Neuropathology in Patients with Congenital Heart Disease and Down Syndrome

This report examines the relationship between congenital heart disease (CHD) and neuropathological findings in three groups of patients: Down syndrome (45 cases), isolated CHD (296 cases), and CHD with multiple anomalies (92 cases). The increase in brain weight in Down syndrome was similar to control standards up to 1 year of age, after which it was less than normal. Among the three groups, there were differences in frequency in cyanotic CHD, history of operation, and macroscopic and microscopic brain malformations. The incidence of calcification in the brain was increased in Down syndrome. Nine children out of the total cohort had cerebrovascular abnormalities. Although CHD is frequent in Down syndrome, the cerebrovasculature is spared; only infrequent minor abnormalities of the circle of Willis were detected.     

Subpleural lung cysts in Down syndrome: prevalence and association with coexisting diagnoses

Background Although subpleural cysts are known to be associated with Down syndrome, their etiology and prevalence remains unknown. Objective To determine the prevalence of subpleural cysts in children with Down syndrome and the association with prematurity, congenital heart disease (CHD), extracorporeal membrane oxygenation (ECMO), and chronic ventilator support. Materials and methods A review of the CT examinations of 25 children with Down syndrome was performed to determine the presence, location, and distribution of cysts along with associated abnormalities. Charts were reviewed and coexistent diagnoses and past treatments were recorded. Results The prevalence of subpleural cysts was 36% with no significant association with CHD, ECMO, or chronic ventilator support. An association was found in the two children with a history of prematurity. The cysts were most commonly found in the anteromedial portion of the lung. Conclusion Subpleural cysts are common in Down syndrome and should not be confused with another pathological process. An association with prematurity was found, but the low number of children in this study makes the connection uncertain. The etiology remains unclear, but it has been hypothesized that the cysts are associated with lung hypoplasia.     

Benign and malignant tumors in Down syndrome: Analysis of the 1514 autopsied cases in Japan

Background: Down syndrome is known for its association with neoplasms. The aim of this study was to examine this association. Methods: We surveyed the association with benign and malignant neoplasms in Down syndrome patients registered in the Annual of Pathological Autopsy Cases of Japan (1974–2000), a database of autopsied cases operated by the Japanese Society of Pathology. Results: In a total of 1514 cases with Down syndrome, there were eight cases with 10 benign tumors (four male and four female) and 104 cases with malignant disorders (61 male, 42 female and one case with unrecorded sex), in which 87 cases with hematopoietic malignancies (83.7%) and 17 cases with solid tumors (16.3%), were identified. The association of gallbladder adenocarcinoma with a benign tumor of the colon was noted in one case, while a further two cases with double benign tumors were confirmed as well. No case with a double malignancy was found. Hematopoietic malignancies (87 cases) included 31 cases (35.6%) with acute myelocytic leukemia, 10 (11.4%) with acute lymphocytic leukemia and two (2.3%) with chronic myelocytic leukemia. The ratio of acute myelocytic leukemia to acute lymphocytic leukemia was 3.1 in the present study. A peak in the age distribution was at 0 years in our data in contrast to the previous data (at 1 year) for myelocytic leukemia. The 17 solid tumors identified included three hepatocellular carcinomas, three extrahepatic cholangiocarcinomas, two gallbladder adenocarcinomas, three brain tumors, and three seminomas. Conclusion: We present new associations of benign and malignant tumors with Down syndrome.     

The Urinary System in Down Syndrome: A Study of 124 Autopsy Cases

We examined 124 autopsy cases of Down syndrome for the presence of renal and urinary tract abnormalities. The cases were divided into three groups: (I) fetuses of 16-22 weeks gestation (n = 18), (II) stillborns or newborns who died on the first day of life (n = 9), and (III) Down patients 1 day to 25 years of age (n = 97). Kidney weight was reduced by a mean of 14.4% compared with expected values. Renal hypoplasia, defined as kidney weight less than two-thirds expected, was found in 18 cases. Glomerular microcysts were found in 23 of 97 cases in group III. Focal dilatation of tubules was found in 10, simple cysts in 7, and immature glomeruli deep in the renal cortex in 18 cases. Obstructive uropathy occurred in 2 of 18 (11.1%) in group I, 2 of 9 (22.2%) in group II, and 4 of 97 (4.1%) in group III. Obstructive uropathy with bilateral cystic dysplastic kidneys resulted in Potter's sequence. We suggest that obstructive uropathy is associated with Down syndrome. When severe, it results in Potter's sequence and an early perinatal death. A chromosomal analysis is recommended in any case of obstructive uropathy in the fetal or neonatal period.     

