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First recorded case of down syndrome: Earliest Case of Down Syndrome Discovered in Medieval Cemetery

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Andrew Curry

At a site called Poulnabrone, on the west coast of Ireland, archaeologists found the skeleton of a baby with Down syndrome who died nearly 4,000 years ago — the oldest confirmed case of Down syndrome.

Hoberman Collection/Universal Images Group via Getty

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At a site called Poulnabrone, on the west coast of Ireland, archaeologists found the skeleton of a baby with Down syndrome who died nearly 4,000 years ago — the oldest confirmed case of Down syndrome.

Hoberman Collection/Universal Images Group via Getty

Geneticists have discovered that a baby buried almost 5,500 years ago had the extra chromosome that causes Down syndrome by analyzing DNA preserved in his skeleton. Researchers say the finding, published Wednesday in the journal Nature, is the oldest confirmed case of Down syndrome.

Babies born with Down syndrome typically have distinctively-shaped eyes and skulls, which the authors of the Nature paper suggest might have set him apart as an infant. Chemical analysis of his bones shows he was breastfed, and when he died at about six months old he was buried in a monumental tomb, along with other children and adults, at a site called Poulnabrone on the west coast of Ireland. “The visible difference of that infant didn’t preclude him being buried in a prestigious setting,” says Trinity College Dublin geneticist Daniel Bradley, who led the new study.

To Lorna Tilley, an Australian archaeologist who specializes in the way past societies cared for people who were sick or disabled, the the fact that the baby was buried in a monumental tomb with other children and adults should come as no surprise. “I’m not sure, unless it was a really dramatic case, it would have been thought of as strange,” she says. “Most babies, in most circumstances, are looked after.”

In fact, the evidence suggests that people in the past devoted significant time and scarce resources to caring for those in need. Scouring the archaeological literature, Tilley and others have turned up evidence that caring for the weak and sick is behavior that goes back as far as Neanderthals. “I take these cases for granted now,” Tilley says. “From the very earliest times, we can see evidence that people who were unable to function were helped, looked after and given what care was available.”

A skeleton found in Vietnam, dubbed Burial 9, was discovered in 2007. A closer look at his bones led to a diagnosis of rare genetic syndrome that often leads to paralysis. “From the bones alone, we can say this person lived with a disease that required help from others to survive,” says archaeologist Lorna Tilley, who helped uncover the 4,000-year-old remains.

Lorna Tilley

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Lorna Tilley

A skeleton found in Vietnam, dubbed Burial 9, was discovered in 2007. A closer look at his bones led to a diagnosis of rare genetic syndrome that often leads to paralysis. “From the bones alone, we can say this person lived with a disease that required help from others to survive,” says archaeologist Lorna Tilley, who helped uncover the 4,000-year-old remains.

Lorna Tilley

In 2007, for example, Tilley was working a site in Vietnam called Man Bac when she helped uncover the twisted, hunched skeleton of a man. Dubbed Burial 9, he was part of a small group of a few dozen Stone Age hunter-gatherers who lived about 4,000 years ago.

A closer look at his bones led to a diagnosis of Klippel-Feil syndrome, a rare, painful genetic disease that results in fused spinal bones and often leads to paralysis. Tilley estimated that his disease became crippling in his teens – and he died from its complications in his mid-20s. “He was at least a partial quadriplegic for the last ten years of his life,” Tilley says.

Tilley, who worked as a nurse and health care policy researcher before becoming an archaeologist, had an idea of what it must have taken to keep Burial 9 alive. Paralyzed from the waist down and with severely limited arm and neck movement, he depended on others to provide food and water, clean him and move him to prevent pressure sores. “From the bones alone, we can say this person lived with a disease that required help from others to survive,” she says.

Archaeologists at work on the site in Vietnam where the skeleton now known as Burial 9 was found.

Lorna Tilley

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Lorna Tilley

Archaeologists at work on the site in Vietnam where the skeleton now known as Burial 9 was found.

Lorna Tilley

The glimpse into one man’s struggle in the distant past led her to develop a concept she calls the “bioarchaeology of care. ” It’s a way for archaeologists to think about evidence for disease or disability in the past to better understand what kinds of care people needed – and what that says about the society that provided it.

It’s changing the way archaeologists and other scholars think about evidence for rare diseases and disabilities in the past. Rather than presenting unusual diagnoses and examples of rare diseases as curiosities, footnotes or isolated case studies, researchers are increasingly using them to better understand the societies that provided them with care.

The people who took care of Burial 9, for example, scratched out a precarious existence using stone tools to fish and raise pigs in prehistoric Vietnam. Signs of malnutrition in the bones of people buried nearby suggested famine was a constant threat. “In a small society which was very stressed, that means somebody who couldn’t contribute or go out hunting or undertake a lot of tasks was supported, accommodated, and adjusted to,” Tilley says. “That tells us people mattered. They were valued.”

