CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder

Gilles de la Tourette syndrome (GTS) is a sporadic or inherited complex neuropsychiatric disorder characterized by involuntary motor and vocal tics. There is comorbidity with disorders like obsessive compulsive disorder and attention deficit hyperactivity disorder. Until now linkage analysis has pointed to a number of chromosomal locations, but has failed to identify a clear candidate gene(s). We have investigated a GTS family with a complex chromosomal insertion/translocation involving chromosomes 2 and 7. The affected father [46,XY,inv(2) (p23q22),ins(7;2) (q35-q36;p21p23)] and two affected children [46,XX,der(7)ins(7;2)(q35-q36;p21p23) and 46,XY,der(7)ins(7;2)(q35-q36;p213p23)] share a chromosome 2p21-p23 insertion on chromosome 7q35-q36, thereby interrupting the contactin-associated protein 2 gene (CNTNAP2). This gene encodes a membrane protein located in a specific compartment at the nodes of Ranvier of axons. We hypothesize that disruption or decreased expression of CNTNAP2 could lead to a disturbed distribution of the K(+) channels in the nervous system, thereby influencing conduction and/or repolarization of action potentials, causing unwanted actions or movements in GTS.     

Microphthalmia with linear skin defects syndrome (MLS): a male with a mosaic paracentric inversion of Xp

The microphthalmia with linear skin defects syndrome (MLS) is an X-linked dominant disorder with male lethality. In the majority of the patients reported, the MLS syndrome is caused by segmental monosomy of the Xp22.3 region. To date, five male patients with MLS and 46,XX karyotype ("XX males") have been described. Here we report on the first male case with MLS and an XY complement. The patient showed agenesis of the corpus callosum, histiocytoid cardiomyopathy, and lactic acidosis but no microphthalmia, and carried a mosaic subtle inversion of the short arm of the X chromosome in 15% of his peripheral blood lymphocytes, 46,Y,inv(X)(p22.13 approximately 22.2p22.32 approximately 22.33)[49]/46,XY[271]. By fluorescence IN SITU hybridization (FISH), we showed that YAC 225H10 spans the breakpoint in Xp22.3. End-sequencing and database analysis revealed a YAC insert of at least 416 kb containing the genes HCCS and AMELX, and exons 2-16 of ARHGAP6. Molecular cytogenetic data suggest that the Xp22.3 inversion breakpoint is located in intron 1 of ARHGAP6, the gene encoding the Rho GTPase activating protein 6. Future molecular studies in karyotypically normal female MLS patients to detect submicroscopic rearrangements including the ARHGAP6 gene as well as mutation screening of ARHGAP6 in patients with no obvious chromosomal rearrangements will clarify the role of this gene in MLS syndrome.     

Discrepancy between the fetus and extra-embryonic tissues in prenatally detected mosaic distal 5p deletion

Discrepancy between the fetus and extra-embryonic tissues in prenatally detected mosaic distal 5p deletion: We present clinical and cytogenetic data on a second-trimester fetus with mosaic del(5)(p15.1) and the extra-embryonic tissues with a normal karyotype. A 34-year-old woman, gravida 2, para 0, underwent genetic amniocentesis at 20 weeks' gestation because of advanced maternal age. Cytogenetic analysis of the cultured amniocytes revealed mosaicism for a distal 5p deletion, mos 46,XY,del(5)(p15.1)[4]/46,XY[26]. The pregnancy was terminated subsequently. Postnatally, the fetus displayed a triangular face, hypertelorism, epicanthal folds, low-set ears, and micrognathia. A karyotype of mos 46,XY,del(5)(pl 5.1)/46,XY was found in the liver, lungs, skin, and cord blood, whereas, the placenta, amnion, and umbilical cord had a karyotype of 46,XY. Our observation of fetoplacental, fetoamniotic, and fetoumbilical discrepancies shows a limitation of using placenta, amnion, and umbilical cord as confirmatory tools for prenatally detected mosaic distal 5p deletion. Our case also reinforces the notion that amniocentesis offers a more reliable diagnosis, compared to chorionic villus sampling.     

Embryonic testicular regression syndrome and severe mental retardation in sibs

The embryonic testicular regression syndrome associated with severe mental retardation is reported in three 46,XY sibs each of whom has a 46,XY chromosome complement. A fourth sib, a sister, also is severely retarded mentally; her chromosome complement is 46,XX. The 46,XY individuals, who were raised as females, presented varying degrees of genital ambiguity, indicating that their gonadal activities had been arrested at different times during embryogenesis. No trace of gonadal tissue could be found in either patient. The coincidence of the embryonic testicular regression syndrome and severe mental retardation in the same sibship is discussed.     