The urinary system in Down syndrome: a study of 124 autopsy cases.

We examined 124 autopsy cases of Down syndrome for the presence of renal and urinary tract abnormalities. The cases were divided into three groups: (I) fetuses of 16-22 weeks gestation (n = 18), (II) stillborns or newborns who died on the first day of life (n = 9), and (III) Down patients 1 day to 25 years of age (n = 97). Kidney weight was reduced by a mean of 14.4% compared with expected values. Renal hypoplasia, defined as kidney weight less than two-thirds expected, was found in 18 cases. Glomerular microcysts were found in 23 of 97 cases in group III. Focal dilatation of tubules was found in 10, simple cysts in 7, and immature glomeruli deep in the renal cortex in 18 cases. Obstructive uropathy occurred in 2 of 18 (11.1%) in group I, 2 of 9 (22.2%) in group II, and 4 of 97 (4.1%) in group III. Obstructive uropathy with bilateral cystic dysplastic kidneys resulted in Potter's sequence. We suggest that obstructive uropathy is associated with Down syndrome. When severe, it results in Potter's sequence and an early perinatal death. A chromosomal analysis is recommended in any case of obstructive uropathy in the fetal or neonatal period.     

Genetic analysis of a group of mentally retarded children

Genetic analysis of 169 mentally retarded (MR) children from Madras, revealed chromosomal abnormalities in 17%. Down syndrome was the major chromosomal anomaly (24/169=14.2%). These included three cases of trisomy-21 mosaics, and one case ofde novo Robertsonian translocation. MR children with chromosomal abnormalities were either mildly or moderately retarded. Syndromes with known etiology occurred in 3% of the MR cases. Microcephaly, neonatal anoxia, perinatal stress and pharmacological attempt for abortion were found to be important pathogenic factors associated with MR. Most of the microcephalies (11/ 169=6.5%) were severely retarded, whereas those associated with neonatal anoxia and perinatal stress were either mildly or moderately retarded. Birthorder effects were found only among Down syndrome patients. Segregation analysis of the three groups of proband families (viz. mild, moderate and severe MR) indicated that autosomal recessive mode of inheritance is compatible in moderate and severe MR proband families. The proportion of X-linked instances of MR is estimated to be about 22% of the cases.     

Congenital malformations and childhood cancer

BACKGROUND: We investigated the epidemiology of congenital malformations and childhood cancer. PROCEDURE: By employing the cases of the Registry of Childhood Malignancies in Hokkaido Prefecture, Japan, from 1969 to 1996, the numbers of malignancies in cases (diagnosis at 0-14 years of age) with Down syndrome (DS), mental retardation (MR) excluding DS, luxatio coxae congenita (LCC), congenital heart disease (CHD) excluding DS, undescended testicle (UT), and cleft palate-lip (CPL) were calculated. Using the percentages of malignancies in the 2,349 cases without malformation, expected numbers of malignancies in the cases with the malformations were calculated. The observed numbers were statistically compared to expected ones. RESULTS: In the DS cases, leukemia developed with a significantly high frequency, but no UT cases developed leukemia. No brain tumor was preceded by DS. This could not be explained only by early death from coexisting diseases such as CHD, insofar as the CHD cases without DS developed brain tumors more frequently than expected. The ratio of acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) was different among the malformations. The MR cases developed ANLL more frequently than expected, whereas the CPL cases developed ALL more frequently. The distribution of the age at diagnosis for Wilms' tumor was different according to the underlying malformation. CONCLUSIONS: Malformations might have some factors that inhibit or delay as well as promote the development of certain malignancies.     