Over the past few years, the approach has been applied to Peruvian mummies, medieval European skeletons and Oetzi, a Stone Age hunter recovered from an icy grave in the Italian Alps. Tilley says there’s ample evidence wounded or disabled Neanderthals were taken care of by members of their social groups, including a Neanderthal man who died more than 45,000 years ago. Known as Shanidar I, the man was missing his lower arm and hand, had a bad limp, and was partially blind and deaf – and lived well into his 40s, undoubtedly with daily help from others.

And in April, researchers in Brazil applied the bioarchaeology of care model to the skeleton of a baby born 6,000 years ago in what is now Brazil. The infant suffered from a severe disease that ravaged its bones. “It’s absolutely obvious this child had something systemically wrong with them,” Tilley says, yet the infant was evidently nurtured for months and buried surrounded by bone collars, bone earrings and dog’s-tooth beads – rich grave goods unlike any others uncovered in burials in the cemetery.

Tilley says the archaeological record – from the Poulnabrone tomb to the jungles of Brazil – shows that global response to the coronavirus crisis is the rule, not an exception, in humanity’s long story. “The most important thing we can learn from the past is the consistency of care,” she says. “The last few months have reinforced that the behavior of care is something that has a continuing timeline from the Neanderthal times right through.”

Andrew Curry (@spoke32) is a journalist based in Berlin, Germany.

Earliest Case of Down Syndrome Discovered in Medieval Cemetery

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The skeleton of a 5- to 7-year-old child (shown here) who lived in medieval France shows signs of having Down syndrome, the earliest such case in the archaeological record.
(Image credit: Rivollat et al./Elsevier.)

The earliest probable case of Down syndrome in the archaeological record comes from a 5- to 7-year-old child who lived in medieval France some 1,500 years ago, new research shows.

The child, who is also the youngest example of the condition in the archaeological record, likely was not stigmatized in life, given that the body was treated in a similar way to others buried at the site, researchers say.

Archaeologists originally discovered the skeleton of the child in 1989, when they excavated it along with 93 other skeletons from a fifth- to sixth-century necropolis located just south of the Abbey of Saint-Jean-des-Vignes in northeastern France. Researchers had suspected the child may have had Down syndrome, but they hadn’t performed a rigorous analysis to confirm the diagnosis. [See Photos of the Remains of an Ancient Plague Epidemic]

So Maïté Rivollat, an archaeologist at the University of Bordeaux, and her colleagues studied the skull of the child, and took a computed tomography (CT) scan of it to understand its internal features.

“Two earlier publications just mentioned the possibility of Down syndrome without [conducting] a detailed study,” Rivollat told Live Science in an email. “The [CT] scan was a new possibility to approach the intracranial aspect of that skull.”

An ancient disorder

Down syndrome is a genetic disorder in which a person has an extra copy of chromosome 21. People born with Down syndrome typically have intellectual disabilities, physical growth delays and certain facial features, including a flat nasal bridge and almond-shaped eyes that slant upward.

British physician John Langdon Down first described Down syndrome as a unique disorder in 1866. Despite this relatively recent identification of the condition, paintings and sculptures have depicted Down syndrome for centuries.

For instance, the earliest depiction of Down syndrome may come from Olmec figurines from Mesoamerica that date as far back as 1500 B.C., according to a 2011 study on the history of Down syndrome published in the Journal of Contemporary Anthropology.

In the archaeological record, the oldest probable case of Down syndrome came from a 9-year-old child who lived in England sometime between A. D. 700 and 900. (A skeleton from a Native American cemetery in California, dating to 5200 B.C., may, in fact, be the earliest archaeological case of Down syndrome, but the evidence is less conclusive, the 2011 study notes.)

A normal life?

The skull of a 5- to 7-year-old child (shown here) who lived in medieval France shows signs of Down syndrome; for instance, the skull was short and broad, and flattened at the base. (Image credit: Rivollat et al./Elsevier.)

To see if the Saint-Jean-des-Vignes child really had Down syndrome, Rivollat and her team studied the dimensions and structure of the child’s skull and compared it with the skulls of 78 other children of similar ages. Their analysis showed the French child had numerous features indicative of Down syndrome, which the other skulls lacked.

For example, the skull was short and broad, and flattened at the base. In addition, it contained thin cranial bones and certain extra bone pieces. The child also had some sinus and dental abnormalities, which aren’t diagnostic of Down syndrome on their own, but are indicative of the disorder when considered along with the other characteristics, the researchers point out in their study, published online last month in the International Journal of Paleopathology.

The archaeologists also studied the way in which the child was buried to obtain clues about how he or she was treated in life, something scientists weren’t able to do with other ancient cases of Down syndrome. Just like other skeletons in the cemetery, the child was placed face-up in its tomb, with its head pointing west and feet pointing east, and its hands situated under its pelvis. That is, the child’s burial treatment was no different from that of other people in the cemetery, Rivollat said.

“We interpret this as meaning that the child was maybe not stigmatized during life, the first time a Down syndrome individual has been so viewed in the context of the ancient community,” the researchers write in their study.

 Follow Joseph Castro on Twitter. Follow us @livescience, Facebook & Google+. Original article published on Live Science.

