A patient with 47, XYY mosaic karyotype and congenital absence of bilateral vas deferens: a case report and literature review.

BACKGROUND: The incidence of 47, XYY syndrome in live-born male infants is 1/1000. Due to its variable clinical symptoms, the diagnosis is easy to miss. The incidence of congenital bilateral absence of the vas deferens (CBAVD) in infertile men is 1-2%. The main cause is the mutation of CFTR and ADGAG2 genes. CASE PRESENTATION: The patient was a 33-year-old man who visited a doctor 5 years ago due to infertility. The investigation revealed that the patient's secondary sexual characteristics, testicular, and penis development were normal, and there was no gynecomastia, but the bilateral vas deferens and epididymis were not palpable. Transrectal ultrasound showed that the left seminal vesicle was missing, and the right seminal vesicle was atrophied. No abnormality was observed in Y chromosome microdeletion. Karyotype analysis indicated that the patient was 46, XY/47, XYY mosaic. Genetic testing found heterozygous mutations at two sites of CFTR (c263T > G and c2249C > T). CONCLUSIONS: Herein, we report the rare case of a male patient with clinical manifestations of infertility, chromosome 46, XY/47, XXY mosaic type, simultaneously manifested as the absence of bilateral vas deferens. Two pathogenic heterozygous CFTR gene mutations were found. Given the low genetic risk of the disease, we recommend that patients undergo intracytoplasmic sperm injection (ICSI) for fertility assessment.

Decreased levels of γ-aminobutyric acid in temporal lobe of children with 47,XYY syndrome.

BACKGROUND: 47,XYY syndrome (XYY) is a male sex chromosome disorder where subjects have one X chromosome and two copies of the Y chromosome. XYY is associated with a physical phenotype and carries increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Imbalance of excitation and inhibition has been proposed as a putative biological basis of disorders such as ASD [1-3] and several studies have reported atypical brain γ-aminobutyric acid (GABA) levels in this population. Given the male preponderance in the prevalence of ASD, the unique presence of the Y chromosome in males leads to the intriguing possibility of investigating boys with XYY syndrome as a model of excess Y-chromosome genes. METHOD: In this study, we investigated the associations of genotype and clinical phenotype with levels of GABA, estimated by regionally localized edited magnetic resonance spectroscopy in boys with 47, XYY syndrome compared to age-matched typically developing (XY) peers. RESULTS: Overall, we observed a decrease in GABA levels in XYY vs. XY, which appeared more significant in the left compared to the right hemisphere. There was no additional significant modulation of GABA levels in XYY according to presence/absence of ASD diagnosis. Interestingly, a positive correlation between bilateral GABA levels and testosterone levels was observed in pubescent XY boys that was not observed in XYY. CONCLUSION: The inhibitory neurotransmitter GABA appears to be reduced in boys with 47,XYY, especially in the left hemisphere. Further, the typical association between GABA and testosterone levels, observed in older typically developing control boys was not evident in boys with 47,XYY.

Testicular function in boys with 47,XYY and relationship to phenotype.

An additional Y chromosome occurs in ~1 in 1,000 males, resulting in the karyotype 47,XYY. The phenotype includes tall stature, hypotonia, neuropsychiatric comorbidities, and an increased risk of infertility in adulthood. Little is known about testicular function in childhood and adolescence in 47,XYY. This cross-sectional study aimed to assess testicular function serum biomarkers, including total testosterone, inhibin B, and anti-mullerian hormone (AMH), in 82 boys with XYY (11.3 ± 3.8 years) compared with 66 male controls (11.6 ± 3.8 years). The association of testicular hormones with physical features, neuropsychological phenotype, and magnetoencephalography (MEG) was assessed with multiple linear regression models. Results indicate males with XYY have significantly lower inhibin B (median 84 pg/ml vs. 109 pg/ml, p = .004) and higher AMH (median 41 ng/ml vs. 29 ng/ml, p = .011); however, testosterone, testicular volume, and stretched penile length were not different from controls. In the exploratory analysis of relationships between hormone concentrations and phenotypic assessments, higher inhibin B concentrations were positively correlated with lower BMI and better cognitive, academic, and behavioral outcomes in the XYY group. Testosterone concentrations were positively associated with better behavioral outcomes in boys with XYY. Higher testosterone and inhibin B concentrations were also associated with shorter auditory latencies measured using magnetoencephalography (MEG) in XYY. With a few exceptions, testicular hormones were not associated with phenotypic outcomes in controls. In conclusion, there is evidence of subtle impaired testicular function in boys with XYY and a newly described relationship between measures of testicular function and some aspects of the XYY phenotype.

