Down syndrome associated with hypothyroidism and chronic pericardial effusion: echocardiographic follow-up

We present a 39-year-old male patient with Down syndrome who was evaluated for fatigue, palpitations and bouts of cyanosis. Physical examination showed features of trisomy-21(Down syndrome), with a slow pulse rate, distant cardiac sounds and absent apex beat. He had normal jugular venous pressure without pulsus paradoxus. The ECG showed QRS microvoltage and flattened P and T segments. The 48-hour ambulatory ECG depicted normal sinus rhythm with intermittent short PR interval without tachyarrhythmias. The chest Xray revealed cardiomegaly without pulmonary venous congestion. Although serial transthoracic echocardiographic examination demonstrated pericardial effusion with features of tamponade, there were no overt signs of clinical cardiac tamponade. Biochemically, the serum thyroxine of 3 pmol/l (normal 10 to 25) and thyroid-stimulating hormone of 160 mU/l (normal 0.20 to 4.20)) were compatible with hypothyroidism. The patient was treated with L-thyroxine sodium daily, which was gradually increased to 0.125 mg daily. Within a few months he lost weight and became more alert; furthermore, the symptoms of hypothyroidism and the pericardial effusion resolved. It can be concluded that Down syndrome may be associated with hypothyroidism and pericardial effusion. These were alleviated following hormone replacement. Regular evaluation of thyroid function tests is important in Down syndrome. (Neth Heart J 2007;15:67-70.)     

Centromeric association of a microchromosome in a Turner syndrome patient with a pseudodicentric Y

A 12-year-old patient with Turner syndrome was found to have a complex mosaicism for a microchromosome (MC) and a psu dic(Y)(q11). The MC was smaller than Yp, appeared pale in G, C and late replicating bands, had a pair of small centromeric dots, was associated with other chromosomes in most metaphases, and was rather stable both in size and during mitosis. The psu dic(Y) was Cd-positive only at the active centromere, had two pericentromeric heterochromatic regions, and lacked the Yq12 band. No cells with both abnormal chromosomes were found. To evaluate the association of the MC with all ordinary chromosomes, 857 G-banded cells with the marker were screened. The MC was considered as associated whenever the distance between it and other chromosome(s) was equal to, or smaller than, 18p. Out of 848 associations registered, 489 (57.7%) were centromeric, 202 (23.8%) telomeric, and 157 (18.5%) interstitial; i.e., centromeric associations were overrepresented (P < 0.001) and showed a random distribution, except for an excessive involvement of chromosome 8. This association pattern, also exhibited by two similar MCs in human beings, the minute Y of a marsupial and certain B chromosomes in plants, probably reflects the Rabl orientation of chromosomes in interphase.     

Offspring of patients with Down syndrome

An incident of birth of a child in 16-year-old patient with typical phenotype of Down's syndrome is described. The karyotype of the proband is 47, XX + 21, while that of the child is 46, XX. Analysis of the literature data and the author's observations showed that the total ratio of trisomics and non-trisomics in the offspring of women with Down's syndrome is 9:18, which considerably differs from theoretically expected and suggests that selection against anomalous gametes exists.     

Infantile spasms in children with Down syndrome

Down syndrome (DS) is the most common genetic cause of mental retardation. It is estimated that 5-13% of persons affected by DS have seizures. Infantile spasms are the most common type of seizures and usually are well controlled with steroids and antiepileptic drugs. We present 11 children at the age of 3 years and 4 months to 10 years and 7 months with DS and infantile spasms, treated at Children's Hospital Zagreb from January 2000 until July 2009. Infantile spasms began at the age of 5 to 10.5 months in 10 children, in one child at the age of 16 months. Only one child had perinatal risk factors for the development of IS. Changes in EEG correlated to hypsarrhythmia. Infantile spasms were treated initially with antiepileptic drugs, most often with valproic acid. Treatment was inefficient in 10/11 patients. After application of ACTH, infantile spasms stopped between 7 and 15 days in 6 patients, until 28th day in 4 patients. Hypsarrhythmia vanished in all children. During follow-up period (2 years and 7 months to 9 years and 5 months) none of the children developed another type of seizures. No major epileptogenic changes were registered in EEG. Antiepileptic therapy was discontinued in 4 children (aged 4 years and 2 months to 5 years). In this group is the boy who died of heart failure. Infantile spasms associated with DS are categorized into symptomatic group. The existence of cerebral pathology and delayed psycho-motor development precedes occurrence of seizures. It is possible to achieve good control of seizures and disappearance of hypsarrhythmia with application of ACTH and antiepileptic drugs.     