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Joseph Bennington-Castro is a Hawaii-based contributing writer for Live Science and Space.com. He holds a master’s degree in science journalism from New York University, and a bachelor’s degree in physics from the University of Hawaii. His work covers all areas of science, from the quirky mating behaviors of different animals, to the drug and alcohol habits of ancient cultures, to new advances in solar cell technology. On a more personal note, Joseph has had a near-obsession with video games for as long as he can remember, and is probably playing a game at this very moment.

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Down’s syndrome and cardiovascular pathology: clinical observation and literature review | Reznik E.

V., Nguyen T.L., Ilyina T.S., Tokmakova E.S., Jobava E.M., Golukhov G.N.


Down syndrome is one of the most common chromosomal anomalies resulting from the mutation of the 21st pair of chromosomes with the formation of its additional copy in the human genome. This syndrome was first described by D. Down in 1866. The 21st chromosome is the smallest human chromosome, which contains 200-300 genes (127 known genes, 98 predicted and 59 pseudogenes) [1]. Patients with Down syndrome have more copies of genes on chromosome 21. The genes themselves are normal, the anomaly lies in the fact that an increased amount of gene products is produced on a given chromosome as a result of overexpression in cells and tissues, which leads to the formation of phenotypic anomalies [2].

The frequency of occurrence is 1 case per 800 newborns [3]. The prevalence of the syndrome does not depend on race, nationality and socioeconomic status. In Russia, the overall incidence of Down syndrome increased from 15. 53 per 10,000 in 2011 to 19.93 per 10,000 in 2017. At the same time, the incidence of Down syndrome only among newborns over this period of time decreased from 9.91 to 7.54 per 10,000 births [4].

Recently, due to improved care and early treatment of complications, the overall life expectancy of patients with Down syndrome has increased significantly, they are beginning to come to the attention of therapists, cardiologists. This article presents a clinical observation of a 59-year-old patient with Down syndrome, who developed acquired heart disease, severe conduction disorders, which led to death.

Clinical observation

A 59-year-old patient was admitted to the cardio intensive care unit of a multidisciplinary hospital with a critical depletion of the power source of the pacemaker (pacer). Complaints at admission did not show the severity of the condition.

According to the medical records, the patient has had hypertension, coronary heart disease, exertional angina complicated by chronic heart failure for more than 10 years. In 2013, pacemaker implantation was performed for atrioventricular blockade of the 3rd degree. Also history of chronic pyelonephritis, C4 chronic kidney disease, Child-Pugh class B cirrhosis (9points), metal osteosynthesis for a closed fracture of the left femur.

At the prehospital stage, depletion of the power source was revealed, in connection with which the patient was hospitalized by an ambulance team in the intensive care unit.

Upon admission, the general condition was severe. Coma I. The skin is pale. Swelling of legs and feet. The number of breaths is 5 in 1 min, the rhythm is wrong. Percussion sound clear pulmonary. Auscultatory breathing is weakened over the lower parts of the lungs, there are no wheezing. Tracheal intubation with an 8 mm tube was performed, artificial ventilation of the lungs was started using the Drager apparatus in the Bipap mode. Heart sounds are muffled, a systolic murmur is heard over the projection point of the aortic valve, which is carried out to the vessels of the neck. The rhythm is wrong. Heart rate (HR) 12–20 in 1 min with pauses up to 15 s (Morgagni-Adams-Stokes attacks). There is no pulse deficit. Arterial pressure is not determined. The tongue is clean and enlarged. The abdomen is of normal shape, soft, painless. There are no symptoms of peritoneal irritation. The liver is painless on palpation, enlarged by 3 cm, a symptom of “jellyfish head”. The spleen is not enlarged percussion, not palpable, painless. Urination is free.

The electrocardiogram (see figure) revealed a complete atrioventricular block with pauses on the monitor for up to 15 seconds. Setting up a temporary pacemaker was unsuccessful. According to emergency indications, a permanent pacemaker was replaced.

A general blood test revealed moderate normochromic normocytic anemia: hemoglobin concentration 84 g/l (normal 112–153 g/l), erythrocyte count 2.94×10 12 /l (normal 3.8–5.15×10 12 /l), hematocrit 30% (norm 34.9–45. 6%), average volume of erythrocytes 86 fl (norm 82–98 fl), average hemoglobin content in erythrocyte 28.0 pg (norm 26.7–33 pg ), the average concentration of hemoglobin in an erythrocyte is 325 g/l (norm 314–349 g/l), color index 0.86 (norm 0.82–1.1), leukocytes 12 × 10 9 / l (norm 4, 5–11×10 9 /l), neutrophils 10.84×10 9 /l (norm 1.8–6.98×10 9 /l). The data of the biochemical blood test and coagulogram upon admission and in dynamics are presented in Table 1.

Computed tomography of the brain showed no evidence of acute cerebrovascular accident. Chest radiography revealed congestion, bilateral hydrothorax.

