A Baby Was Recently Born Who Had Very Ambiguous Genitalia
Iran J Reprod Med. 2014 May; 12(5): 351–356.
A newborn with ambiguous ballocks and a complex X;Y rearrangement
Mohammadreza Dehghani
i Department of Molecular Medicine, University of Pavia, Pavia, Italy.
2 Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Elena Rossi
1 Section of Molecular Medicine, Academy of Pavia, Pavia, Italy.
Annalisa Vetro
3 Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Gianni Russo
iv Department of Pediatrics, Endocrine Unit, University Vita-Salute, San Raffaele Hospital, Italian republic.
Zahra Hashemian
5 Shahid Sadoughi Hospital, Shahid Sadoughi Academy of Medical Sciences, Yazd, Iran.
Orsetta Zuffardi
1 Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Received 2014 Feb 12; Accepted 2014 Feb 23.
Abstract
Background: In most mammals, sex is adamant at the kickoff of gestation by the constitution of the sexual practice chromosomes, XY in males and XX in females.
Case: Here nosotros study an interesting case characterized past ambiguous ballocks and ovotestis in a newborn carrying an apparently female person karyotype (46 XX). Array Comparative Genomic Hybridization (Array-CGH) revealed an unbalanced rearrangement resulting in the deletion of the distal Xp and the duplication of the proximal Xp contiguous region with presence of the Y chromosome from Ypter to Yq11. Fluorescent in situ hybridization (FISH) showed that this portion of the Y was translocated to the tip of the abnormal 10 and that the duplicated portion of chromosome 10 was inverted. Birthday, the abnormal chromosome was a dicentric one with the centromere of the Y chromosome apparently inactivated.
Conclusion: The presence within the translocated Y chromosome of the SRY gene explains the devolopment of testes although it is non clear the reason for the genitalia ambiguity.
Key Words: Ambiguous genitalia, 46, XX testicular DSD, Inverted duplication and Xp terminal Deletion(Invdup del), Rearrangement, Array Comparative Genomic Hybridization, FISH
Introduction
In mammals, sex activity is adamant at the early gestation according to the constitution of the sex chromosomes, XY in males and Twenty in females (1). The Y chromosome is responsible for the evolution of testis thank you to the SRY factor at distal Yp whose role in sex activity decision is to initiate testis rather than ovary evolution from early bipotential gonads ( 1-3 ).
Sex development can be divided into 2 sequential processes: sex determination, in which the undifferentiated gonadal primordium commits to developing into either testes or ovaries; and sex differentiation, in which gonadal hormones act on the internal and external genitalia, resulting in differentiation into sexually dimorphic reproductive structures (ane, 4, 5). Disorders of Sexual Evolution (DSDs) in humans are characterized past a complete or partial mismatch betwixt the genetic sex and the phenotypic sex. Collectively, DSDs occur in at least one in 100 live births and include relatively balmy forms such as hypospadias (1/500 births) too as more astringent weather condition such as cryptic genitalia (one/4,500 births) and complete sex reversal (46, XY females and 46, XX males; ane in xx,000 births). Interestingly, DSDs business relationship for 7.5% of all nativity defects (two, six-nine).
46, XX testicular DSDs is the new term and classification of Xx males or XX sex reversal (10). Based on the person's phenotype or the genetic cause of 46, Xx testicular DSDs, ii classification are recognized, the first includes three clinical categories: a) Twenty males with normal genitalia, b) XX males with ambiguous genitalia, and c) XX true hermaphrodites with ovarian and testicular tissues. XX males can be divided into two molecular categories, according to the presence or absence of the Y-chromosome sequences (12-xiv). In 46, XX testicular DSD, individuals with two X chromosomes in each cell, which is the pattern that is normally institute in females, have a male appearance.
