Difficult diagnosis and management of an heterokaryotypic monochorionic twin pregnancy with discordant fetal sex and 45,X/47,XYY karyotypes

We report twins for whom ultrasound examinations revealed a Turner syndrome in the female fetus and a normal male fetus. A selective pregnancy termination was decided on the female fetus with hydrops. The death of both twins called in question the chorionic diagnosis. Amniotic fluid cytogenetic analysis revealed a 45,X karyotype in the female twin and a 47,XYY karyotype in the male twin. Molecular cytogenetic analysis on genital and renal cells showed different levels of 45,X/47,XYY mosaicism in both twins; molecular analysis on the amniocytes showed monozygosity. Monozygotic twins with discordant sex are very rare. This study showed the difficult diagnosis and management of a monochorionic twin pregnancy with discordant fetal sex.     

Monozygotic twins with discordant karyotypes: a case report

A monochorionic twin pregnancy had normal male karyotype on chorionic villous sampling. At delivery, one twin presented as morphologically normal, the other as trisomy 21. A twinning event and chromosome division error shortly after conception resulted in monozygotic twins with discordant tissue karyotypes and blood chromosome chimerism for trisomy 21.     

Familial 46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree

Reported here is a family with which 46,XX males and 46,XX true hermaphrodites coexist. The propositus was a paternal uncle with 46,XX true hermaphroditism. One of his brothers fathered a 46,XX daughter with true hermaphroditism; a second brother fathered two 46,XX males. Both fathers have normal male karyotypes and phenotypes. No evidence for chromosomal mosaicism or any additional chromosomal abnormalities was obtained. We conclude that inheritance of the abnormality is most likely via paternal transmission of an autosomal testis-determining factor. This family provides evidence to support the hypothesis that 46,XX true hermaphrodites and 46,XX males represent alternative manifestations of the same genetic defect.     

An unusal case of hermaphroditism--a 46,XX/69,XXY chimera

A diploid/triploid karyotype is an uncommon but important cause of true hermaphroditism and ambiguous genitalia. Individuals have a recognisable phenotype and characteristic hydatidiform placental changes. We report a 46,XX/69,XXY chimeric hermaphrodite. This case highlights the typical features (large placenta, intrauterine growth retardation, asymmetric growth, cranio-facial anomalies, syndactyly and pigmentary dysplasia). It illustrates the importance of obtaining skin and gonadal karyotypes in the case of genital ambiguity, as the venous lymphocytic karyotype is usually diploid.     

End-stage renal disease and primary hypogonadism associated with a 46,XX karyotype.

OBJECTIVE--To determine the cause of absent sexual development in a 17-year-old girl with end-stage renal disease. DESIGN--Case study. PARTICIPANT--Seventeen-year-old girl with end-stage renal failure. INTERVENTIONS--None. MEASUREMENTS/MAIN RESULTS--The patient had phenotypically normal external female genitalia, müllerian duct hypoplasia, and no ovaries. Her serum gonadotropin levels were in the castrate range at baseline and after gonadotropin-releasing hormone stimulation. Her karyotype, in lymphocytes and cultured fibroblasts, was 46,XX. Analysis of genomic DNA, following polymerase chain reaction-amplication with oligonucleotide primers corresponding to the Y-encoded zinc finger protein ZFY and the testis-determining SRY gene, showed Y chromosome material in a male control but none in the patient. CONCLUSIONS--The results suggest a diagnosis of Frasier syndrome, a disorder characterized by true gonadal dysgenesis and end-stage renal disease occurring in normal phenotypic girls. Although previously reported only in individuals with a 46,XX karyotype, our studies indicate that Frasier syndrome may also occur in 46,XX girls. Delayed puberty is not uncommon in renal failure. This case illustrates the importance of measuring gonadotropin levels in teenage girls with delayed puberty and renal failure, particularly if the origin of the renal disease is obscure.     