According to echocardiography (EchoCG), the aortic root is compacted, calcified, the aortic pulsation is rhythmic, the diameter of the aorta at the level of the sinuses of Valsalva is 26 mm. Calcification of the aortic valve with mild aortic stenosis (gradient 33/17 mm Hg, blood flow through the aortic valve 2. 91 m/s) [5] and mild insufficiency (small central regurgitation flow, low density, regurgitation jet width 2 mm) [6], the number of valves is not reliably determined. Mitral valve prolapse: systolic prolapse of the anterior leaflet up to 2 mm, opening is not impaired. Hypertrophy of the myocardium of the left ventricle (144 g/m 2 ): thickness of the interventricular septum (IVS) in diastole 11 mm, thickness of the posterior wall of the left ventricle (LV) in diastole 11 mm. Expansion of the cavity of the left atrium: the maximum anteroposterior size of the left atrium is 43 mm, the volume is 74 ml. The left ventricle is not dilated: the LV end-diastolic size is 38 mm, the LV end-diastolic volume is 60 ml. LV ejection fraction 50%. Local contractility is not broken. IVS dyssynchrony. The right ventricle is not dilated: end-diastolic size 34 mm, right atrial area 16 cm 2 . The divergence of the sheets of the pericardium up to 6 mm behind the posterior and lateral walls of the left ventricle. In the right departments, the EX-electrode. Estimated systolic pressure in the pulmonary artery 30 mm Hg. Art.

Despite the therapy (including inotropic and respiratory support, change of pacemaker for emergency indications), on the 8th day of hospitalization, ineffective pacing, asystole were registered, resuscitation was carried out without effect, and biological death was stated.

The pathoanatomical diagnosis coincided with the clinical one:

“Main disease: valvular aortic stenosis: aortic valve perimeter 6.5 cm, orifice diameter 0.8 cm, calcification of the aortic valve cusps, myocardial hypertrophy (heart weighing 381 g, left ventricular wall thickness 1.7 cm).

Background disease: Down’s syndrome: hydronephrosis of the kidneys on both sides, hypoplasia of the left kidney.

Complications: violation of the conduction of the heart: atrioventricular blockade of the 2nd or 3rd degree. Implantation of a two-chamber pacemaker “EX-460-DR” from 2013. Critical depletion of the power source of the pacemaker. Change of EX-460-DR to EX-460-DR from 10/15/2020. Pulmonary edema. Bilateral hydrothorax (left 300 ml, right 800 ml). Ascites 200 ml. Acute venous congestion. Necrosis of the epithelium of the convoluted tubules of the kidneys. Cerebral edema.

Resuscitation and intensive care: puncture and catheterization of the right jugular vein from 10/15/2020. Orotracheal intubation from 10/15/2020. Artificial lung ventilation from 10/15/2020 to 10/23/2020.

Concomitant diseases: aortic atherosclerosis (grade 1, stage II). Chronic pyelonephritis. Chronic simple bronchitis. Diffuse pneumosclerosis. Adhesions of the pleural cavities on both sides. Child-Pugh class B cirrhosis of the liver (9 points). Moderate normochromic normocytic anemia.

Down syndrome

Down syndrome is caused by a mutation of the 21st pair of chromosomes with the formation of its additional copy in the human genome. Factors that increase the risk of having a child with trisomy 21 include the age of the mother. Thus, a woman has a risk of 1:1925 at the age of 20, 1:885 at 30, 1:365 at 35, 1:110 at 40, and 1:50 at 45. Heredity and disruption of gamete formation also play a role [7].

There are 3 forms of Down syndrome: simple trisomy on the 21st chromosome, translocation trisomy and mosaic variant. In the case of simple trisomy, the cell genome is represented by 47 chromosomes and includes 3 chromosomes in the 21st pair. Most often, this type occurs during the formation of reproductive cells (in 95% of cases – oocytes, less often – spermatozoa) and is associated with a violation of chromosome separation during the first or second meiotic cell division, which leads to the appearance of an additional copy of the 21st chromosome. Karyotypes of children: females — 47, XX, +21, males — 47, XY, +21. Occurs in 90-95% of cases. The translocation variant involves the transfer of a fragment of a chromosome to another (more often between the 14th and 21st, 21st and 22nd, 22nd and 21st chromosomes) and accounts for 5–6% of all cases of Down syndrome. Karyotypes for girls – 46, XX, der (21, 21) +21 or 46, XX, der (14, 21) +21, for boys – 46, XY, der (21, 21) +21 or 46, XY, der (14, 21) +21. The mosaic form affects only some cells of the body, therefore it is the most difficult to diagnose. The frequency of occurrence is 2–3% of all cases of Down syndrome [8]. There are several types of mosaic trisomy: cellular, tissue and chimerism. In the first case, it is represented by an alternation of normal and trisomic cells, in the second case, by tissues affected by trisomy, the latter variant is formed by the fusion of two fertilized eggs, one or both of which are affected by mosaicism, with the formation of one embryo [4, 5].

