Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.

BACKGROUND: Haploinsufficiency of the gene encoding for transcription factor 4 (TCF4) was recently identified as the underlying cause of Pitt-Hopkins syndrome (PTHS), an underdiagnosed mental-retardation syndrome characterised by a distinct facial gestalt, breathing anomalies and severe mental retardation. METHODS: TCF4 mutational analysis was performed in 117 patients with PTHS-like features. RESULTS: In total, 16 novel mutations were identified. All of these proven patients were severely mentally retarded and showed a distinct facial gestalt. In addition, 56% had breathing anomalies, 56% had microcephaly, 38% had seizures and 44% had MRI anomalies. CONCLUSION: This study provides further evidence of the mutational and clinical spectrum of PTHS and confirms its important role in the differential diagnosis of severe mental retardation.

Partial trisomy of long arm of chromosome 4 as a result of dir dup (4)(q27q31.3) de novo.

The phenotype of a girl at age of 12 years with a partial trisomy 4q caused by unique direct duplication 4q27 --> q31.3 included the thick, broad and straight eyebrows, upward slanting palpebral fissures, a deep-set eyes, narrow bridge and long back of the nose, flattened philtrum columns, narrow of vermilion borders of both upper and lower lips, protrusion of maxillary alveolar processus and anterior teeth together with shortened and posteriorly situated mandible, malocclusion corresponding with II class of Angle and long fingers, narrowing towards distal phalanges has been described. Further investigations are needed to delineate the clinical spectrum of features essential for partial trisomy 4q.

A natural history of a child with monosomy 5p syndrome (Cat-cry/Cri-du-chat syndrome) during the 18 years of follow-up.

A record of a natural history of a long-term case study devoted to monosomy 5p (Cat-cry/Cri-du-chat) syndrome has been described rarely. Knowledge on the range of the changes in phenotype attributable to advancing age can be useful in clinical diagnosis of monosomy 5p at the different developmental stages, including adolescence, as well in prognosis for genetic counseling. In this case a detailed analysis of the morphologic phenotype in a girl with del(5)(p13.3) observed from 4 months to 18 years of age is reported. The comparative analysis of the girl's phenotype in different developmental stages has revealed that microcephaly, flat occipital region, face asymmetry, wide spaced palpebral fissures, epicanthic folds, small mouth fissure, thin mucous lip, small and low set ears and short IV metacarpals has not changed with advancing age. However, facial asymmetry was more evident, frontal tubers were less prominent, nasal root and back became prominent nasal back became elongated, the subnasal region was shorter and marked malocclusion appeared.

Physical and developmental phenotype analyses in a boy with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) is a rare genetic condition with characteristic facial traits, organ malformations, functional impairment and developmental delay due to partial short arm monosomy of chromosome 4. Although several hundreds of cases have been published to date, a systematic collection of its clinical symptoms and anthropological traits is missing in the literature, and reports on abilities and needs of children with WHS are scanty. Results of detailed physical and developmental phenotype analyses in a 1 10/12-year-old boy with monosomy 4p15.2-pter are presented. Physical analyses were based on systematic data acquisition. They disclosed a total of 32 clinical symptoms and 46 anthropological traits. Developmental analyses were based on the child's interactive play in an environment structured according to Montessori principles. They disclosed a total of 44 abilities and a number of needs to be satisfied by the environment for the support of the child's psychic and intellectual growth. While the physical phenotype is important for the diagnostic process, the developmental phenotype is essential for parental counseling.

XYY syndrome and acute myeloblastic leukemia.

A 69-year-old man with hypogonadism was found to have a 47,XYY karyotype. Clinical and laboratory data revealed acute nonlymphocytic leukemia (ANLL) of the M2 type. The association between the XYY and ANLL-M2 is most likely accidental coincidence.

Immortalization and characterization of Nijmegen Breakage syndrome fibroblasts.

