Chromosome studies in patients with congenital malformations and mental retardation.

16 (41%) out of 39 individuals referred by physicians because of sexual anomalies showed abnormal karyotypes; the corresponding figure for those investigated due to suspected autosomal aberrations was 37 out of 104 (36%). A special survey was also conducted among 51 mentally defective children with at least 3 malformations; 5 individuals (10%) were observed with chromosome abnormalities plus 3(6%) with rare variants. These results were compared with those presented in 26 other surveys reported in the literature.     

16q subtelomeric deletion in proband with congenital malformations and mental retardation

We present a female child with mild mental retardation and congenital malformations. After fluorescence in situ hybridization (FISH) we found only abnormal karyotype in all cells. We used rapid FISH and original DNA probes--PAC62.10.1 and PAC20.19.N, specific for segments of chromosome 16q24. Karyotype of proband 46,XX.ish del(16)(q24.2:) (PAC20.19.N,PAC62.10.1-). Parent karyotypes are normal. This case may suggest the presence of clinical picture 16q- with defined clinical polymorphism at small telomeric loss, and also its necessary of the use of molecular-cytogenetic techniques in genetic departments.     

Chromosome X-linked mental retardation and marfanoid syndrome

In the present paper we report two pairs of slightly to moderately mentally retarded brothers with Marfanoid habitus and similar craniofacial changes. They had a long and narrow face, small mandible, high-arched palate and hypernasal voice, as previously reported by Lujan et al. (1984) in 4 mentally retarded males of a large kindred. The present data suggest the existence of a specific type of X-linked mental retardation with Marfanoid habitus.     

Mental retardation and congenital malformations associated with a ring chromosome 9

Summary A 46,XY,r(9)(p24q34) complement was observed in a 35-month-old boy with multiple congenital anomalies. The main clinical features included intrauterine growth retardation, dwarfism, microcephaly, peculiar face, undescended testes, seizures and severe psychomotor retadation.It appears that 4 reported cases of r(9) can be devided into two groups. Three of them, including the present case, share clinical features with those of cases with 9p-. On the other hand, one case showed a different combination of malformations.Supported in part by a grant (No. 057364) from the Ministry of Education, Japan and a grant from the Ministry of Health and Welfare, Japan.     

Dysmorphology and mental retardation: molecular cytogenetic studies in dysmorphic mentally retarded patients

In an institutionalised population of 471 mentally retarded adult residents (436 males and 35 females), 18 patients (16 males and 2 females) with dysmorphic features were selected to perform FISH studies by using subtelomeric probes to discover cryptic terminal deletions or duplications, undetectable with standard banding techniques. In the 13 investigated patients, no abnormalities were found with a selected battery of subtelomeric probes. The results of cryptic chromosomal rearrangement studies are variable but the frequency of positive diagnostic findings seems to be lower than previously expected.     

Chromosome characteristics of X-linked mental retardation. II. Autosomes

The frequencies of chromosome and chromatid breaks and gaps were studied in blood lymphocytes of three groups of individuals: 21 males with X-linked mental retardation characterized by fragile X chromosome; 52 males with non-differentiated X-linked mental retardation having no fra(X) chromosome in their cells; 15 intellectually normal males. The lymphocytes were cultured both in medium 199 and in Eagle's medium supplemented with fluoro-deoxyuridine. The significantly higher frequencies of various autosomal lesions were observed in the individuals with the fragile X chromosome syndrome and in those with mental retardations without fra(X) chromosome, in comparison with normal males. The significant difference in some autosome lesions was also found between both groups of the patients. The distribution of chromosome lesions in autosomes of different groups was significantly higher in chromosomes A and lower in groups B, E, F and G, than expected in accordance with their relative length in the haploid set. In all the groups of individuals studied, the predominant localization of chromosome and chromatid breaks and gaps was observed in fragile sites 1p31, 3p14, 6q26 and 16q23.     

Structural chromosomal abnormalities in patients with mental retardation and/or multiple congenital anomalies: a new series of 24 patients

Chromosomal abnormalities are a major cause of mental retardation and/or multiple congenital anomalies (MCA/MR). Screening for these chromosomal imbalances has mainly been done by standard karyotyping. The objective of this study was to report standard chromosome analysis and FISH screening of a series of 24 patients with MCA/MR. Structural chromosomal abnormalities were detected in 24 alterations and included 5 deletions, 2 duplications, 6 unbalanced translocations, 3 inversions, 2 insertions, 3 derivative chromosomes, 2 marker chromosomes and 1 isochromosome. We confirm that a high percentage of MCA/MR cases hitherto considered idiopathic is caused by chromosomal imbalances. We conclude that patients with MCA/MR should be routinely karyotyped.     