Healthy growth in children with Down syndrome

Objective

To provide cross-sectional height and head circumference (HC) references for healthy Dutch children with Down syndrome (DS), while considering the influence of concomitant disorders on their growth, and to compare growth between children with DS and children from the general population.

Study design

Longitudinal growth and medical data were retrospectively collected from medical records in 25 of the 30 regional hospital-based outpatient clinics for children with DS in the Netherlands. Children with Trisomy 21 karyotype of Dutch descent born after 1982 were included. The LMS method was applied to fit growth references.

Results

We enrolled 1,596 children, and collected 10,558 measurements for height and 1,778 for HC. Children with DS without concomitant disorders (otherwise healthy children) and those suffering only from mild congenital heart defects showed similar growth patterns. The established growth charts, based on all measurements of these two groups, demonstrate the three age periods when height differences between children with and without DS increase: during pregnancy, during the first three years of life, and during puberty. This growth pattern results in a mean final height of 163.4 cm in boys and 151.8 cm in girls (−2.9 standard deviation (SD) and −3.0 SD on general Dutch charts, respectively). Mean HC (0 to 15 months) was 2 SD less than in the general Dutch population. The charts are available at www.tno.nl/growth.

Conclusions

Height and HC references showed that growth retardation in otherwise healthy children with DS meanly occurs in three critical periods of growth, resulting in shorter final stature and smaller HC than the general Dutch population shows. With these references, health care professionals can optimize their preventive care: monitoring growth of individual children with DS optimal, so that growth retarding comorbidities can be identified early, and focusing on the critical age periods to establish ways to optimize growth.     

A fragile X female with Down syndrome

Summary Clinical and cytogenetic aspects of a female infant with trisomy 21 and the fragile X [fra (X)] chromosome are reported. Most of the facial characteristics of the patient are those observed in Down syndrome, but some features such as long face with prominent forehead and lower jaw, and large ears are related to the fra (X) syndrome. The origin of an additional chromosome 21 may be ascribed to maternal first meiotic nondisjunction in our case. It has been suspected that female carriers of the fra (X) chromosome may be predisposed to meiotic nondisjunctional events. However, there is probably no relationship between the two chromosomal abnormalities in our case because of the maternal age at the delivery.     

A microchromosome derived from chromosome 11 in a patient with the CREST syndrome of scleroderma.

A patient with the CREST syndrome of scleroderma was found to carry a mosaicism for a supernumerary microchromosome. The microchromosome was approximately 1 micron in size and present in over half of the lymphocyte metaphases examined. It bound centromeric proteins specifically recognized by CREST autoimmune sera (including the patient's serum). In situ hybridization with a panel of chromosome-specific alpha-satellite probes showed that the microchromosome was derived from chromosome 11, most or all of its chromatin consisting of the chromosome 11 subset of alpha-satellite DNA. It had no detectable telomeric sequences. Microchromosomes observed by electron microscopy had no visible free ends. The chromatin looked exactly the same as it did in normal chromosomes. Although we have no direct evidence for a circular structure, we conclude that the microchromosome originated by an interstitial deletion including the alpha-satellite DNA sequences and subsequent ring formation. The newly formed chromosomal element proved to be relatively stable somatically and was transmitted through meiosis. Since it possesses at least some structural and functional features of a centromeric region, the microchromosome can be thought of as an isolated centromere.     

Growth curves of children with Down syndrome.

Growth curves of 105 children with Down syndrome (50 boys and 55 girls) were established. At birth height, weight and head circumference of Down syndrome children were lower than these parameters in controls. This delay remained stable until puberty. For weight there was no clear-cut pubertal growth spurt. For stature, the prepubertal growth spurt occurred earlier (at the age of 11 years in boys and 9 1/2 years in girls) than in controls but was less marked. As a result, Down syndrome patients had a short stature with a quite normal weight. These reference curves, available since prenatal diagnosis of Down syndrome is performed routinely, are helpful for monitoring normal and abnormal development in Down syndrome patients.     