46,XY phenotypic male with focal segmental glomerulosclerosis caused by the WT1 splice site mutation

OBJECTIVE: Frasier syndrome is characterized by progressive glomerulopathy due to nonspecific focal and segmental glomerulosclerosis (FSGS), 46,XY sex reversal and the development of gonadoblastoma from dysgenetic gonads. Donor splice site heterozygous mutations in intron 9 of the Wilms' tumor gene (WT1) cause this disease. We investigated whether WT1 mutations showed clinical heterogeneity. PATIENTS AND METHODS: A 6-year-old phenotypic boy was diagnosed as having FSGS. His karyotype was 46,XY. Gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests revealed normal luteinizing hormone, follicle-stimulating hormone and testosterone responses. The other patient was a 7-year-old 46,XY female with FSGS. Prophylactic gonadectomy was performed and gonadoblastoma was found. By polymerase chain reaction and direct sequencing, WT1 was analyzed in these patients. RESULTS AND CONCLUSION: Both patients had IVS9 + 5G-->A in intron 9 of the WT1. Our study indicates a normal 46,XY phenotypic male patient with FSGS. The phenotypic variations of the WT1 splice site mutations are further expanded.     

High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction

Our goal in the present work was to determine whether male patients with untreated hypogonadism have an increased risk of developing rheumatic/autoimmune disease (RAD), and, if so, whether there is a relation to the type of hypogonadism. We carried out neuroendocrine, genetic, and rheumatologic investigations in 13 such patients and 10 healthy male 46,XY normogonadic control subjects. Age and body mass index were similar in the two groups. Nine of the 13 patients had hypergonadotropic hypogonadism (five of whom had Klinefelter's syndrome [karyotype 47,XXY]) and 4 of the 13 had hypogonadotropic hypogonadism (46,XY). Of these last four, two had Kallmann's syndrome and two had idiopathic cryptorchidism.     

Partial androgen receptor deficiency and mixed gonadal dysgenesis in Drash syndrome

Summary Drash syndrome associates a nephropathy characterized by a diffuse mesangial sclerosis of early onset, Wilms tumor, and male pseudohermaphroditism (MPH). A patient with Drash syndrome is reported with the following: karyotype 46,XY, external genitalia near normal female, mixed gonadal dysgenesis, severe androgen receptor deficiency demonstrated for the first time in this syndrome. The possibility of a common genetic denominator with the del 11p13 WAGR complex is suggested. MPH/nephroblastoma association is common. Androgen receptor deficiency has been observed in one case of each syndrome, respectively.     

Lenz microphthalmia syndrome: three additional cases with rare associated anomalies

Lenz microphthalmia syndrome is an extremely rare inherited disorder, characterized by unilateral or bilateral microphthalmia. In rare cases affected patients exhibit complete absence of eye or blepharoptosis resulting in visual impairment. Additional physical abnormalities are often associated with this disorder, orofacial, digital, skeletal and urogenital abnormalities. Here we present three cases of Lenz microphthalmia with additional manifestations: two brothers of first cousin mating, the elder one has bilateral congenital cataract which is a rare ophthalmological finding in this syndrome and a third case who presented to us because of ambiguous genitalia. She was 12 years old, and reared as a female. Chromosomal analysis showed 46,XY karyotype, and hormonal studies indicated 5-alpha reductase deficiency. This is the first report of the association of 5-alpha reductase deficiency with Lenz microphthalmia syndrome.     

Mosaic down syndrome with a marker: molecular cytogenetic characterization of the marker chromosome

Down syndrome is a complex disorder characterized by well defined and distinctive phenotypic features. Approximately 2-3% of all live-born Down individuals are mosaics. Here we report a boy with suspected Down syndrome showing mosaicism for two different cell lines where one cell line is unexpected. The cytogenetic analysis by G-banding revealed a karyotype of 47 XY+21 [20]/46,X+marker [30]. Further, molecular cytogenetic analysis with spectral karyotyping identified the marker as a derivative of Y chromosome. The delineation of Y chromosomal DNA was done by quantitative real-time PCR and aneuploidy detection by quantitative fluorescence PCR. The Y-short tandem repeats typing was performed to estimate the variation in quantity as well as to find out the extent of deletion on Y chromosome using STR markers. Fluorescence in situ hybridization using Y centromeric probe was also performed to confirm the origin of the Y marker. Further fine mapping of the marker was carried out with three bacterial artificial chromosome clones RP11-20H21, RP11-375P13, RP11-71M14, which defined the hypothetical position of the deletion. In our study we defined the extent of deletion of the marker chromosome and also discussed it in relation with mosaicism. This is the first report of mosaic Down syndrome combined with a second de novo mosaic marker derived from the Y chromosome.     