In Down syndrome, birth weight is usually reduced, height, weight, and head circumference are below normal due to hypotension, a small oral cavity, and concomitant diseases of the gastrointestinal tract and cardiovascular system. Patients tend to gain weight with age due to hypothyroidism, high leptin levels, and low basal metabolic rate. There is also a variable degree of mental retardation in patients. Intelligence Quotient ranges from moderate (50–70) to low (35–50). Such children are worse adapted to life and slowly adapt. The typical behavior model of such patients implies an affectionate, caring and rather sociable person, but autistic character traits are becoming more common among them, observed already at the age of 2–3 years [6, 7].

The “gold standard” for diagnosing the disease is chromosomal analysis, which allows you to detect an additional copy of the chromosome. Molecular genetic methods such as quantitative fluorescent polymerase chain reaction and in situ interfacial hybridization provide rapid diagnosis and can be used in preterm infants [9].

Antenatal screening for Down syndrome allows you to determine the likelihood of having a child with this pathology, it is recommended for women of all age groups in the I and II trimesters of pregnancy. Screening in the first trimester is carried out using statistical programs (Astraia, etc. ) and includes an assessment of three components: parental age risk, biochemical risk (serum human gonadotropin + PAPP protein + PIGF) and ultrasound risk (according to the thickness of the collar space), then the total risk is calculated. The detection rate of the syndrome during screening is 80–82%, with a false positive rate of 3% [10]. Currently, only ultrasound screening is performed in the second trimester – at 19-21 weeks more than 10 markers of Down syndrome are evaluated during pregnancy. Second trimester screening, which was previously performed in the form of a triple or quadrotest (included the determination of the level of serum human gonadotropin, unconjugated estriol, alpha-fetoprotein and inhibin A or 17-hydroxyprogesterone at a period of 15–19 weeks), is now canceled due to low economic and clinical efficiency. Down syndrome was detected in 80% of cases [11]. If the threshold level of the total risk according to the results of the first screening is more than 1:250, a chorionic villus biopsy is used at 11–12 weeks or a safer and no less reliable amniocentesis at 16–18 weeks of pregnancy [10] for accurate verification of the diagnosis.

Children with Down syndrome often have malformations of the cardiovascular, respiratory, nervous, immune, endocrine, genitourinary, and musculoskeletal systems. Of greatest interest are congenital heart defects (CHD) and blood vessels due to the fact that they are the main cause of death for people with Down syndrome. According to statistics, among such patients, 13% of children and 24% of adults die from cardiac causes [12]. In addition to CHD, respiratory infections and leukemia reduce the survival of patients. Recently, due to improved care and early treatment of complications, the overall life expectancy of patients with Down syndrome has increased significantly [12].

Congenital heart defects in Down syndrome

40–50% of newborns with Down syndrome have CHD [9, 10, 13–15]. They are the main cause of death in patients in the first 2 years of life [16]. The most common CHDs are a complete or incomplete atrioventricular canal (or the so-called atrioventricular septal defect (AVSD)), ventricular septal defect (VSD), atrial septal defect (ASD), patent ductus arteriosus (Botall’s) and tetralogy of Fallot [10, 15] . AVSD and VSD are typical malformations in Down syndrome [17]. The most common malformation in newborns is AVSD, accounting for 40% of all CHD cases. VSD is the second most common — 35% of all CHD cases [9, 13].

The mutation that contributes to the development of AVSD in Down syndrome is located on the 21st chromosome [18]. To date, two specific genetic loci for AVSD have been identified. One of them is the AVSD1 locus present on chromosome 1p31-p21 [19]. Another locus is present on chromosome 3p25 and the corresponding cysteine-rich gene, EGF-like domain 1 (CRELD1) [20, 21]. AVSD is a CHD in which the VSD and ASD merge and there is a pathology of the atrioventricular valves [22]. Allocate complete or incomplete AVSD [23]. Incomplete AVSD is characterized by the presence of separate atrioventricular valves, an ostium primum ASD, an inlet VSD, and a cleft mitral valve. It is caused by incomplete fusion of the endocardial cushions [24].

Complete AVSD is characterized by a common atrioventricular valve, an ostium primum ASD, and an inlet type VSD. It is caused by complete non-fusion of endocardial cushions [25]. In complete AVSD, the common atrioventricular valve has 5 large cusps: 3 lateral (adjacent to the free walls) and 2 bridging (septal) [26]. With AVSD, there is a disproportion between the output and input sizes of the left ventricle, the first of which is larger than the second compared to the normal heart, where they are the same.

On routine antenatal ultrasound scanning, AVSD is best seen in the four-chamber position of the heart as a common atrioventricular valve [27]. However, the sensitivity of antenatal ultrasound in AVSD is very low [28]. Postpartum diagnosis of AVSD is carried out using electrocardiography, chest x-ray, echocardiography. Echocardiographic findings include abnormal configuration of the atrioventricular valve, loss of normal displacement of the atrioventricular valve, abnormal papillary muscle position, left ventricular inlet/outlet disproportion, ostium primum ASD, inlet VSD, and other concomitant CHD [19, 22].

