to as Trisomy 21. 95% of individuals diagnosed with Down syndrome present with Trisomy 21 which is the most common form of the genetic condition. 3% of individuals diagnosed will have the type translocation, and the remaining 2% will present with mosaic Down syndrome. There is no hereditary element to Trisomy 21 and mosaicism. ⅓ of cases of Down syndrome resulting from translocation have a hereditary component, accounting for around 1% of all the syndrome cases.

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What are the main symptoms of Down syndrome?

The main symptoms of Down syndrome include characteristic facial features such as a flattened face, especially across the bridge of the nose, almond-shaped eyes, a short neck, small ears, and poor muscle tone.

Congenital heart defects are a major symptom of Down syndrome, and other health conditions can include hearing loss, obstructive sleep apnea, ear infections, and eye diseases.

Individuals with the syndrome may be diagnosed with an intellectual or cognitive disability and developmental delays.

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How does someone get tested for Down syndrome?

Screening and testing for Down syndrome can start prenatally. Prenatal screens estimate the chances of the fetus having Down syndrome while diagnostic testing is able to provide a definitive diagnosis with a very high rate of accuracy.

Postnatally the initial diagnosis of Down syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

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Medical information on Down syndrome

Cognitive impairment, muscle hypotonia at birth, and dysmorphic features occur to some extent in all individuals with Down syndrome (DS). In addition, various anomalies of the respiratory, cardiovascular, gastrointestinal, hematological, immune, endocrine, musculoskeletal, renal and genitourinary systems, and sensory organs, are often associated with DS, as well as psychiatric disorders (Arumugam, 2016). The syndrome is characterized by extensive phenotypic variability; most of the mentioned anomalies occur in only a fraction of affected individuals.

In 1866, John Langdon Down first described a set of characteristics of the disorder that is now referred to as DS. In 1959, Jerome Lejeune discovered that an extra copy of chromosome 21 caused the condition.

While intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance (Lot, 2012; Couzens et al., 2011; Tsao and Kindelberger, 2009). Weakness in language abilities has been noted in all children with DS (Dykens et al., 2006; Fidler et al., 2005; Rondal et al., 2003). But even here, there is performance improvement with age as noted in lexical store, comprehension of interpersonal relations, and visual motor processing. Socialization and competence in daily living skills appear to improve through age 30 years in DS (Dressler et al., 2010). Children with DS appear to present memory profiles that are distinct from Williams and fragile-X syndromes in that DS is characterized by good immediate visual memory and rapid phonological retrieval with poor verbal working memory skills (Conners et al., 2011; Edgin et al., 2010b).

A modern understanding of neurocognitive function in DS was established by Nadel (1986), who suggested that intellectual disabilities gradually arose in early childhood from developmental arrest of late-maturing brain structures, including the prefrontal cortex, hippocampus, and cerebellum. Incomplete development of the prefrontal cortex, hippocampus, and cerebellum has a variety of effects on DS cognition (reviewed by Fernandex et al., 2015). The impairment of the prefrontal cortex in DS precludes real-world abilities to creatively troubleshoot and overcome problems.

Consistent with the underdevelopment of the hippocampus, individuals with DS are impaired in verbal and nonverbal assessments of intermediate or long-term memory. Also in accordance with hippocampal abnormalities, teenagers and adults with DS have trouble navigating in real environments when forced to use geometric and layout information (Edgin et al., 2012).

Overt structural pathology in the cerebellum of DS patients causes difficulties with gross motor coordination; however, these difficulties are nuanced (Baxter et al., 2000; Aylward et al., 1997). Older children and adults with DS display atypical patterns of movement and problems with handwriting and other tasks that require use of fine digits (Galli et al., 2010; Latash et al., 2002).

Researchers have charted IQ declines in children with DS that begin around the time toddlers learn to walk (Fernandex et al., 2015). Cognition deteriorates to varying degrees in typically developing DS individuals as they enter advanced age, despite moderate compensation through the posterior-anterior shift (Davis et al., 2008).

Infants and toddlers born with trisomy 21 start life with deficits in mastery motivation, an intrinsic quality that compels very young children to explore and gain control over the surrounding environment (Niccols et al., 2003). Deficits in mastery motivation cripple the emergence of instrumental learning in those with DS (Fidler, 2006; Fidler et al. 2005). Infants with DS take longer than chronological age-matched controls to move from shorter chains of continuous goal-directed behaviors to longer chains and are less happy when performing more complex chain-linking (Ruskin et al., 1994; Dunst 1988). Gradually, motivational issues exacerbate the cognitive disabilities that arise from poor brain development (Cicchetti and Sroufe 1976).