Nijmegen Breakage Syndrome (NBS) is a very rare autosomal recessive chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency and a high incidence of malignancies. Cells from NBS patients are hypersensitive to ionizing radiation (IR) and display radioresistant DNA synthesis (RDS). NBS is caused by mutations in the NBS1 gene on chromosome 8q21 encoding a protein called nibrin. This protein is a component of the hMre11/hRad50 protein complex, suggesting a defect in DNA double-strand break (DSB) repair and/or cell cycle checkpoint function in NBS cells. We established SV40 transformed, immortal NBS fibroblasts, from primary cells derived from a Polish patient, carrying the common founder mutation 657del5. Immortalized NBS cells, like primary cells, are X-ray sensitive (2-fold) and display RDS following IR. They show an increased sensitivity to bleomycin (3.5-fold), etoposide (2.5-fold), camptothecin (3-fold) and mitomycin C (1.5-fold), but normal sensitivity towards UV-C. Despite the clear hypersensitivity towards DSB-inducing agents, the overall rates of DSB-rejoining in NBS cells as measured by pulsed field gel electrophoresis were found to be very similar to those of wild type cells. This indicates that the X-ray sensitivity of NBS cells is not directly caused by an overt defect in DSB repair.

Sequence polymorphisms of the EDA and the DL genes in the patients with an X-linked and an autosomal forms of anhidrotic ectodermal dysplasia.

Oligodontia, sparse hair and deficiency of eccrine sweat glands are the features characteristic for the phenotype of the patients with anhidrotic ectodermal dysplasia (EDA). This syndrome is caused by mutations in the EDA or DL (downless) genes, encoding members of the TNF ligand and TNF receptor families, involved in the communication between the cells during embryonic life. We investigated both the coding and noncoding regions of the EDA and the DL genes in the patients exhibiting clinical symptoms of ectodermal dysplasia. Sequence analysis of the amplified fragments of the EDA gene revealed polymorphisms in introns three, four and five. The polymorphism in intron four was found in about 60% of the patients and was no more frequent than in the normal individuals. The two other polymorphisms were rare. Polymorphisms were also observed in exons 9 and 12 of the DL gene, but they did not alter the sequence of the protein product of the gene. Our results indicate that in order to accelerate screening for the mutations of the EDA gene and reduce the costs, the amplified fragments should not contain intronic sequences. However, in the case of the DL gene, where polymorphic sites are located in exons, restriction analysis with the use of appropriate enzyme should be conducted, but usually sequencing analysis could not be avoided.

Distortion products otoacoustic emissions in diagnosis of hearing loss in Down syndrome.

This study was carried out to investigate the features of hearing impairment in subjects with Down syndrome. Forty-seven children and 14 adults with Down syndrome were included in the study. In all cases, a complete otorhinolaryngological examination was performed, followed by audiological assessment. Depending on age, intellectual level and middle ear status the following examinations were performed: pure-tone 'play audiometry', tympanometry, acoustic reflex, auditory brain response (ABR) and distortion products otoacoustic emissions (DPOAE). The results were compared with age matched control groups. Among the group of children with Down syndrome, we have frequently found impairment of the conductive function of the middle ear which was expressed by pathological tympanometry. Tympanometry of B and C type was detected in 56% of ears. The amplitude of DPOAE was lower in children with Down syndrome than in the control group. This difference was more expressed in adults with Down syndrome. DPOAE examination results in subjects with Down syndrome without conductive hearing loss indicate early age related inner ear impairment.

[Sex chromosome aberrations in patients with menstruation disorders]. / Les aberrations des chromosomes sexuels chez les patientes présentant des troubles de la menstruation.

We studied 150 women with primary/secondary amenorrhea and/or oligomenorrhea; in 61 cases we found an abnormal karyotype (i.e. 40.7%): 51 cases in the first group of 110 patients with amenorrhea (i.e. 46%) and 10 cases in the second group of 40 patients with oligomenorrhea and/or secondary amenorrhea (i.e. 25%). The chromosome aberrations we found consisted in X aneuploidy, male karyotype and the different structural changes as mono- and dicentric X isochromosomes, dicentric, ring, deleted or inverted X chromosomes. Our results suggest a cytogenetic examination in patients with primary amenorrhea as well as in patients with oligomenorrhea and/or amenorrhea secundaria.