A case of a parthenogenetic 46,XX/46,XY chimera presenting ambiguous genitalia.

Sex-chromosome discordant chimerism (XX/XY chimerism) is a rare chromosomal disorder in humans. We report a boy with ambiguous genitalia and hypospadias, showing 46,XY[26]/46,XX[4] in peripheral blood cells. To clarify the mechanism of how this chimerism took place, we carried out whole-genome genotyping using a SNP array and microsatellite analysis. The B-allele frequency of the SNP array showed a mixture of three and five allele combinations, which excluded mosaicism but not chimerism, and suggested the fusion of two embryos or a shared parental haplotype between the two parental cells. All microsatellite markers showed a single maternal allele. From these results, we concluded that this XX/XY chimera is composed of two different paternal alleles and a single duplicated maternal genome. This XX/XY chimera likely arose from a diploid maternal cell that was formed via endoduplication of the maternal genome just before fertilization, being fertilized with both X and Y sperm.

Severe myelinopathy in 49,XXXXY syndrome.

49,XXXXY is a rare aneuploidy with neuroanatomic findings scarcely reported in the literature. Given the fact that many of its phenotypic characteristics are similar to Klinefelter patients, 49,XXXXY has been treated as a variant of Klinefelter syndrome in the past. Newer studies have shown that intellectual disabilities and cardiac sequelae are more common in 49,XXXXY making the need for more precise characterization of the disorder essential. Prior case studies have demonstrated focal (and to a lesser extent confluent) white abnormalities as well as enlarged perivascular cysts (often in clustered arrangements) in the brains of these patients, but high resolution magnetic resonance images of severe myelinopathy are infrequently documented. Presented here is an exceptional manifestation of this rare disease with substantial findings in the brain exhibiting both confluent white matter changes and diffuse perivascular cysts. Cases such as this one serve to expand the differential considerations for confluent dysmyelinating disease and improve diagnostic efficacy.

Pregnancy outcomes in prenatally diagnosed 47, XXX and 47, XYY syndromes: a 30-year French, retrospective, multicentre study.

OBJECTIVE: Sex chromosome aneuploidies are frequently detected fortuitously in a prenatal diagnosis. Most cases of 47, XXX and 47, XYY syndromes are diagnosed in this context, and parents are thus faced with an unexpected situation. The objective of the present study was to characterize a French cohort of prenatally diagnosed cases of 47, XXX and 47, XYY and to evaluate the termination of pregnancy (TOP) rate before and after France's implementation of multidisciplinary centres for prenatal diagnosis in 1997. METHODS: This retrospective study identified respectively 291 and 175 cases of prenatally diagnosed 47, XXX and 47, XYY between 1976 and 2012. For each case, the indication, maternal age, karyotype and outcome were recorded. RESULTS: Most diagnoses of the two conditions were fortuitous. The occurrence of 47, XXX was associated with advanced maternal age. The overall TOP rate was higher for 47, XXX (22.9%) than for 47, XYY (14.6%), although this difference was not statistically significant. However, the TOP rates fell significantly after 1997 (from 41.1% to 11.8% for 47, XXX and from 25.8% to 6.7% for 47, XYY). CONCLUSION: The TOP rates after prenatal diagnoses of 47, XXX and 47, XYY fell significantly after 1997, following France's implementation of multidisciplinary centres for prenatal diagnosis. © 2016 John Wiley & Sons, Ltd.

Prenatal diagnosis of an epignathus associated with a 49,XXXXY karyotype--a case report.

BACKGROUND: Epignathus is a rare form of congenital teratoma, originating from the base of the skull, most commonly the hard palate, or mandible. It has been associated with a poor prognosis due to complications including polyhydramnios and respiratory compromise at birth as a consequence of upper airway obstructions. It is usually not associated with chromosomal aberrations. We present a case of prenatally diagnosed epignathus associated with a gonosomal pentasomy 49,XXXXY. CASE: A 34-year-old gravida 1, para 0 was referred to our unit with a sonographically suspected gastroschisis at 26+6 weeks' gestation. A detailed ultrasound scan revealed a large mixed echogenic mass seen in continuation with the mouth in the midline. Based on the appearance, an epignathus was suspected. No other fetal anomalies were detected. Karyotyping showed a 49,XXXXY karyotype of the fetus. The couple decided to continue the pregnancy after detailed counseling about results and prognosis. A cesarean section was necessary and performed at 29+0 weeks' gestation due to a pathological Doppler and cardiotocogram. Because of the enormous epignathus intubation of the newborn was not possible. A tracheostomy was performed for ventilation and oxygenation, which failed and the newborn died 30 min after birth. CONCLUSION: Prenatal diagnosis by ultrasound has improved perinatal management. This should include assessment of the tumor size and spread in order to establish an accurate prognosis and to anticipate likely problems which are to be encountered during pregnancy or at the time of delivery. To our knowledge, this is the first reported case of a prenatally diagnosed epignathus with a gonosomal pentasomy 49,XXXXY.