Cytogenetic analysis of down syndrome in Libya

The frequency of Down syndrome in Libya was 1 in 516 live births. The mean age of Down mother was 35.62 years. Eighty two percent of the Down mothers were over 30 years of age as compared to 36% of the control Libyan mothers. As there was a greater percentage of late conceptions, the maternal age appears to be influential in the birth of Down syndrome in Libya. Cytogenetically 96% of the cases were that of trisomy 21. There was one case each of mosaic and 21/21 translocation, and four cases of 14/21 translocation as evidenced by Giemsa banding. Twenty two percent of the cases of Down syndrome also had other associated congenital abnormalities. The unique features involved in genetic counselling in this population are discussed. This study reflects the enormous problem of Down syndrome in the Arab world.     

Acute respiratory infections during pregnancy and congenital abnormalities: a population-based case-control study

Diseases of respiratory system caused by acute infections are among the most common maternal diseases during pregnancy. The objective of the study was to estimate the association between congenital abnormalities and acute respiratory infections during the first trimester of pregnancy. The data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities including 22 843 cases with congenital abnormalities, 38 151 population controls without congenital abnormalities and 834 malformed controls with Down syndrome between 1980 and 1996 was evaluated. 2118 cases with congenital abnormalities (9.3%), 3455 population controls (9.1%) and 92 malformed controls with Down syndrome (11.0%) had mothers with acute respiratory infections. Of 25 different congenital abnormality groups, esophageal atresia/stenosis showed a high adjusted prevalence odds ratios (POR) with 95% confidence interval (CI) for acute respiratory infections during the first trimester of pregnancy in case mothers compared with population controls (3.6, 1.4-9.1) and malformed controls (1.9, 1.0-3.5), respectively. In addition there was an association between medically recorded acute respiratory infections during the first trimester of pregnancy and a higher risk for some other congenital abnormalities, such as posterior cleft palate and multiple congenital abnormalities. In conclusion a possible association between some congenital abnormalities, particularly esophageal atresia/stenosis and maternal acute respiratory infections cannot be excluded due to the interactions of the microbial agents, related drug treatments and last but not least the indirect effect of maternal diseases, such as fever-hyperthermia, hypoxia and dietary deficiency. However, periconceptional multivitamin/folic acid supplementation during the early pregnancy was able to reduce the acute respiratory infection related risk for congenital abnormalities.     

Cholelithiasis in infants with Down syndrome. Three cases and literature review.

Only four cases of cholelithiasis have been reported in patients with Down syndrome and none in Down syndrome infants. The cases of three Down syndrome infants (all males) with cholelithiasis are reported. Each exhibited different fetal complications, and in each, Down syndrome was diagnosed at birth. Gallstones apparently were congenital (a rarity) in one infant, since they were detected on the first day of life. Cholelithiasis was an incidental finding in another of the infants when, at 12 weeks old, he had renal ultrasonography because of a urinary tract infection. The third infant was 4 months old when sonographic studies revealed a gallstone. Despite the confirmation of cholelithiasis in all three infants, none has since had any signs or symptoms that suggest the need for intervention. Cholelithiasis is probably more common in Down syndrome infants than has been supposed, but whether Down syndrome infants with gastrointestinal (GI) malformations are more likely to have gallstones than are children with similar GI malformations but with normal karyotypes is unknown.     

Cholelithiasis in infants with Down syndrome: report of two cases

Down syndrome is a chromosomal disorder most often observed in the newborn period. Various facial, limb and internal abnormalities are found in this disorder but cholelithiasis in infancy has been described in only one report. We report two infants with Down syndrome associated with cholelithiasis. Except for polycythemia and indirect hyperbilirubinemia, no hemolytic process or biochemical abnormalities were evident in both patients. We believe that the cause of gallstones in our cases may have been polycythemia in the newborn period. To our knowledge this is only the second report of gallstones in infancy in Down syndrome.     

Congenital heart disease in 740 subjects: epidemiological aspects

Between March 1997 and February 2000, 740 children with congenital heart disease (CHD) were studied in the Paediatric Cardiology Unit of King Fahad Hospital, Hofuf in Saudi Arabia. There were 351 boys and 389 girls (M:F ratio 0.9:1). Newborns accounted for 24% of cases and 53% of cases were detected in the 1st year of life. Ventricular septal defect was the commonest anomaly (39.5%), followed in descending order of frequency by atrial septal defect, pulmonary stenosis and patent ductus arteriosus. In general, the distribution of lesions was similar to that reported elsewhere in the world but there were fewer obstructive aortic lesions and transposition of the great arteries was rarer than in most other reports. The incidence of CHD showed no seasonal variation and Down syndrome was the commonest associated cause.     