[Epilepsy in a child with ring chromosome 14]. / Padaczka u dziecka z chromosomem pierscieniowym 14.

A case of epilepsy in a child with ring chromosome 14 is presented. The typical features for the ring chromosome 14 syndrome in 5 years old girl i.e. psychomotor retardation, microcephaly, generalized hypotonia and some dysmorphism were found. Photoanthropometric method by Stengel-Rutkowski et al. for better estimate of dysmorphic pattern was used. It made possible to ascribe the features to partial deletion of the long arm segment of chromosome 14. Computer tomography revealed brain atrophy.

[Ultrasound diagnosis of four fetuses with Fraser syndrome during pregnancy]. / Ocena ultrasonograficzna czterech plodów z zespolem Frasera w okresie ciazy.

The authors present results of sonography analysis of four fetuses with Fraser syndrome. First woman had prenatal diagnosis by ultrasounds and ascites of fetus with polyhydramnion were diagnosed in two of her successive pregnancies. The second pregnant woman was observed by ultrasound and lack of kidney was detected. The third pregnant one was diagnosed at first trimester of pregnancy and results of sonography examination were at norm. After delivery, Fraser syndrome in all of these children was diagnosed. Findings on sonography included: ascites of fetus, polyhydramnion, hydrocephalus and nonvisualization of kidney. Sonography is more efficient in the diagnosis of Fraser syndrome in a fetus whose parents had had a previous affected child because of diverse anomalies were observed.

[Sister chromatid exchange in lymphocytes of drivers]. / Wymiany chromatyd siostrzanych w limfocytach u kierowców.

The frequencies of sister chromatid exchanges (SCE) in the group of 18 drivers were studied. The habit of cigarette smoking was considered. Mean values of SCE/metaphase between the group of drivers and the reference group and in the comparison with nonsmoking and smoking drivers did not show significant differences. Several cells with extremely high values of SCE (19-25) were observed in the group of smoking drivers.

[Familial translocation t (9;16) in a patient with irregular menstrual cycles]. / Rodzinna translokacja t (9;16) u pacjentki z nieregularnymi cyklami miesiaczkowymi.

In this report we present a family with identified carriers of unique reciprocal translocation t (9; 16) (q31; q13) detected through karyotyping of the patient with irregularity of menstrual cycles. Genetic risk for birth of a child with congenital anomalies was estimated as low (0.6%). However, risk for abortion was high. We suggest introducing cytogenetic studies in such cases.

[Spontaneous menstruation in patients with Turner syndrome in our observations]. / Samoistne miesiaczkowanie u pacjentek z zespolem Turnera--wlasne obserwacje.

OBJECTIVES: Patients with Turner syndrome (TS) may present a wide spectrum of gonadal function including spontaneous menstruation and fertility. DESIGN: The aim of our study was to present the patients with Turner syndrome (TS) with spontaneous menstruations considering specific karyotype and X-inactivation processes. MATERIALS AND METHODS: 5 women from group of 55 patients in age from 15 to 38 years with diagnosis of TS and gonadal function were found. Clinical analysis included the evaluation of spontaneous pubertal development and hormones levels. Cytogenetic analysis was performed on peripheral blood samples using GTG banding technique. X inactivation studies were done by dynamic RBG technique. RESULTS: In two patients with mosaic karyotype and predominant 46,XX line two pregnancies were observed. They had regular menses and normal sexual development. In one patient (karyotype: 45,X[2]/46,XX[98]) spontaneous abortions and premature birth were present. Second patient was (46,XX[245]/46,X,r(X)(p22q26)[5]) in pregnancy in this time. Another three patients menstruated irregularly. The menarche appeared later. The karyotypes were: 46,X,del(X)(p11.3) in two patients and 45,X[64]46,X,r(X) (p22q26)[18]/46,XX[4] in one. CONCLUSIONS: We conclude that spontaneous menstruations and possibility of pregnancy depend on specific karyotype in patients with TS.