X pentasomy in an intracytoplasmic sperm injection pregnancy detected by nuchal translucency testing.

Althoughmaternally derived X pentasomy following intracytoplasmic sperm injection (ICSI) is rare, prenatal detection of a case offers insight into etiology and diagnosis. A 29-year-old gravida 1 whose pregnancy resulted from ICSI was referred for ultrasound screening at 11 weeks' gestation. Nuchal translucency thickness was 3.2 mm, and the fetal nasal bone was absent. Subsequent evaluation revealed karyotype 49,XXXXX. DNA microsatellite analysis showed the extra X chromosomes were maternal in origin. Termination of pregnancy was performed at 15 weeks. Because of the increased risk of sex chromosomal abnormalities in ICSI pregnancies, patients should be counseled prior to fertilization and standard prenatal care should include nuchal translucency measurement and any other elements necessary for indicated pregnancies to obtain a diagnosis.

Congenital radioulnar synostosis, azoospermia, and pseudodicentric Y chromosome.

Congenital radioulnar synostosis is a rare skeletal defect associated with certain chromosomal abnormalities. We describe the first report of its occurrence in association with a pseudodicentric Y chromosome in a 27-year-old man with azoospermia and testicular dysfunction.

The craniofacial complex in 47, XXX females.

A study of the craniofacial complex in four 47, XXX Finnish females, or females with an extra X chromosome, was carried out using cephalometric analysis comprising linear and angular measurements. The lengths of the anterior and posterior cranial bases, the calvarium, mandibular ramus and posterior and upper anterior face heights were found to be significantly shorter than in female controls, while the angles between the foraminal and clival planes, the mandibular plane and cranial base, the maxillary and occlusal planes, the maxillary and mandibular planes and the foraminal and mandibular planes, and also the gonial angle, were significantly enlarged. The present findings of reduced linear measurements, together with the results of studies on the craniofacial complex of 47, XXY and 47, XYY males, suggest dimensional variation between these groups from the promoting effect of an extra Y chromosome and the retarding effect of an extra X chromosome on craniofacial growth.

Prenatal sonographic diagnosis of the 49,XXXXY syndrome.

The 49,XXXXY syndrome is a rare sex chromosome anomaly with an approximate incidence of 1 in 85,000 male live births. The diagnosis is usually ascertained postnatally by the association of mental retardation, variable growth deficiency, Down syndrome-like facial dysmorphy, hypogenitalism and other malformations, especially involving the heart and skeleton. Prenatal diagnosis of the pentasomy 49,XXXXY is generally fortuitous and sonographic features have rarely been described in the literature. We report here on two cases of 49,XXXXY syndrome diagnosed prenatally because of sonographic abnormalities. In the first, amniocentesis was performed at 26 weeks' gestation for polyhydramnios, unilateral clubfoot and micropenis. In the second, a karyotype was carried out on chorionic villi at 13 weeks' gestation for cystic hygroma. These observations and the six previously reported cases demonstrate that cystic hygroma in first or second trimester of pregnancy may be associated with sex chromosome aneuploidy other than Turner syndrome. Moreover, they emphasize the importance of detailed sonographic examination in the second trimester, as small penis and abnormal posturing of the lower extremities are very suggestive of the 49,XXXXY syndrome.

Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?

Congenital hydrocephalus associated with aqueductal stenosis and/or agenesis of the corpus callosum has been described in newborn males with mutations in L1CAM, a gene that encodes a neural cell adhesion molecule. These males usually have severe mental retardation and may have spastic paraplegia and adducted thumbs. In contrast, Hirschsprung disease, or absence of ganglion cells in the distal gut, has rarely been described in such individuals. We report a male infant who had severe hydrocephalus identified in the prenatal period with evidence of aqueductal stenosis and adducted thumbs at birth. He developed chronic constipation, and rectal biopsy confirmed the diagnosis of Hirschsprung disease. Molecular testing of the L1CAM gene revealed a G2254A mutation, resulting in a V752M amino acid substitution. A common polymorphism in RET, but no mutation, was identified. Our patient represents the third example of coincident hydrocephalus and Hirschsprung disease in an individual with an identified L1CAM mutation. We hypothesize that L1CAM-mediated cell adhesion may be important for the ability of ganglion cell precursors to populate the gut, and that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause intestinal aganglionosis.