This is usually a severe, hemodynamically significant malformation, but it is compatible with life, and with mild impairment, patients can live up to 20 years or more [22]. AVSD is subject to surgical correction. Its purpose is to close the VSD, ASD and restore the atrioventricular valves [27]. Patients who undergo surgery have a 15-year survival rate of about 90%. From 9% to 10% of them need reoperation within 15 years [29].

VSD is a congenital heart disorder in which there is a communication (hole) between the left and right ventricles with blood shunting from left to right and the development of pulmonary hypertension [22, 30]. Color Doppler imaging with transthoracic echocardiography is the most highly sensitive diagnostic method. Approximately 85% to 90% of small isolated VSDs spontaneously close within the first year of life. Surgical closure of the VSD is indicated for moderate to large defects with left ventricular dysfunction, in cases of progressive aortic insufficiency, or after an episode of endocarditis [31].

ASD is a CHD in which there is a communication (hole) between the left and right atrium, through which blood is discharged [22, 32]. ASD often does not lead to the appearance of clinical symptoms [33]. Diagnostic imaging is important in determining defect size and is critical in determining management. Transthoracic echocardiography is the “gold standard” for imaging [32]. ASDs smaller than 5 mm often close spontaneously during the first year of life. ASDs larger than 1 cm most often require surgical closure of the defect [34].

In addition, it is necessary to note the possibility of developing cardiovascular complications of CHD in patients with Down syndrome, including pulmonary hypertension, arrhythmia, and conduction disturbance, the presence of which is a predictor of an unfavorable prognosis for the patient [35].

Acquired CVD in patients with Down syndrome

The anatomy of the heart in people with trisomy 21 without overt congenital heart disease is not completely normal. Shortening of the IVS and an increase in its membranous portion have been reported in neonates with Down syndrome without congenital heart disease [36]. In addition, valvular dysplasia was detected in 64% of cases. Also, when assessing the state of the heart in a random group of adults with Down syndrome, a large number of patients with mitral valve prolapse or aortic regurgitation were identified [37-39]. Systolic function in adolescents with Down’s syndrome without congenital heart disease [40] and the results of cardiorespiratory test (treadmill test with assessment of respiratory function) [41] were adequate, suggesting the possibility of normal physical activity, although reduced performance was noted [42] .

In patients with Down’s syndrome, premature aging and a tendency to obesity have been described. Not only do they develop degenerative changes in appearance, such as skin and hair, earlier than mentally retarded people without Down syndrome, but they also develop symptoms of Alzheimer’s disease earlier than the general population. By the age of 45, almost all people with Down syndrome develop senile plaques, neurofibrillary tangles, and granulovacuolar degeneration of nerve cells. People with Down syndrome have a shorter life expectancy than the general population [43]. Also, people with Down syndrome have a higher probability of overweight and obesity than people without this disease, more frequent development of diseases of the thyroid and parathyroid glands, osteoporosis, metabolic syndrome, and type 2 diabetes [44-46]. Obesity is more common among women with Down syndrome than among men. Probable determinants of obesity included elevated leptin levels, decreased resting energy expenditure, comorbidities, poor diet, and low levels of physical activity. Obesity was positively associated with obstructive sleep apnea, dyslipidemia, hyperinsulinemia, and gait disturbance [47, 48].

According to E. Vianello et al. [49], adults with Down syndrome rarely develop atherosclerosis, arterial hypertension, and coronary heart disease (Table 2). A study [50] found that adults with Down syndrome had lower carotid intima-media thickness, systolic and diastolic blood pressure, and higher levels of C-reactive protein, triglycerides, and total body fat than controls. . Adults with Down syndrome may be protected from atherosclerosis despite increased levels of total body fat and increased risk factors for CVD. This trend is explained by overexpression of protective antiatherosclerotic factors due to genes located on the 21st chromosome [51]. Moreover, it has been suggested that higher levels of adiponectin [52] and fatty acid binding proteins [49], may play a role in protecting adults with Down syndrome from atherosclerosis.

It is also reported that the cardiovascular system of patients with Down syndrome is characterized by altered autonomic control of cardiac activity and autonomic dysfunction. Down syndrome patients without congenital heart disease demonstrate a decrease in heart rate and blood pressure in response to isometric grip exercises, tilt testing, and cold press testing [54, 55]. Patients with Down syndrome show less parasympathetic inhibition and sympathetic excitation in response to passive vertical tilt. These effects may be mediated by a lesser change in baroreflex sensitivity in people with Down syndrome [55]. Autonomic dysfunction may also partially explain the insufficient increase in heart rate during the maximum exercise treadmill test in these patients [54].

There are no statistics on the life expectancy of patients with Down syndrome in our country. According to foreign data [3], the average life expectancy in this disease has increased in recent years from 25 to 53–58 years. In the presented observation, the patient lived to be 59 years old and died of multiple organ failure due to untimely replacement of the pacemaker, acute decompensation of heart failure.


In the clinical observation presented by us, a patient with a diagnosis of Down syndrome confirmed in childhood had no data for the presence of congenital heart disease;years, was diagnosed with mild degenerative aortic stenosis and aortic valve insufficiency.