Chromosome studies in twelve patients with retinoblastoma

Summary Chromosome studies in 12 children suffering from retinoblastoma revealed a significantly elevated frequency of aneuploids, chromatid-type aberrations and stable abnormalities of the chromosome type. A similar increase in the occurrence of chromosome abnormalities was found in cases of retinoblastoma not exposed to therapeutic irradiation. These findings indicate that an increased fragility of the chromosomes must be assumed in patients with retinoblastoma, which may be associated with a general increase in the predisposition to develop tumors.

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Zusammenfassung Chromosomenuntersuchungen von 12 Kindern mit Retinoblastom erwiesen eine signifikante Erhöhung von Aneuploidie, Chromatidenaberrationen und stabilen Anomalien des Chromosomentyps. Eine ähnliche Zunahme war im Vorkommen von Chromosomenanomalien auch in den nicht strahlenbehandelten Fällen von Retinoblastom zu beobachten. Die Ergebnisse weisen darauf hin, daß bei Patienten mit Retinoblastom mit einer erhöhten Chromosomenbrechbarkeit zu rechnen ist, die mit einer erhöhten Anfälligkeit zur Tumorbildung verbunden sein kann.

     

Chromosome studies in patients with ulcerative colitis

Summary Chromosome preparations from 16 patients with ulcerative colitis showed a significant increase in structural chromosome abnormalities as compared to controls. The most striking finding was the high incidence of breaks affecting both chromatids at the same locus (7.1% of mitoses in patients, 0.6% in controls). There was also an excess of chromatid breaks, gaps of one or both chromatids, acentric fragments and morphologically abnormal chromosomes. The possible causes of chromosomal breakage and the eventual relationship of this breakage to the high incidence of colon carcinoma in these patients are discussed.

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Zusammenfassung Chromosomenpräparationen von 16 Patienten mit Colitis ulcerosa zeigten eine signifikante Vermehrung struktureller Chromosomenanomalien im Vergleich mit den Kontrollen. Das auffälligste Ergebnis war die hohe Häufigkeit von Isochromatidenbrüchen (7,1% der Mitosen bei Patienten, 0,6% bei Kontrollen). Chromatidenbrüche sowie gaps einer oder beider Chromatiden sowie azentrische Fragmente und morphologisch abnorme Chromosomen waren ebenfalls vermehrt. Die möglichen Ursachen der Chromosomenbrüchigkeit und ihre möglichen Beziehungen zu der hohen Häufigkeit des Coloncarcinoms bei diesen Patienten werden diskutiert.

     

An excess of mental retardation and/or congenital malformations in carriers of reciprocal translocations. A difficult and delicate problem in genetic counseling

Excess of mental retardation and/or congenital malformations in reciprocal translocations in man. A difficult problem in genetic counselling: In this report the Leuven experience (1970-1984) on reciprocal translocations is summarized. A total number of 154 unrelated index-patients, carriers of different types of reciprocal translocations, and their families were investigated. The excess of MR/CM in de novo and familial balanced translocation carriers is illustrated and discussed.     

Chromosome 22q11 deletions in patients with selected outflow tract malformations

The incidence of 22q11 deletions and its effect on the phenotype were established in 170 patients with selected outflow tract malformations and transposition of the great arteries (conotruncal defects). Cases were seen both prospectively and retrospectively. All patients had a dysmorphological evaluation by the clinical geneticist and a cytogenetic analysis including FISH analysis for 22q11 deletions. A chromosomal abnormality was present in 29 patients, including a 22q11 deletion in 22/170 patients (13%). The 22q11 deletion was found in 11% of tetralogy of Fallot, in 11% of pulmonary atresia and VSD, in 44% of pulmonary atresia. VSD and collateral arteries, in 20% of truncus arteriosus, in 60% of interrupted aortic arch and in 25% patients with aberrant subclavian artery. They were absent in double outlet right ventricle or in transposition of the great arteries. No parental deletion was found. All patients had clinical characteristics of the velocardiofacial syndrome. This study confirms a high incidence of chromosome 22q11 deletions in patients with selected outflow tract malformations, with great clinical impact for further management and genetic counseling.     

Chromosome studies in 14 patients with disseminated sclerosis

Summary Short term lymphocyte cultures were performed in 14 patients with disseminated sclerosis. The karyotype of all patients was normal, but the frequency of structural chromosome aberrations was increased as compared to 10 healthy controls of same age. There were chromatid type aberrations including gaps and breaks of one or both chromatids and chromosome type aberrations such as acentric fragments dicentis, rings and other abnormal chromosomes. These results confirm the findings of Khondkarian et al. (1967).

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Zusammenfassung Bei 14 Patienten mit multipler Sklerose wurden kurzfristige Lymphocytenkulturen durchgeführt. Alle Patienten hatten ein normales Karyogramm, Strukturanomalien waren jedoch häufiger als bei den 10 gesunden Kontrollpersonen gleichen Alters. Sie bestanden aus Gaps und Brüchen eines oder beider Chromatiden, azentrischen Fragmenten, dizentrischen Chromosomen, Ringen und anderen anormalen Chromosomen. Diese Ergebnisse bestätigen die Befunde von Khondkarian et al. (1967).