[Risk of reproduction disorders in carriers of mutual chromosomal translocations, and methods for detection of translocation carriers]. / Ryzyko zaburzen reprodukcji u nosicieli translokacji chromosomowych wzajemnych a sposób wykrycia nosicielstwa translokacji.

It is believed that the method of detection of chromosomal translocation carrier state may be a prognostic factor for the risk of giving birth to an ill child with unbalanced karyotype. For verification of this view 30 families were studied which had balanced mutual translocations identified by means of GTG banding technique in the Genetics Laboratory of the Child's Health Centre. In each family the risk was estimated of the development of an undifferentiated karyotype in live born offspring and fetuses in the 2nd trimester of pregnancy using a method evolved by Stengel--Rutkowski et al. (1988). In the group of families identified by examination of a child with abnormalities the individual risk of development of an undifferentiated karyotype in a newborn was from 0.45% to 19.78% and in a fetus it was 4.5% to 46%. In the group of families identified by spontaneous abortion the risk in the newborns was from 0 to 7% and in the fetuses in 2nd trimester it was 0 to 35%, while in the families undergoing cytogenetic examinations for indications other than reproduction disturbances the risk of an unbalanced karyotype in the newborns was from 0 to 23%, and in the fetuses from 0 to 34%. Since in each group of families high-risk translocations were found, the used methods of preliminary estimation of the risk based on the used ways of family identification are open to reservations.

[Turner syndrome in a girl with marker chromosome in karyotype]. / Zespól Turnera u dziewczynki z chromosomem markerowym w kariotypie.

OBJECTIVES: There are suggestion, that Turner syndrome (TS) patients with mosaic karyotype for a Y-DNA-containing cell line are at risk of Y-induced gonadoblastoma. The TS patients in whom some or all cells contain a marker chromosome of unknown origin and those in whom there is clitoromegaly or other evident virillisation should be tested by FISH or PCR techniques. DESIGN: The aim of our study to present a TS girl with mosaic karyotype and marker chromosome, which origin from X chromosome was detected by FISH method. MATERIAL AND METHODS: 5-years old girl in whom TS was established. Clinical analysis included the full dysmorphic and clinical phenotype of TS. Chromosome analysis was performed on peripheral blood samples using routine cytogenetic methods and FISH technique. RESULTS: Clinical examination of girl showed many typical signs of TS besides of normal weight and length at birth and not typical for TS patients heart defect. First routine chromosome analysis, at age of 6 month, showed only 45,X cell line, Second study revealed mosaic karyotype with marker chromosome. FISH analysis for interphase nuclei and metaphase chromosomes using X centromere probe explained origin of marker from X chromosome. The karyotype was 45,X[155]/46,X,+mar[8].fish mar(X)(DXZ1+). CONCLUSION: Presence of marker chromosome in karyotype of patient with TS may modify their phenotype and it is a indication for molecular examination by FISH technique.

[Clinical examinations, chromosomal and molecular DNA in patients with Swyer syndrome]. / Badanie kliniczne, chromosomowe i molekularne DNA u pacjentek z zespolem swyera.

Two girls with Swyer syndrome (SS) were described. Diagnosis was established according to clinical data and ultrasound, laparoscope, histopathological, hormonal and cytogenetical examinations. One presents diagnostic possibilities followed advanced methods in genetics. The GTG and RBG high resolution bounding technique and replication analysis of short arms (Xp and Yp) were employed. Normal structure of end segments of X and Y chromosomes was mentioned. Molecular DNA analysis by polymerase chain reaction (PCR) did not find any mutation in SRY gene. Normal structure of this gene does not exclude possibility of SS existence. Our data implicates on the other mechanism of these disturbances.