Individuals with DS participate in special education or mainstream schooling. Despite efforts to the contrary, they are exposed to significant cognitive difficulties in these settings that will end in only some limited success and skills achievement. Less-than-favorable learning histories and dependence on caregivers might create the impression of diminishing returns on further educational activities. The result is seclusion from peers and negative self-perceptions that prime feelings of inadequacy and depression (Ali et al., 2012; Capone et al., 2006; Fidler et al., 2005, 2006; Dykens et al., 2002).

Children with DS are predominantly brachycephalic (62.3%), but they can also be hyperbrachycephalic (27.3%), dolichocephalic (7.8%), or mesocephalic (2.6%). In a retrospective analysis of 524 individuals with DS, more than 50% had craniofacial defects such as a downward slant of the eye lids medially (83.9%), ear anomalies (66.9%), palpebronasal (epicanthal) folds (56.9%), and a flat face (50.9%) (Kava et al., 2004). In addition, hypertelorism (increased interocular distance) and a flat nasal bridge appear to be predominant in this population (Rahul et al., 2015).

The oral dysmorphic features common among people with DS are a fissured tongue and a high arched palate (Rahul et al., 2015; Shukla et al., 2014). In addition to these two traits (each with a prevalence of 79%), a recent epidemiological survey of children with DS (n=570) in India noted other oral manifestations such as macroglossia (83%), marginal gingivitis (93%), microdontia (63%), hypodontia (41%), an anterior open bite (23%) and periodontitis (11.5%) (Rahul et al., 2015). In addition, other aberrant oral conditions such as malocclusion (between 3% and 55%), congenital absence of teeth (34%), delayed teeth eruption (10%), angular cheilitis (22%), and ankyloglossia (13%) have also been reported in children with DS (Shukla et al., 2014).

Abnormalities of the musculoskeletal system have frequently been reported in the literature and mostly relate to ligament laxity, a distinctive feature of DS. In the cervical spine region, ligament laxity can give rise to occipitocervical instability and atlantoaxial instability (AAI). About 10-35% of patients with DS are affected by AAI (Cremers et al., 1993; Roy et al., 1990; Alvarez and Rubin, 1986) but only 1-2% present with cervical myelopathy (Hankinson and Anderson, 2010; Pueschel et al., 1987; Pueschel et al., 1984). In addition, os odontoideum (separation of a portion of the dens from the body of the axis [C2]) (Semine et al., 1978), hypoplasia of the atlas (Matsunaga et al., 2007; Taggard et al., 2000), bifid atlantal arches (Menezes, 2008) or ossiculum terminale (congenital non-union of the dens from a terminal ossicle located above the transverse ligament) (Ali et al., 2006) can coexist in DS.

Other musculoskeletal abnormalities include dislocation/subluxation of the patella, deformities such as genu valgum, pes planus, metatarsus primus varus, and scoliosis (Yam et al., 2008; Diamond et al., 1981), all of which have been attributed to ligament laxity (Galli et al., 2014). In addition, brachycephaly, brachydactyly, wide hands, fifth finger clinodactyly, increased web space between the great and second toes, and short stature have been documented as possible morphological changes (Roizen and Patterson, 2003).

The most common reasons for hospitalization of children with DS are respiratory disorders (predominantly because of infection) and congenital heart malformations (Englund et al., 2013; Fitzgerald et al., 2013). Common respiratory problems include upper respiratory tract anomalies, recurrent aspiration, obstructive sleep apnea and recurrent respiratory tract infections (Pandit and Fitzgerald, 2012).

Obstructive sleep apnea is the most common respiratory disorder, occurring in 30-50% of individuals with DS (Lal et al., 2015). It can be associated with a narrowed airway, enlarged tonsils and adenoids, macroglossia, mid-face hypoplasia, delayed development of oromotor function, and micrognathia (Goffinski et al., 2015; Austeng et al., 2014). Children with DS can present with obstructive airway disease caused by macroglossia, a constricted nasopharynx, congenital subglottic stenosis, laryngomalacia ('malacia' denotes any abnormal softening of the tissues), tracheobronchomalacia, and tracheal stenosis (Pravit, 2014; Jacobs et al., 1996).

The congenital cardiac disorders most commonly associated with DS are atrioventricular defects (45%) and ventricular septal defects (VSD) (35%), while abnormalities such as isolated secundum atrial septal defects (8%), isolated tetralogy of Fallot (4%) and isolated patent ductus arteriosus are less frequent (Freeman et al., 1998). The major complication of cardiac anomalies in DS is pulmonary artery hypertension, which can progress to cardiogenic shock and eventually death (de Rubens Figueroa et al., 2003).

Incidence of cardiovascular abnormalities in a DS population was estimated as 42% in a study in the United Kingdom (Irving and Chaudhari, 2012), while the prevalence of congenital cardiac diseases ranged between 40% and 76% depending on the cohort studied (Paladini et al., 2000). The chromosome 21 aneuploidy can result in endocardial cushion defects (complete or incomplete) (Ferencz et al., 1989).