In most cases (fourscore%), individual with this disorder have male person external ballocks and, after puberty, develop normal pubic hair and normal penile size, only small testes, gynecomastia, and sterility resulting from azoospermia. Approximately twenty% of the 46,Xx testicular DSD individuals accept cryptic genitalia at birth ranging from cryptorchidism or hypospadias to a frank ambivalence making difficult gender assignment. In these cases gonads are constituted by ovotestis or mixed gonadal dysgenesis with ovarian-like structures at one side and testis differentiation at the other one.
Although nearly of the Xx DSD subjects suffer from a condition only related to aberrant gonads/genitalia, some of them present with a complex syndrome equally it is the example of the palmoplantar hyperkeratosis with squamous jail cell carcinoma of skin and 46,XX sex reversal (OMIM #610644) due to autosomal recessive mutations in the RSPO1 gene (fifteen). To date, many cases of XX males with or without SRY and apparently with no other Y-chromosome sequences have been reported ( 14). Approximately 85% of the XX testicular DSD cases are phenotypically male with unambiguous male genitalia at nascency and are SRY positive. Most of these individuals and are non diagnosed until that puberty fails to keep commonly (16, 17). Usually they have a shorter-than-boilerplate stature (mean height: 168.ii cm, compared to normal hateful height: 173.5 cm), gynecomastia, small testes, and azoospermia ( 18 ). They rarely present with singular ballocks (xix-22).
The remaining fifteen% of individuals with Twenty testicular DSD have ambiguous genitalia and SRY is positive in only a minority of the individuals (16, 23 ). Here we presented the example of a newborn ascertained because of ambiguous gentalia and some dysmorphic features.
Case report
New born is only kid of non-consanguineous couple. The first pregnancy ended in a spontaneous abortion. At birth the proband had normal stature and normal weight with 9/x Apgar. At clinical test we found brow prominence, hypertelorism, saddle nose, thin lips, low set and small ear and bilateral clinodactyly of fifth fingers. The clitoris was hypertrophic and in the inguinal region two small masses were detected. A unic urethral meatus was present below 2 hypotrophic labia minora. Scrotum-like labia majora and hypospadias were also present. In echosonography gonads were not present in pelvic. The inguinal masses were removed and their histology revealed that they were ovotestes.
PHA-stimulated lymphocytes cultures were prepare from peripheral blood from the patient and the parents and the assay was done on GTG banded metaphases, according to established guidelines. The karyotype was 46, XX with one short arm of the X chromosomes slightly longer. The karyotype of the parents was normal. Assortment-CGH analysis was performed by using oligonucleotide aCGH platforms (180K SurePrint G3 Human Kit, Agilent Technologies, Santa Clara, CA), as reported elsewhere (23). A 46, 20 reference Dna (NA15510, Coriell Cell repositories) was used for all experiments. Changes in Dna copy number at a specific locus were observed as the deviation of the log2ratio value from 0 of at to the lowest degree three sequent probes, past using Genomic Workbench 5. 5.0.14 software (Agilent, ADM-two algorithm with a threshold of five). Oligomer positions refer to the Human Genome GRCh37 (hg19) assembly. Array-CGH analysis showed a complex rearrangement with the deletion of the distal Xp of about 10 Mb between Xpter and Xp22.2, and a 19.9Mb duplication of a proximal Xp contiguous region; the Xp region between 10227817-15816305 was normal; a 16.8 Mb portion of the Y chromosome was likewise present consisting in the entire short arm and a function of long arm with breakpoint in Yq11.22 (Figure one). The final definition was:
oligonucleotide aCGH platforms (180K SurePrint G3 Human Kit, Agilent Technologies, Santa Clara, CA) showed a complex rearrangement with the deletion of the distal Xp of about ten Mb betwixt Xpter and Xp22.2, and a xix.9Mb duplication of a proximal Xp contiguous region; the Xp region between 10227817-15816305 was normal; a sixteen.viii Mb portion of the Y chromosome was also nowadays consisting in the unabridged curt arm and a role of long arm with breakpoint in Yq11.22
Arr Yp11.32q11.22 (11091-16824972) x1, Xp22.33p22.2 (61091-10207876) x1, Xp22.2p21.three (15,834,910-25,337,964) x3
To confirm array-CGH results and demonstrate the inversion of Xp duplicated region, FISH experiments were performed. All BAC probes used were selected according to the UCSC Human Genome Browser and were obtained from the human library RPC1-eleven. Alphoid probes were kindly provided past Mariano Rocchi (http://www.biologia.uniba. it/rmc/). X-inactivation analysis was performed according to Allen et al (24). Fluorescent in situ hybridization (FISH) confirmed the Xp deletion, demonstrated that the portion of the Y was translocated to the tip of the abnormal chromosome 10 and does non comprise SRY and that the duplicated portion of chromosome X was inverted (Effigy two and iii). Altogether, the aberrant chromosome was a dicentric i with the centromere of the Y chromosome apparently inactivated.