[Genetic risk of families with t(1;2)(q42;q33) GTG, RHG, QFQ, FISH]. / Ryzyko genetyczne rodzin obciazonych translokacja chromosomowa t(1;2)(q42;q33) GTG, RHG, QFQ, FISH.

OBJECTIVES: A central concept in genetic counseling is the estimation of the probability of recurrence of unfavourable pregnancy outcomes (abortion, stillbirth and birth at malformed child). In case of chromosomal changes estimates are made on basis of segregation analyses in actual pedigree. If we have a few of pedigree members than risk estimate should be performed on basis combined our data and empiric data from literature. We present individual genetic risk for carriers of unique reciprocal translocation t(1;2)(q42;q33) detected through karyotyping of the patient with miscarriage. MATERIAL AND METHODS: The pedigree consisted 5 families of t(1;2)(q42;q33) carriers with 15 members of progeny was evaluated according to Stene and Stengel-Rutkowski. Cytogenetic analysis of persons of these families (7 persons) was performed on blood samples using GTG, RHG, QFQ and FISH techniques. Additional RCT pedigree analysis of Stengel-Rutkowski et at Collection, Polish Collection, Lituanian Collection, Bielorussian Collection and an available literature cases were performed. RESULTS: The translocation was classified as translocation at risk for double segment imbalances for trisomy 1q42-->qter together with monosomy 2q33-->qter or monosomy 1q42-->qter together with trisomy 2q33-->qter after 2:2 disjunction after adjacent-1 segregation of the meiotic chromosomes. Two improved risk values for RCT with segments 1q42-->qter, 2q33-->qter were obtained i.e. 6/44 (13.6% +/- 5.2%) and 4/20 (20% +/- 8.9%). The probability of occurrence for this translocation carriers was estimated as 7% (medium risk). On basis of direct analysis at presented pedigree a risk for miscarriage was estimated as 2/9. CONCLUSIONS: 1. Carrierships of t(1;2)(q42;q33) increased population risk value for unbalanced progeny at birth by 7% (medium risk) and for miscarriage 2/9. 2. Causative relation between presence of t(1;2)(q42;q33) and miscarriages is suggested. 3. Updated, new genetic risk values for RCT at risk for single segment 1q42-->qter imbalance is 6/44 (13.6% +/- 5.2%) at birth and for single segment 2q33-->qter imbalance is 4/20 (20% +/- 8.9%).

[Familial complex chromosome translocation of t(1;4;10)(q21.3;q27;q26.1) verified by FISH]. / Rodzinne wystepowanie zlozonej translokacji chromosomowej t (1;4;10) (q21.3;q27;q26.1) zweryfikowanej metoda FISH.

The inheritance complex chromosome translocation is a rare. A familial complex chromosome rearrangement t(1;4;10)(q21.3;q27;q26.1) involving three chromosomes ascertained due to four spontaneous abortions in phenotypically normal childless woman there is presented. Cytogenetic analysis according to classic banding techniques were verified by fluorescent in situ hybridization (FISH) technique.

[Pedigree analysis of childless families of reciprocal chromosome translocation carriers]. / Analiza rodowodowa bezdzietnych rodzin obciazonych nosicielstwem translokacji chromosomowych wzajemnych.

OBJECTIVES: Pedigree analysis of childless families of unique reciprocal chromosome translocation (RCT) carriers may be useful for clinical prognosis and genetic counselling. MATERIAL AND METHODS: The group 13 childless families of RCT carriers were detected. Cytogenetic analysis of RCT was performed on blood samples using GTG and RBG banding technique. RESULTS: Thirteen pedigrees were constructed on basis of 64 cytogenetic results and anamnestic data of 62 spontaneous abortions and 7 stillbirths. Familial RCT were found in ten families. In addition fourteen relatives of the RCT carriers have had healthy children. Further observations showed other three healthy children among progeny of eight families. Low risk for unbalanced progeny at birth were estimate in most families. CONCLUSION: Childless families of RCT carriers have possibility to have healthy offsprings. Spontaneous abortions are result of RCT carrierstrip.