Thyroid dysfunction in Down syndrome

We investigated the thyroid function of 151 patients with Down syndrome. Compared with a control group of 89 siblings nearest in age to their brother or sister with Down syndrome, the mean thyroid-stimulating hormone (TSH) value was significantly higher in patients with Down syndrome than in subjects without Down syndrome. However, the mean thyroxine (T4) levels in both groups were nearly the same. In the Down syndrome group there was a trend for TSH values to increase and for T4 values to decrease with advancing age. Of the 151 patients with Down syndrome, ten had both significantly elevated TSH levels (greater than or equal to 9.5 microU/mL) and significantly decreased T4 levels (less than or equal to 5.5 micrograms/dL), 21 had only abnormally high TSH values, seven had only markedly increased T4 levels (greater than or equal to 12.0 micrograms/dL), and three had only significantly decreased T4 levels. The intellectual function of patients with both abnormal TSH and T4 levels was significantly lower (mean IQ, 41.7) than that of Down syndrome patients with only increased TSH values (mean IQ, 53.8) and that of Down syndrome patients with normal thyroid function (mean IQ, 55.3). This study provides further evidence that there is an increased prevalence of thyroid dysfunction in patients with Down syndrome.     

Risk factors for early death in transient myeloproliferative disorder without phenotypic features of Down syndrome: a case report and literature review

Not only in newborns with Down syndrome, but newborns without phenotypic features of Down syndrome also develop transient myeloproliferative disorder (TMD). In these cases, trisomy 21 and related chromosomal abnormalities are either constitutionally mosaic or limited to blood cells. Risk factors for early death of these patients are unknown so far. We here report a fatal case of TMD without phenotypic features of Down syndrome and review literature to identify risk factors associated with early death. Not only are gestational age and white blood cell count risk factors for early death in TMD with Down syndrome, but they also appear to be risk factors in TMD without Down syndrome.     

Anomalies of the Brain and Congenital Heart Disease: A Study of 52 Necropsy Cases

During routine autopsy examinations several macroscopic anomalies of brains were noted in children with congenital heart disease (CHD). To define these observations 52 autopsies of cases with CHD as well as 52 controls were compiled. Cases were divided into two groups according to the absence (group I) or presence (group II) of a multimalformative syndrome (MMS). Fifty percent of the sample was associated with MMS. Brain anomalies were classified into grades I, mild and focal; II, intermediate, focal or diffuse; and III, severe and diffuse. Group I was associated with brain anomalies (mainly of grades I and II with altered gyri) in 19 of 28, whereas in Group II the brains frequently had compromise of lobes, gyri, and fissures, 18 of 24. The relationship between the types of CHD, grade of brain anomalies, and MMS is delineated. The high frequency of brain anomalies associated with CHD but without other malformations (67.8%) suggests a clinical counterpart of these lesions.     

Phenotypic heterogeneity and parental origin of extra chromosome 21 in Down syndrome

We compared the frequency of phenotypic features of 40 children with Down syndrome between individuals with a maternally or paternally derived extra chromosome 21, using quantitative FISH for comparing heteromorphisms of the nucleolar organizing region. Parental origin was determined in 90% of families. Hypotonia and craniofacial abnormalities were present in 90% or more individuals, irrespective of parental origin of chromosome 21. Congenital heart defects were more frequent in cases with a maternally derived extra chromosome 21. Imprinted gene(s) may contribute to the development of congenital heart defects in Down syndrome.     