a: FISH assay with BAC RP11-294K6 (half dozen,503,905-6,527,019 Mb) confirmed the Xp22.33p22.3 deletion identified past array-CGH. b: FISH assay with BAC RP11-639O7, roofing the SRY factor, demonstrated that the portion of the Y chromosome translocated to the tip of the abnormal chromosome Ten contains the SRY factor. The short arrows indicate the derivative 10. In the box to a higher place a cut out of chromosomes X is shown; on the right the derivative Ten
a: FISH analysis with alphoid probes specific for chromosome X (ruddy) and for chromosome Y (dark-green) showed that the Y centromere has clearly detached signals suggesting its inactivation. b: FISH analysis with BACs within the Xp duplicated region demonstrated that the duplication is inverted : RP11-124B4 (green) in Xp22 at 14,955,137-15,105,389 Mb and RP11-171N17 (cherry-red) in Xp22 at 21,969,414-22,248,218 Mb. The short arrow indicates the derivative X
10 chromosome inactivation studies revealed that the derivative X was inactivated in all the 96 metaphases analyzed (data not shown).
Word
Approximately 20% of the 46, 20 testicular DSD individuals accept ambiguous ballocks at nativity ranging from cryptorchidism or hypospadias to a frank ambiguity making difficult gender consignment. In these cases gonads are constituted by ovotestis or mixed gonadal digenesis with ovarian-similar structures at 1 side and testis differentiation at the other one. Here nosotros presented a instance with ambiguous genitalia at birth and inguinal mass with histology of ovotestis after surgery.
In most of the XX males SRY is transposed to the tip of Xp as a result of a recurrent Xp;Yp translocation arising predominantly by non-allelic homologous recombination betwixt of PRKX and PRKY in a item Y chromosome background consisting in a polymorphic cryptic inversion (25, 26). In our case, the SRY gene is indeed located at the stop of one Ten chromosome but the rearrangement is completely different and much more complex leading to a classical inv dup del (Xp) in which the absenteeism of the brusk arm telomere has been repaired the revenue of a portion of the Y chromosome containing its centromere (27, 28). Every bit a result, the rearranged chromosome was dicentric although the Y centromere appears inactivated according to the finding of two alphoid spots e'er detached (Figure 2a). We may speculate that originally the dicentric was unstable with loss of the Y chromosome portion in some cells. This hypothesis might explicate the presence in the proband of ambigous ballocks otherwise incomprehensible. This rearrangement is sporadic and therefore this condition doesn't have recurrent take a chance.
Our proband is a newborn and and so far presents minor dysmorphic signs as brow prominence, hypertelorism, saddle nose, sparse lips, low set and pocket-size ear and bilateral clinodactyly of fiveth fingers. It seems likely that the deleted and duplicated portions of the X chromosome are responsible for them. The finding of the preferential inactivation of the abnormal Ten as stated in blood cells should avert severe pathogenic consequences. This bodes well that the proband won't develop a real medical condition. Certainly, although role of distal Xp is deleted, the proband should not have brusque stature beingness the 2 PAR regions containing the SHOX1 fully preserved.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094661/
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