Investigation of the ZFY gene in XX true hermaphroditism and Swyer syndrome

Summary Four patients with 46,XX true hermaphroditism and one patient with 46,XY pure gonadal dysgenesis (Swyer syndrome) were analyzed with a Y chromosome-derived probe that detects a specific fragment on the short arm of the Y chromosome in the putative testicle-determining region and also a fragment on the short arm of the X chromosome. Normal males and females, an individual with Turner syndrome, and patients with various causes of anomalous gonadal differentiation accompanied by cytogenetically present Y chromosome were used as controls. The Y-specific fragment was not detected in any of the persons with 46,XX true hermaphroditism. However, this fragment was positive in the 46,XY female and in all Y-bearing patients. Cytogenetic and molecular absence of the ZFY sequence in 46,XX true hermaphrodites calls for explanations other than the classic embryogenie theory. The absence of testicular differentiation in the ZFY-positive XY female evidences functionally altered sex determination or, alternatively, defective gonadal receptors.     

Osteosarcoma arising from osteochondroma of the tibia: case report and cytogenetic findings

Osteochondroma is a cartilage capped benign tumor developing mainly at the juxta-epiphyseal region of long bones. The rate of malignant transformation, mainly into chondrosarcoma, is estimated to be less than 1-3%. Transformation into osteosarcoma is very rare and has been reported only thirteen times. There is little information on treatment and outcome. We report the case of a secondary osteosarcoma arising in the left tibia of a 23-year-old male, 10 years after the initial diagnosis of osteochondroma and after two partial resections. Malignant transformation occurred at the stalk and not at the cartilage cap, as would normally be expected. Chromosome banding analysis revealed the karyotype: 46,XY, t(3;13)(q21;q34) [2]/46,XY [18]. Records from additional cases will help determine the parameters that define these rare secondary bone lesions.     

New cytogenetic variant of Orbeli's syndrome (46,XY/45,XY,-D/46,XY,Dq+)

Summary A newborn child with multiple congenital abnormalities, including severe hypoplastic thumb and atresia recti, is described. The cytogenetic analysis revealed a mosaicism 46,XY/45,XY,-D/46,XY,Dq+. The combination of mosaic D-monosomy and two cardinal features of 13q-syndrome give the possibility to consider this case as new cytogenetical variant of the Orbeli's syndrome.

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Zusammenfassung Ein Neugeborenes mit multiplen kongenitalen Abnormitäten einschließ-lich erheblicher Hypoplasie der Daumen und Atresia recti wird beschrieben. Die cytogenetische Analyse ergab ein Mosaik 46,XY/45,XY,-D/46,XY,Dq+ Die Kombination von Mosaik D-Monosomie und den zwei Hauptsymptomen des 13q-Syndroms läßt in diesem Falle eine neue cytogenetische Variante des Orbeli-Syndroms vermuten.

     

Paracentric inversion in the short arm of chromosome 1. Report of a family and review of the literature

In general, carriers of paracentric inversions are phenotypically normal, although individual reports describe like occurrence of infertility, miscarriages and mental retardation in inversion carriers. We present a family with paracentric inversion of 1p [karyotype: 46,XY/XY, inv(1)(p13.2p36.2)] in 7 of the 12 investigated family members. The index patient, a four year-old boy was referred for motor and mental retardation. The possible relationship between the paracentric inversion and the MR/MCA syndrome in the index patient of this family is briefly discussed.     