Prevalence and distribution of children with congenital heart diseases in the central Anatolian region, Turkey

Congenital heart diseases (CHD) are the most frequent malformation at birth. The aims of this study were to assess the prevalence of congenital heart disease, their different types, and the detection rate among children in the central Anatolian region in Turkey. The study was conducted during an eight-year period (March 1995-December 2002). The prevalence of CHD in a large tertiary care hospital in the central Anatolian region in Turkey was studied. The diagnosis of a structural defect was based on echocardiographic study. The following age groups were considered: neonates, infants and toddlers, preschool children, schoolchildren, and adolescents. In the study period, 1,693 children were found to have CHD; 1253 patients were neonates and infants. Total prevalence of CHD over the study period was 7.77 per 1000 live-born. The prevalence increased from 6.35 to 9.65 per 1000 live births between 1995 and 2002 (p < 0.05). The average age at diagnosis was 2.2 +/- 3.64 years (1 day to 18 years, median 5 months). There were 863 (51%) boys and 830 (49%) girls, with a male/female ratio of 1:1. Isolated ventricular septal defect (32.6%) was the most frequent acyanotic anomaly, and tetralogy of Fallot (5.8%) was the most frequent cyanotic anomaly. The commonest non-cardiac anomalies with CHD were musculoskeletal anomalies. Down syndrome was determined in 83 patients (78.3%) from all syndromic CHD cases. Congenital heart disease is a very significant health problem. It requires urgent measures in terms of organization of early diagnosis and proper management. The prevalence rate is comparable to that of similar developed countries. Increasing incidence of CHD might be attributed to more diagnoses with new technologic development or it may indicate a real increase in the defects.     

Prevalence and clinical picture of celiac disease in italian down syndrome patients: a multicenter study

BACKGROUND: A multicenter research study of Down syndrome patients was carried out to estimate the prevalence of celiac disease in patients with Down syndrome and to show clinical characteristics and laboratory data of Down syndrome patients. METHODS: The authors studied 1,202 Down syndrome patients. Fifty-five celiac disease patients (group 1) were compared with 55 immunoglobulin A antigliadin-positive antiendomysium antibodies-negative patients (group 2) and with 57 immunoglobulin A antigliadin-negative antiendomysium antibodies-negative patients (group 3). RESULTS: Celiac disease was diagnosed in 55 of 1,202 Down syndrome patients (4.6%). In group 1, weight and height percentiles were shifted to the left, whereas these parameters were normally distributed in groups 2 and 3. In celiac patients, diarrhea, vomiting, failure to thrive, anorexia, constipation, and abdominal distension were higher than in the other two groups. Low levels of hemoglobinemia, serum iron, and calcium were observed more frequently in group 1. The diagnosis of celiac disease was made after a mean period of 3.8 years from the initiation of symptoms. Sixty-nine percent of patients showed a classic presentation, 11% had atypical symptoms, and 20% had silent celiac disease. Autoimmune disorders were more frequent (30.9%) in group 1 than in the other two groups examined (15%; P < 0.05). CONCLUSIONS: This study reconfirms a high prevalence of celiac disease in Down syndrome. However, the diagnostic delay, the detection of atypical symptoms or silent form in one third of the cases, and the increased incidence of autoimmune disorders suggest the need for the screening of celiac disease in all Down syndrome patients.     

Early detection of podiatric anomalies in children with Down syndrome

Aims: To verify the importance of podiatric evaluation in patients with Down syndrome for the early diagnosis and treatment of minor orthopaedic problems. Methods: Case-control study of 50 children affected by Down syndrome (aged 4-10 y) without major orthopaedic malformations compared to 100 healthy children. A complete podiatric examination was performed on all patients and controls. Results: Children with Down syndrome showed several orthopaedic anomalies including bony deformity of the forefoot (90%), flat foot (60%), isolated calcaneal valgus (24%), knee valgus (22%) and pronated flat foot (16%). These abnormalities were responsible for postural alterations as confirmed by baropodometric examination.

Conclusion: The data demonstrated a greater incidence of minor orthopaedic alterations and suggest the necessity of regular podiatric examinations in the follow-up of this syndrome.     

Cytogenetic studies in Down syndrome.

Cytogenetic studies were carried out in 645 patients with Down syndrome. Free trisomy of chromosome 21 was present in 600 cases (93%). Translocation karyotypes were observed in 26 cases (4%). Seventeen patients (2.6%) had mosaicism. Two (0.3%) patients had additional karyotypic abnormalities along with trisomy 21.