Trisomy 21 q: 46,XX,21s+/47,XX,+21q−(q22→qter) mosaicism (de novo) in a down syndrome child

A three year old girl with clinical features of Down syndrome and mental retardation is reported. Karyotype of the proband was 46,XX,21s⁺/47,XX,21q→(q22−qter), resulting in partial trisomy for chromosome 21. Her father, phenotypically normal, was a carrier for 21s+variant chromosome (46,XX,21s⁺). The maternal age was 32 years. This case further confirms that the Down phenotype is due to the trisomy of the distal segment of the band q22 of chromosome 21.     

46,XX maleness and 46,XX 21-hydroxylase deficiency in dizygotic twins: association or coincidence?

46,XX maleness is a rare abnormality of gonadal differentiation. We present dizygotic twins, one having ambiguous genitalia due to 2-hydroxylase deficiency, and the other having normal male genitalia with 46,XX maleness. One of the twins was referred to the endocrinology unit at 2 days old because of ambiguous genitalia. The other twin with bilateral undescended testes located in the inguinal canal was diagnosed with 46,XX maleness. The karyotype was 46,XX. Molecular analysis revealed the presence of SRY in the latter twin without Müllerian structures. Association of congenital adrenal hyperplasia (46,XX 21-hydroxylase deficiency) and 46,XX maleness in twins has not been previously reported.     

Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature

The main factor influencing the sex determination of an embryo is the genetic sex determined by the presence or absence of the Y chromosome. However, some individuals carry a Y chromosome but are phenotypically female (46,XY females) or have a female karyotype but are phenotypically male (46,XX males). 46,XX maleness is a rare sex reversal syndrome affecting 1 in 20,000 newborn males. Molecular analysis of sex-reversed patients led to the discovery of the SRY gene (sex-determining region on Y). The presence of SRY causes the bipotential gonad to develop into a testis. The majority of 46, SRY-positive XX males have normal genitalia; in contrast SRY-negative XX males usually have genital ambiguity. A small number of SRY-positive XX males also present with ambiguous genitalia. Phenotypic variability observed in 46,XX sex reversed patients cannot be explained only by the presence or absence of SRY despite the fact that SRY is considered to be the major regulatory factor for testis determination. There must be some other genes either in the Y or other autosomal chromosomes involved in the definition of phenotype. In this article, we evaluate four patients with 46,XX male syndrome with various phenotypes. Two of these cases are among the first reported to be diagnosed prenatally.     

Monozygotic twins discordant for the acquired immunodeficiency syndrome

Monozygotic twin girls discordant for acquired immunodeficiency syndrome were born to parents with antibodies to human T-cell lymphotropic virus type III. One twin had clinical evidence of the syndrome with tests positive for antibody, whereas the other at the age of 3 years was clinically, serologically, and virologically normal.     

45,X/46,XX mosaicism in turner’s syndrome

Summary A short-statured phenotypic female with primary amenorrhoea, infantilism, shield chest and 9% sex chromatin bodies in buccal smears had 2 cell lines, 45/46, in cultured leucocytes. She was diagnosed as a case of Turner's syndrome with X/XX chromosomal mosaicism. This patient is another example of modification of the Turner phenotype by the presence of a normal XX cell line. The report highlights the importance of cytogenetic investigations in short-statured females who do not possess all the clinical features of the classical form of Turner’s syndrome. From the Chaudhuri Centre for Medical Genetics, Calcutta-14.     

Interstitial Deletion of the Long Arm of Chromosome 13 and Retinoblastoma

A female infant is reported in whom bilateral retinoblastoma developed due to interstitial delection of the long arm of chromosome 13. Her chromosome karyotype examined with peripheral lymphocytes proved to be 46, XX, del (13) (q12.3 q21.2). Parental chromosome karyotypes were normal. Clinical symptoms were bilateral retinoblastoma, retardation of growth and development, and mild microcephaly. No other marked dysmorphic features were noted.     