A large deletion/insertion-induced frameshift mutation of the androgen receptor gene in a family with a familial complete androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disorder with a normal 46, XY karyotype caused by abnormality of the androgen receptor (AR) gene. One Chinese family consisting of the proband and 5 other members with complete androgen insensitivity syndrome (CAIS) was investigated. Mutation analysis by DNA sequencing on all 8 exons and flanking intron regions of the AR gene revealed a unique large deletion/insertion mutation in the family. A 287 bp deletion and 77 bp insertion (c.933_1219delins77) mutation at codon 312 resulted in a frameshift which caused a premature stop (p.Phe312Aspfs*7) of polypeptide formation. The proband's mother and grandmother were heterozygous for the mutant allele. The proband's father, uncle and grandfather have the normal allele. From the pedigree constructed from mutational analysis of the family, it is revealed that the probably pathogenic mutation comes from the maternal side.     

Meiotic studies of a 38,XY/39,XXY mosaic boar

Klinefelter's syndrome (KS) is the most common sex chromosome abnormality identified in human males. This syndrome is generally associated with infertility. Men with KS may have a 47,XXY or a 46,XY/47,XXY karyotype. Studies carried out in humans and mice suggest that only XY cells are able to enter and complete meiosis. These cells could originate from the XY cells present in mosaic patients or from XXY cells that have lost one X chromosome. In pig, only 3 cases of pure 39,XXY have been reported until now, and no meiotic analysis was carried out. For the first time in pig species we report the analysis of a 38,XY/39,XXY boar and describe the origin of the supplementary X chromosome and the chromosomal constitutions of the germ and Sertoli cells.     

Molecular cytogenetic evaluation in a patient with a translocation (3;21) associated with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES)

Blepharophimosis, ptosis, epicanthus inversus syndrome type I (BPES; OMIM 110100) is an autosomal dominant disorder affecting craniofacial development and ovarian function. We have identified a patient with BPES who carried a de novo reciprocal translocation [46, XX,t(3;21)(q23;q22.1)]. Fluorescence in situ hybridization analysis at band 3q23 using probes derived from BAC 175G20 (Research Genetics), PACs 108L15 and 169C10 (RPCI1), and cosmids AC174D4, AC68D3, AC44F5, and AC125C5 (Lawrence Livermore National Laboratory) was performed. The patient's breakpoint was found to lie within the overlapping region of the BAC and PACs but centromeric to all the cosmids. However, a 10.5-kb BamHI-digested fragment, common to the BAC and PAC clones, was shown to cross the breakpoint. The results have placed our patient's breakpoint proximal to that of the previously reported patient [46,XY,t(3;4)(q23;p15.2)] and within a 10.5-kb interval. This is the second patient in which a breakpoint was refined by molecular cytogenetics. Our findings emphasize the significance of this region for BPES.     

45,X/46,XY qh? Karyotype and Aspermia. A case report

A 41-years old male with short stature, abnormal male sex differentiation, aspermia and schizoid character disorder is described. The patient was studied from clinical, endocrinological and genetic perspectives. Cytogenetical analysis revealed a chromosomic mosaicism formed by two normal lines 45X and 46,XY qh^?. Molecular studies on AZF region evidenced that it was conserved. The correlation of the symptoms with the cytogenetic finding is discussed.     

A successful second delivery outcome using refrozen thawed testicular sperm from an infertile male true hermaphrodite with a 46, XX/46, XY karyotype: case report

We report a successful second delivery of a healthy infant fathered using refrozen thawed testicular sperm from an infertile male chimera. We also examined sex chromosome distribution of the seminiferous tubule. Intracytoplasmic sperm injection (ICSI) was performed using the remaining refrozen testicular sperm, which had been stored during the first treatment. Biopsied testicular cells were examined by fluorescence in situ hybridization (FISH) and the peripheral lymphocyte karyotype was tested using a G-band. Following ICSI, a second pregnancy was established, and a healthy girl was successfully delivered at 40 gestational weeks without complications. Although the husband’s lymphocyte chromosomal analysis revealed a 46, XX [28]/46, XY [2] karyotype, the seminiferous tubule cells on histological examination by FISH were chimeric sex chromosome type XX [18]/XY [82]. In conclusion, this is a very rare case report of a successful subsequent delivery of a healthy infant (46, XX) from an infertile true hermaphrodite (46, XX/46, XY) using refrozen thawed testicular sperm. The seminiferous tubule cells’ karyotype ratio differed from that of the lymphocytes.     

Mosaic 45,xy,-21/46,xy in a child with G deletion syndrome I.

A mosaic 45,XY,-21/46,XY was found in a boy with G deletion syndrome I who showed microcephaly, downward, antimongoloid slanted eyes, micrognathism, large, low set ears, small penis and bilateral inguinoscrotal hernia.