Thus, due to the increase in the life expectancy of patients with Down syndrome, they are beginning to fall into the field of view of therapists, cardiologists, resuscitators who provide assistance to the adult population. Currently, the management of such patients is carried out from the standpoint of general recommendations. It is necessary to study the characteristics of the course of CVD in this category of patients in order to provide them with adequate medical care. In the future, it is possible to develop separate clinical recommendations or include separate sections in general recommendations on the management of such patients.

A case of Down syndrome with congenital acute leukemia and congenital heart disease


Chromosomal diseases (CD) are becoming increasingly important for modern medicine due to their increasing contribution to the structure of general morbidity, infant mortality and disability [1]. In the structure of congenital diseases, the share of chromosomal diseases, according to Rosstat, accounts for 5% [1, 2]. Down’s syndrome (trisomy of the 21st chromosome) is the most common CP. According to statistics, 1 out of 700 children is born with Down syndrome [1, 2]. In this disease, a variety of malformations are found: congenital heart defects (CHD) (50-60%), malformations of the gastrointestinal tract (13%), hypothyroidism (5%), etc.

The most common CHD is the ventricular septal defect (VSD), both as an isolated defect and in combination with other defects (for example, non-closure of the foramen ovale) [2].

Children with Down syndrome are at high risk of developing blood cancers such as acute leukemia (AL). Foreign literature has shown that the incidence of AL in children with Down syndrome is 150 times higher than in children of the same age without trisomy 21 [3, 4]. Trisomy of the 21st chromosome is believed to play a leading role in the pathogenesis of AL. Congenital AL is a very rare disease and accounts for less than 1% of all childhood leukemias.

Despite the fact that a large number of works have been devoted to Down’s syndrome, isolated cases of a combination of Down’s syndrome with hematoproliferative blood disease and congenital heart disease have been described in the literature. The authors who described cases of congenital AL in children with Down’s disease note a high mortality rate in concomitant oncological diseases [4—6].

The aim of the study is to present a rare clinical case of Down syndrome with congenital AL and CHD.

Material and methods

A retrospective analysis of an electronic database of patients aged 0–17 years inclusive, who underwent inpatient treatment for congenital heart disease at the Federal Center for Cardiovascular Surgery of the Ministry of Health of Russia (Astrakhan) from January 1, 2010 to December 31, was performed 2018

Statistical analysis of the obtained data was carried out using Microsoft Excel 2016 software (database formation, descriptive statistics, graphical presentation of data). Comparison of frequency signs was carried out using the criterion χ 2 . Differences were considered statistically significant at p <0.05.


Before describing the clinical case, in our opinion, it is of interest to analyze the incidence and types of CHD in children with Down syndrome. At the first stage of the study, we analyzed combinations of congenital heart disease, perinatal history, life history of these children and comorbidities.

From January 1, 2010 to December 31, 2018, 5953 children were treated in hospital for CHD, of which 319 (5.36%) children had Down syndrome (see table) . There were 169 (52.98%) boys and 150 (47.02%) girls, the ratio was 1.13:1. No pronounced gender differences were found.

Table . Types and combinations of congenital heart defects in children with Down syndrome

901 88











10 900 07
















5. 19








5.33 9000 7









9017 9








5. 02

Aortic coarctation

4 0.94

Tetrada Falllo




17 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 9000 79





Double outlet of the great vessels


0.31 05

AVSD – atrioventricular septal defect; VSD – ventricular septal defect; ASD – atrial septal defect; LLC – an open oval window; PDA – open ductus arteriosus.

The most common types of isolated malformations were VSD (43/13.48%), AVSD (25/7.84%), ASD (25/7.84%), PDA (17/5.53%), tetralogy of Fallot (13/4.08%).

Of the combined CHD, the most common were VSD + OOO (22 / 6.90%), AVSD + OOO (21 / 6.58%), AVSD + ASD (19 / 5.96%), VSD + ASD (17 / 5.33%), ASD+OAP (16/5.02%).

High-grade pulmonary hypertension was diagnosed in 39.57% of cases, grade II heart failure was registered in 36.36% of children, and grade I in 63.64%.

The timing of CHD diagnosis varied: in 33 (10.34%) children, CHD was diagnosed prenatally, in 138 (43.26%) children on the first day after birth, in 122 (38.25%) children in the period from 1 to 12 months of life, in 26 (8.15%) – after 1 year.

Down syndrome was diagnosed in 175 (54.85%) children at birth and in 144 (45.14%) children after the first month of life.

Almost all mothers had a burdened obstetric anamnesis: threatened miscarriage, infectious diseases (pyelonephritis, toxoplasmosis, colpitis, cytomegalovirus infection), anemia, 235 (73. 67%) mothers had preterm birth, 42 (13.17%) ) – childbirth by caesarean section.