Monozygotic twins with Turner syndrome develop slipped capital femoral epiphysis on growth hormone therapy

Monozygotic twins with Turner syndrome have rarely been reported. An increased incidence of slipped capital femoral epiphysis has been associated with growth hormone therapy, as well as with Turner syndrome, but has never been described in twins with Turner syndrome. We report the first case of monozygotic twins with Turner syndrome with a 46,Xi(Xq) karyotype, both of whom developed slipped capital femoral epiphysis during growth hormone therapy. This report adds to existing reports of monozygotic twins with Turner syndrome and contributes to recognition of the potential clinical course in such patients. In addition, the association between slipped capital femoral epiphysis, growth hormone therapy, and Turner syndrome is emphasized.     

Fetal cystic hygroma and Turner's syndrome

Large nuchal cystic hygromas were observed in five second-trimester aborted fetuses at autopsy. Two female fetuses with generalized edema were karyotyped as 45,X. One of these was the twin of a 46,XX normal female sibling. The association of generalized edema with large nuchal cystic hygromas was seen only in these two fetuses and represents strong phenotypic evidence of Turner's syndrome. However, the absence of hydrops was not a reliable indicator of normal karyotype. One fetus without generalized edema was karyotyped as 47,XY, +21, inv(9). The remaining cases had normal karyotypes. Placental histology was not useful in discriminating monosomy X from other conditions, but placental tissue culture was important in obtaining a cytogenetic diagnosis. Karyotyping is recommended in all cases of fetal cystic hygroma.     

Pseudohermaphroditis, with testes and a 46, XX karyotype.

A 14 4/12-year-old white girl, evaluated for progressive virilization and clitormegaly, was found to have the unusual combination of a 46, XX karyotype, well-developed Mullerian structures, and dysgenetic testes with Leydig cell hyperplasia. Although there have been previous case reports of 46, XX males, in all of these patients development of the Mullerian ducts had been suppressed. When contemporary classifications of human disorders of sexual differentation were reviewed, no report of a similar patient was found. We speculate that the genotype and phenotype in our patient correspond to the genetic intersexuality of the hornless goat, thereby raising the possibility that the human autosome may play a role in the control of sexual development.     

Three new 46,XX male patients: a clinical, cytogenetic and molecular analysis

BACKGROUND: XX males range phenotypically from completely masculinised individuals to true hermaphrodites and include a subset of SRY negative patients. The correlation between genotype (SRY+/-) and phenotype is still unclear. AIM: To report three new patients with this rare condition, one of whom was diagnosed prenatally and another was SRY negative, and to verify in our patients whether the presence of SRY results in a more masculinised phenotype. PATIENTS AND METHODS: We present two phenotypically normal XX male patients (10 and 13.5 years) and one 3.1 years old XX male with ambiguous external male genitalia Prader IV. The patients were diagnosed by clinical, hormonal, sonographic, genetic and histological criteria. RESULTS: Basal hormonal status was normal for phenotype but an excessive response to GnRH testing was noticed in the second patient together with insufficient hCG stimulation in all three patients. Pelvic ultrasound displayed male structures without Müllerian ducts; testicular biopsy, performed only in the intersex patient, showed Sertoli and Leydig cell hypoplasia. Chromosome analysis confirmed 46,XX karyotype. FISH analysis and molecular analysis by PCR were positive for Yp fragments/SRY gene on Xp in two patients and negative in the patient with ambiguous external genitalia. CONCLUSIONS: In our observation Y chromosome-specific material containing the SRY gene translocated to the X chromosome results in a completely masculinised phenotype. In the intersex patient, incomplete masculinisation without SRY suggests a mutation of one or more downstream non-Y testis-determining genes.     