Trisomy 21 Down syndrome

Summary In a series of 374 families with Down syndrome progeny, structural chromosome rearrangements were detected in the parents of six children with regular trisomy. The aberrations were reciprocal translocations and inversions. In all three informative families, the parent who transmitted the extra chromosome was not the one with the structural rearrangement. Among the three non-informative families there was one in which both parents carried different reciprocal translocations. In two other families a chromosome aberration was detected: a triple X mother and a father with a Philadelphia chromosome. Omitting the four parents with possible biased asccrtainment, 0.4% had a chromosome rearrangement. When the parents with constitutional chromosome aberrations and those with mosaicism, described previously, are combined, the frequency of chromosomally abnormal parents lies between 1.9% and 3.2%. When correlated with parental transmission of the extra chromosome, mosaicism rather than structural rearrangements appears to be of ctiologic significance.     

Antioxidants in Down syndrome

Individuals with Down syndrome (DS) have high levels of oxidative stress throughout the lifespan. Mouse models of DS share some structural and functional abnormalities that parallel findings seen in the human phenotype. Several of the mouse models show evidence of cellular oxidative stress and have provided a platform for antioxidant intervention. Genes that are overexpressed on chromosome 21 are associated with oxidative stress and neuronal apoptosis. The lack of balance in the metabolism of free radicals generated during processes related to oxidative stress may have a direct role in producing the neuropathology of DS including the tendency to Alzheimer disease (AD). Mitochondria are often a target for oxidative stress and are considered to be a trigger for the onset of the AD process in DS. Biomarkers for oxidative stress have been described in DS and in AD in the general population. However, intervention trials using standard antioxidant supplements or diets have failed to produce uniform therapeutic effect. This chapter will examine the biological role of oxidative stress in DS and its relationship to abnormalities in both development and aging within the disorder. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.     

Antioxidants in Down syndrome

Individuals with Down syndrome (DS) have high levels of oxidative stress throughout the lifespan. Mouse models of DS share some structural and functional abnormalities that parallel findings seen in the human phenotype. Several of the mouse models show evidence of cellular oxidative stress and have provided a platform for antioxidant intervention. Genes that are overexpressed on chromosome 21 are associated with oxidative stress and neuronal apoptosis. The lack of balance in the metabolism of free radicals generated during processes related to oxidative stress may have a direct role in producing the neuropathology of DS including the tendency to Alzheimer disease (AD). Mitochondria are often a target for oxidative stress and are considered to be a trigger for the onset of the AD process in DS. Biomarkers for oxidative stress have been described in DS and in AD in the general population. However, intervention trials using standard antioxidant supplements or diets have failed to produce uniform therapeutic effect. This chapter will examine the biological role of oxidative stress in DS and its relationship to abnormalities in both development and aging within the disorder. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.     

Trisomy 21 Down syndrome

Summary The lymphocyte chromosomes of trisomy 21 Down syndrome patients and their parents in a random series of 374 families were analyzed, the objective being the identification of parental mosaicism. The numbers of parents in whom at least two trisomy 21 cells were detected were seven mothers and three fathers, a frequency of 2.7% of families. Confirmation of mosaicism was by identification of parental transmission of the extra chromosome to the progeny, by repeat chromosome analysis, and/or by the presence of more than one affected child. If to these are added six others in whom only one trisomic cell was detected, but with no other supporting evidence, the frequency could be as high as 4.3%. Differences in parental age at the birth of Down syndrome progeny may be accounted for by differences in frequencies of mosaicism in germ cells and somatic tissue. Mosaicism was found more frequently in the mothers than in the fathers, but more data are required for confirmation of a real difference.     

The challenge of Down syndrome

Down syndrome (DS) has been recognized as a clinical entity for about 150 years, but it is only recently that there has been hope for the possibility to understand its pathogenesis and to use this information to devise approaches for the prevention and treatment of its numerous features. The earlier pessimism was due to several reasons, including: (i) the nature of the genetic defect that leads to the syndrome; (ii) the multiplicity of systems involved; and (iii) the high degree of variability of the phenotype. However, science has now caught up with the problem, and recent developments, especially in genetics, genomics, developmental biology and neuroscience, suggest that these potential impediments might not be as arduous as once appeared. As a result, basic research on DS is now rapidly accelerating, and there is hope that the findings will be translatable into benefit for people with DS.     

Hopelessness of mothers who have children with Down syndrome

This study was conducted to determine hopelessness status of mothers who have children with Down syndrome. Beck Hopelessness Scale was used in this restrictive type study. The average value of mothers enrolled in the study was detected as 8.29 +/- 2.49. Age, education level, socio-economical status, work and the problems between parents were also examined and it was found that there is a relationship between the education level, socio-economical status, the problems between parents and the hopelessness scale (p < 0.01). Consequently, it is apparent that the mothers who have children with Down syndrome need social and psychological support to overcome their feelings of hopelessness.