Ear problems such as inner ear dysplasia/hypoplasia, vestibular malformations, lateral semicircular anomalies, and conductive, mixed or neurosensory hearing loss are common in patients with DS (Blaser et al., 2006). Moreover, a high prevalence of chronic otitis media with effusion (60%) has also been reported (Maris et al., 2014).

Vision problems evident in DS include severe refractive errors (50%) and cataracts (15%) (Bull, 2011). In addition, strabismus (47%), nasolacrimal duct obstruction (36%), and nystagmus (16%) have been reported (Stephen et al., 2007). Other ophthalmic conditions such as retinal hemorrhage and macular hypoplasia are rare among affected children (Stephen et al., 2007).

Gastrointestinal defects such as duodenal stenosis/atresia (3.9%), anal stenosis/atresia (1.0%), Hirschsprung disease (0.8%), esophageal atresia with or without tracheoesophageal fistula (0.4%), and pyloric stenosis (0.3%) (Freeman et al., 2009) have been reported (overall frequency 7%). The prevalence of celiac disease in DS is about 5% in Italian patients, manifesting in classical form with diarrhea and vomiting (65%), a silent form (20%), or with atypical symptoms such as short stature/anemia (11%) (Bonamico et al., 2001).

Abnormalities of the immune system have been associated with DS (Kusters et al., 2009). Moreover, increased incidences of leukemia, hypothyroidism, malnutrition (zinc deficiency), celiac disease and diabetes mellitus in children with DS aggravate their immune deficiency (Ram and Chinen, 2011). Leukemia is estimated to be 15 to 20 times more frequent in children with DS (Whitlock, 2006). DS is an independent risk factor for the development of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) (Lange, 2000). ALL in DS is characterized by unique clinical features that include heightened sensitivity to methotrexate and an increased propensity to infections (Whitlock, 2006).

Thyroid dysfunction is the most common endocrine abnormality in patients with DS (Iughetti et al., 2014; Hawli et al., 2009). Estimates of its prevalence vary widely, ranging between 3% and 54% in adults (Hawli et al., 2009). In one study, the frequency of hypothyroidism in neonates with DS was estimated to be 28 times higher than expected in the general population (Purdy et al., 2014).

Renal and urinary tract malformations were found in 3.2% of DS patients in the retrospective cohort study by Kupferman et al. (2009). They reported a high risk of cystic dysplastic kidney, renal agenesis, hydronephrosis, anterior urethral obstruction, and anterior urethral obstruction in this population. Other urogenital anomalies such as cryptorchidism (undescended or maldescended testes), bladder exstrophy, posterior urethral valves, hypospadias (urethral opening on the inferior aspect of the penis), testicular microlithiasis, testicular malignancy, and infertility have also been noted in DS (Ebert et al., 2008; Vachon et al., 2006; Mercer et al., 2004). A review of the literature by Mercer et al. (2004) reported renal hypoplasia, glomerular microcysts, and obstructive uropathy as the most common urological abnormalities in DS.

The prevalence of psychiatric disorders in DS ranges between 22.1% and 38% (Dykens et al., 2015). Some risk factors associated with psychiatric disorders in DS are age, gender, serotonin dysfunction, sleep problems, life stressors, hypothyroidism, cardiac surgery, obesity, mosaicism, family genetics, personality, and strength (Dykens, 2007). Recently, high rates of psychosis and depression have been reported among young adults and adolescents with DS (Dykens et al., 2015; Zigman, 2013; Collacott et al., 1992). Other psychopathologies noted in adults with DS include phobias, obsessive-compulsive disorders, anorexia nervosa and other eating disorders, Tourette syndrome, and paraphilias (aberrant sexual desires) (Dykens et al., 2015).

Weisfeld-Adams and colleagues (2016) described a patient with a de novo 2.78-Mb duplication on chromosome 21q22.11 including 16 genes. The patient was born to a 36-year-old mother diagnosed with high risk for Down syndrome on prenatal biochemical screening. At five years of age, some facial features were compatible to features typical to Down syndrome, including a round, flat face with upslanting palpebral fissures, prominent epicanthal folds, flat nasal bridge, and mild macroglossia. Hands were small with bilateral fifth finger clinodactyly and bilateral single transverse palmar creases; the feet showed a wide gap between the first and second toes. The girl had mild developmental delay.

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FDNA Telehealth is a leading digital health and AI (Artificial intelligence) company operating in the rare disease and genetic condition field. FDNA has developed a portfolio of AI-based technologies for screening, diagnostics and support for rare genetic analysis. As a precision medicine solution, FDNA Telehealth assists patients and their families stranded or paused within their diagnostic odyssey.

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Over 400 million people are living with a rare disease globally, but most of them are misdiagnosed or paused within their diagnostic odyssey. Get a faster and more accurate analysis with FDNA Telehealth.