Comorbid diseases in children were represented by cleft palate and soft palate (3/0.94%), congenital AL (1/0.31%), intestinal obstruction (1/0.31%), hip dysplasia (1/0.31%), renal dysplasia (1/0.31%), anemia I degree (75/23.51%), hypothyroidism (1/0.31%), Hirschsprung disease (1/0.31%), bronchopulmonary dysplasia (1/0.31%), testicular hypoplasia (1/0, 31%), perinatal lesions of the central nervous system (234/73.35%).

In all children, the genotype of Down’s syndrome is genetically confirmed, and a delay in all types of development is noted.


Girl D ., was born on July 31, 2015 from the 4th pregnancy against the background of mild preeclampsia, anemia of the first degree. The child’s mother did not undergo an ultrasound examination. The pregnancy ended in premature delivery at 36 weeks by caesarean section.

Child’s body weight at birth – 2500 g, body length – 47 cm, Apgar score – 5/7 points.

After birth, the child’s condition is severe, due to cardiovascular insufficiency. The child was examined in the maternity hospital, and on the basis of clinical and instrumental data, the diagnosis was made: CHD — VSD, LLC, PDA.

On August 11, 2015, the child was delivered to the FCSSH of the Russian Ministry of Health (Astrakhan) accompanied by an intensive care team. On admission, the patient was in a serious condition.

In the hospital, clinical and instrumental studies were carried out, on the basis of which the diagnosis of CHD: double discharge of the great vessels from the right ventricle, subaortic VSD, open foramen ovale, open ductus arteriosus was confirmed.

Complete blood count on the day of admission to the hospital (11.08.15): leukocytosis (l. 50.42∙10 9 /l), blast cells – 40% per 100 leukocytes. Congenital AL was suspected based on laboratory findings.

Taking into account the severity of congenital heart disease on August 12, 2015, according to vital indications, an operation was performed – the formation of a central systemic-pulmonary anastomosis with a prosthesis under cardiopulmonary bypass.

On August 13, 2015, to confirm or refute the diagnosis of congenital AL, the child was consulted by a regional hematologist; D. Rogacheva for a correspondence consultation. It is recommended to start chemotherapy.

On the 2nd day after surgery, acute cardiovascular failure developed, the child’s condition was severe. Artificial lung ventilation, inotropic support, antibiotic therapy, anticoagulant therapy, correction of acid-base balance are carried out.

On the 3rd-4th day after surgery, the patient’s condition is severe, the severity is due to heart failure, respiratory and renal-hepatic failure, sepsis. Artificial lung ventilation, inotropic support, antibiotic therapy, anticoagulant therapy, correction of acid-base balance are carried out. It was decided to refuse chemotherapy due to severe liver failure.

On the 5th-8th day after surgery, the patient’s condition is severe, the severity is due to heart failure, respiratory, renal and hepatic failure, sepsis. Therapy is underway.

From 2 to 15 days after surgery, the child’s condition progressively worsened due to increasing signs of multiple organ failure.

On the 15th day after surgery, the dynamics were negative, cardiopulmonary insufficiency, hemodynamic disturbances, hepatomegaly, and anuria increased. Started resuscitation, which did not lead to success. The child died on the 15th day after surgery.

Final clinical diagnosis: CHD — double outlet of the great vessels from the right ventricle. VSD. Open oval window. Open ductus arteriosus. OL. Multiple organ (cardiovascular, respiratory, renal and hepatic) insufficiency. Ventilator-associated bilateral pneumonia due to Klebsiella pneumoniae . Prematurity 36 weeks. Down Syndrome.

Clinical diagnosis confirmed at autopsy.


CHD is the most common comorbidity in children with Down syndrome. It is assumed that the cause of the development of CHD in Down syndrome is the overexpression of ɑ1- and ɑ2-types of collagen IV, located on the 21st chromosome. The authors who studied the frequency and structure of CHD in children with Down syndrome suggested that CHD is a prenatal marker of Down syndrome [7].

For prenatal diagnosis of congenital malformations, genetic screening is widely used: ultrasound and biochemical study of specific markers. However, in our patients CHD and Down syndrome are diagnosed in most cases after birth. Probably, the results obtained by us are due to the remoteness of the residence of pregnant women from regional centers. The retrospective analysis made it possible to identify 319 children with Down syndrome and congenital heart disease out of 5953 children admitted from January 1, 2010 to December 31, 2018 in the Federal Center for Surgery (Astrakhan) for the surgical treatment of congenital heart disease. The incidence of CHD in children with Down syndrome was 5.36% of the total number of children with CHD. When assessing gender, no significant differences between boys and girls were found. Similar results were obtained by other authors who studied the incidence of congenital malformations [7].

In the postoperative period, the number of leukocytes and blast cells increased, the maximum values ​​were observed on the 5-7th day after surgery. At the same time, the amount of hemoglobin, erythrocytes and platelets decreased. The increase in the number of leukocytes and blast cells could probably be partly due to the addition of a bacterial infection and the development of an infectious-inflammatory process.

Thus, in our observation, 1 out of 319 children had congenital AL as a concomitant disease. In the available literature, we found single descriptions of the combination of Down syndrome, CHD and OL. It is important to note that in 100% of cases the prognosis in children with such a combined disease is unfavorable [9].