     

A new syndrome: multiple congenital abnormalities and mental retardation in two brothers

In this report we present two brothers with abnormal neurological development, hypotonia, short stature, pylorus stenosis, pectus excavatum, brachycephaly due to craniosynostosis, frontal bossing, depressed nasal bridge, high arched-wide palate, downslant palpebral fissures, low-set, large ears, thin upper lip and bilateral cryptorchidism. The brothers were born to a couple of second cousins and were the third and fourth pregnancies of the mother. The father, the mother and the eldest sibling were phenotypically and chromosomally normal. The clinical findings of the brothers were found to be similar. These clinical findings were compared with syndromes showing some of the symptoms, namely Apert, FG, Floating-Harbor, Shprintzen-Goldberg and Rett Syndromes. However, when the findings were detailed, we observed that they did not match completely any of the syndromes in a discernable way. The MECP2 gene mutation was analysed because of mental retardation, poor neurological evolution and large ears, but no mutation was found. So these cases are presented as a new syndrome with apparent autosomal recessive inheritance.     

Clinical genealogical and molecular genetic study of patients with mental retardation

The results of clinical, genealogical, cytogenetic and molecular genetic studies of 113 patients from 96 families with different forms of mental retardation from Ukraine are presented. This study was held as part of the CHERISH project of the 7-th Framework Program. The aim of the project is to improve diagnostics of mental retardation in children in Eastern Europe and Central Asia through detailed analysis of known chromosomal and gene's aberrations and to find the new gene-candidates that cause mental retardation. All patients have normal chromosome number (46XY or 46XX). The cases with fragile-X syndrome were eliminated using molecular genetic methods. Genome rearrangements were found among 28 patients using cytogenetic analysis, multiplex ligation-dependent probe amplification (MLPA analysis) ofsubtelomeric regions and array-based comparative genomic hybridisation (array CGH screening). In 10 cases known pathogenic CNV's were identified, 11 cases are unknown aberrations; their pathogenicity is being determined. The rest cases are known nonpathogenic gene rearrangements. Obtained results show the strong genetic heterogeneity of hereditary forms of mental retardation. The further studies will allow to identificate genes candidates and certain mutations in these genes that may be associated with this pathology.     

Possible excess of mental handicap and congenital malformations in autosomal reciprocal translocations.

The most pertinent data of the 32 cases of reciprocal autosomal translocations detected in the laboratory since the initiation of the banding-techniques are summarized. One third of these balanced translocations were detected in patients presenting with mental handicap and/or malformative symptoms.     

Distraction osteogenesis for obstructive apneas in patients with congenital craniofacial malformations

Infants with congenital craniofacial malformations often have associated severe mandibular hypoplasia causing obstruction of the hypopharynx by retroposition of the base of the tongue into the posterior pharyngeal airway. Management depends on the severity of the airway obstruction. Most cases can be managed by prone positioning until the infant outgrows the problem at 3 to 6 months of age. In more critical cases, monitoring of oxygen saturation, temporary placement of a nasopharyngeal tube, and placement of an endotracheal tube will be useful procedures. Tracheotomy is an effective method for more severe cases, but longstanding tracheotomies result in high morbidity and occasional mortality. Mandibular distraction was performed in seven patients, ranging in age from 1 to 18 months, with critical obstructive apnea secondary to mandibular hypoplasia characterized by an apnea/hypopnea index greater than 20 apneas per hour and oxygen saturation below 80 percent. Two patients were tracheotomized previously. Mandibular lengthening, from 16 to 25 mm on the left side and from 10 to 22 mm on the right, was achieved in 21 to 25 days. Improvement of airway obstruction parameters was measured on polysomnograms and lateral cephalograms. Mandibular lengthening by gradual distraction is a successful method for young patients with severe mandibular hypoplasia causing critical obstructive apneas. Avoidance of tracheotomy or early decannulation in previously tracheotomized patients is a great advantage for patients with congenital craniofacial malformation.     

MECP2 mutation in male patients with non-specific X-linked mental retardation

In contrast to the preponderance of affected males in families with X-linked mental retardation, Rett syndrome (RTT) is a neurological disorder occurring almost exclusively in females. The near complete absence of affected males in RTT families has been explained by the lethal effect of an X-linked gene mutation in hemizygous affected males. We report here on a novel mutation (A140V) in the MECP2 gene detected in one female with mild mental retardation. In a family study, the A140V mutation was found to segregate in the affected daughter and in four adult sons with severe mental retardation. These results indicate that MECP2 mutations are not necessarily lethal in males and that they can be causative of non-specific X-linked mental retardation.