The Pallister-Killian syndrome in a child with rare karyotype—a diagnostic problem

The Pallister-Killian syndrome is a clinically recognizable syndrome, usually due to a tissue-specific mosaicism for a 12p isochromosome [i(12p)]. We report a rare case of Pallister-Killian syndrome with 12p mosaicism, tetrasomy/trisomy/disomy in fibroblasts and trisomy/disomy in lymphocytes. Marker chromosomes were investigated with conventional cytogenetic techniques and fluorescent in situ hybridisation (FISH). The karyotype was established as: mos47,XX,+12p/47,XX,+i(12p)/46,XX. The cytogenetic result of the extra mosaic 12p presented in lymphocytes suggested the diagnosis of trisomy 12p, although, in combination with clinical manifestations, the Pallister-Killian syndrome was considered and confirmed by the cytogenetic analysis of fibroblasts.     

Down syndrome with XO/XX mosaicism.

A 2-month-old girl with Down syndrome was found to have 47, XX, +21/46, X, +21 mosaicism. No symptoms indicative of infantile Turner syndrome were observed.     

Tissue limited mosaicism for unbalanced autosomal translocation in a child with congenital anomalies and mental retardation

We studied a patient with a sporadic mental retardation/multiple congenital anomalies syndrome. Chromosome analysis showed a 46,XX, inv(9)(p11;q13) karyotype in all lymphocytes. Fibroblasts from two separate skin biopsies revealed a mosaic karyotype. Some 22.5% of fibroblasts had a karyotype like that of the lymphocytes, while 77.5% of fibroblasts had a karyotype 46,XX,inv(9)(p11;q13),der(12),t(12;?)(p13;?). The data in this case emphasize the drawbacks of confining cytogenetic analysis to lymphocytes.     

Normal male phenotype or hypospadias and female karyotype. XX male syndrome in children and adolescents

A morphologically normal 46 XX karyotype has been found in 8 patients with male phenotype, either normal (3 cases) or hypospadiac (5 cases) studied at age 1 month to 15 years. Five had cryptorchidism. Pubertal follow-up was obtained in 6 patients and showed that they had hypogonadism with small testes, and a mean adult height of 163 cm. The hormonal investigations gave normal results before puberty, then after the onset of puberty a hypergonadotropic hypogonadism. Testicular biopsy showed alterations from age 8 years. Studies using Y-specific probes in 3 patients have shown the presence of Y genetic material in 2 and absence in 1, thus demonstrating genetic heterogeneity of the XX males.     

Correlation between cord insertion type and chorionic villus vascularization of the co-twin in diamniotic–monochorionic twin pregnancies

Background

Recent evidence suggests that cord insertion type of one twin correlates with chorionic plate vascularization of the monochorionic co-twin. Specifically, for twins with paracentral cords, chorionic plate vascularization is significantly greater when the co-twin has a velamentous, rather than paracentral cord insertion.

Aims

To determine whether this correlation between cord insertion type and vascularization of the co-twin also extends to the deeper chorionic villus tree.

Study design

Morphometric analysis of chorionic villus vascularization in CD31-immunostained sections of a retrospective cohort of gestational age-matched third trimester monochorionic placentas with discordant paracentral/velamentous (PC/V) or concordant paracentral/paracentral (PC/PC) cord insertions.

Outcome measures

Vascular numerical density (number of vascular profiles per unit villus stromal area) of intermediate villi (> 80 μm diameter) and terminal villi (< 80 μm).

Results

For twins with paracentral cord insertion, the vascular numerical density of intermediate villi was significantly higher for twins in a discordant PC/V relationship than for those in a concordant PC/PC relationship (P < 0.05), thus replicating previous findings in superficial chorionic vessels. For terminal villi, in contrast, the vascular numerical density of twins with paracentral cords in a PC/V combination was significantly lower than of those in a PC/PC combination, and similar to that of their co-twins with velamentous cord insertion.

Conclusions

Early placental angiogenesis in monochorionic twin gestations may be influenced by implantation and cord localization of the co-twin. The regulation of terminal villus angiogenesis appears to be dissociated from more proximal villus angiogenesis and independent of cord insertion of the co-twin.