Trisomy 21 [Down syndrome (DS)] is the most common genetic cause for intellectual disability (Yang et al., 2002). It results from a triplicate state (trisomy) of all or a critical portion of chromosome 21 (Roizen and Patterson, 2003; Rachidi and Lopes, 2007). An area of ∼5 Mb, between loci D21S58 and D21S42 (symbolized DCR), has been identified as being associated with mental retardation and most of the facial features of the syndrome. In particular, a subregion that includes D21S55 and MX1, located in band 21q22.3, if triplicated, has been associated with several morphologic features in addition to mental retardation, including oblique eye fissure, epicanthus, flat nasal bridge, protruding tongue, short broad hands, clinodactyly of the fifth finger, gap between the first and second toes, hypotonia, short stature, Brushfield spots, and characteristic dermatoglyphics (Delabar et al., 1993). Additional phenotypic characteristics may map outside the minimum critical region (Korenberg et al., 1994; Lyle et al., 2009).
As DS is caused by genomic dosage imbalance, it was hypothesized by Prandini et al. (2007) that variation in the expression of genes on chromosome 21 influences the phenotypic variability among affected individuals. However, other euploid genes show greater variance of expression in human trisomy 21 tissues than in euploid tissues. This change in expression may contribute to producing the variable phenotypic abnormalities observed in DS (Chou et al., 2008).
Because of the extensive number of chromosome 21 genes, there is a high incidence of congenital anomalies such as congenital heart disease and gastrointestinal malformations (Van Trotsenburg et al., 2006). There is also an increased risk for leukemia and early onset of Alzheimer-like neuropathology in individuals with DS (Antonarakis and Epstein, 2006; Rachidi and Lopes, 2007).
The XX male syndrome (OMIM ID 400045), now termed 46,XX testicular disorder of sex development (DSD), is a rare condition, with a frequency of one in 20 000–25 000 male newborns (Vorona et al., 2007). It presents with a spectrum of clinical features ranging from phenotypic males to ambiguous and ovotesticular DSD individuals. The clinical features of classic XX males are indistinguishable from those of XXY Klinefelter patients. The genitalia are those of a normal male and the testes are small with azoospermia. Important phenotypic differences are that XX males are shorter with a mean height between that of normal females and normal males and the pubic hair may be distributed in the female pattern (De la Chapelle, 1981; Kolon et al., 1998; Rajender et al., 2006). Most individuals with 46,XX testicular DSD present after puberty with normal penile size, but small testes, gynecomastia, and azoospermia. Sex role and sex identity are reported as male (Zenteno Ruiz et al., 2001). If untreated, male patients with 46,XX testicular DSD experience the consequences of testosterone deficiency (Lambert et al., 2010).
Normal male sex determination relies on the presence of the Y chromosome and specifically on the expression of the SRY gene (sex-determining region Y) at the appropriate time and place during gonadal development (Berta et al., 1990; Sinclair et al., 1990; Koopman, 1995; Zenteno Ruiz et al., 2001; Hersmus et al., 2012). In addition, several autosomal genes acting in association with SRY contribute to the normal development of the male phenotype (Slaney et al., 1998; Rajender et al., 2006; Kojima et al., 2008; Polanco et al., 2009).
On the basis of the analysis and detection of the SRY gene, 46,XX male patients can be categorized as SRY positive or SRY negative (Kim et al., 2010). SRY-positive individuals usually have normal male genitalia and hypergonadotropic hypogonadism secondary to testicular failure (De la Chapelle, 1981), and most carry the SRY gene translocated to the X chromosome during paternal meiosis (Wang et al., 2009); however, SRY/autosomal translocations have also been reported in some XX male patients (Queralt et al., 2008; Chien et al., 2009). The diagnosis of SRY-positive patients is usually made at adulthood during infertility investigations (Ergun-Longmire et al., 2005). The group of SRY-negative patients includes those with ovotesticular DSD (characterized by the presence of both testicular and ovarian tissues in the gonads of the same individual) (Berger Zaslav et al., 2009; Parada Bustamante et al., 2010) and patients with testicular DSD (with both gonads developing as testes) (Rajender et al., 2006). In the absence of the SRY gene, the upregulation or super-expression of some members of the SOX family (Sry-related HMG-box) has been proposed to be involved in XX male etiology (Kojima et al., 2008; Polanco et al., 2010). The diagnosis of SRY-negative testicular DSD is usually made during childhood upon investigation of ambiguous genitalia and gynecomastia (Alves et al., 2010).
The aim of this study was to report and discuss a rare case of DS associated with XX testicular DSD in an Egyptian patient, emphasizing the cytogenetic aspects and etiologic mechanisms.
A male patient was referred to the outpatient clinic of the clinical genetics department, National Research Centre, at the age of 2 weeks to rule out DS. He was the fourth child of a consanguineous healthy Egyptian couple. He was delivered at full term by normal vaginal delivery and had average birth weight. The maternal and paternal ages were 35 and 40 years, respectively. There was no family history of genetic disorders, and detailed maternal history of previous abortion, still birth, or termination was not significant. There was no exposure to teratogens, radiation, or environmental insult.
On examination, the patient had brachycephaly, an upward slanting of the eyelids, hypertelorism, depressed nasal bridge, epicanthic folds, upturned nostrils, sparse eyebrows, microstomia, protruding tongue, micrognathia, microtia, and low-set ears. He also had a right Simian crease and a left incomplete Simian crease. There was a bilateral gap between the big toe and other toes. Systemic examination revealed no abnormality apart from umbilical hernia. Genital examination revealed a palpable gonad felt in the right inguinal canal and an impalpable gonad on the left side. He had a hypoplastic scrotum and a penile length of 3.5 cm with the urethral opening at the tip. Pelvic sonar revealed both testes situated at the medial end of both inguinal canals, with no uterine shadow. Echocardiogram was normal, ruling out congenital heart disease. His thyroid profile revealed normal results, ruling out any associated thyroid dysfunction.
The growth evaluation of the patient showed normal ranges for weight (2.8 kg, −1.3 SD) and height (49 cm, −0.5 SD), whereas head circumference was 32 cm (−2 SD).
The patient was diagnosed clinically with DS with ambiguous genitalia. He was then referred to the human cytogenetics department for karyotyping for confirmation and final diagnosis.
Chromosomal analysis was performed from peripheral blood samples using the GTG-banding technique according to Seabright (1971) and Verma and Babu (1995). Analysis of the karyotype revealed an XX sex chromosomal constitution, associated with trisomy 21, in all analyzed metaphases (47,XX,+21; Fig. 1). Karyotype description followed the International System for Human Cytogenetic Nomenclature recommendations (Shaffer et al., 2009). Fluorescence in-situ hybridization (FISH) was carried out on peripheral blood lymphocytes to rule out the presence of a mosaic or a chimeric cell line and to identify the presence of the SRY gene. This was done using commercial probes according to the manufacturer’s instructions (Vysis FISH probes; Abbott Molecular Inc., Des Plaines, IL).
The probes used included the CEP X (DXZ1)/CEP Y (DYZ3) cocktail probe that hybridizes to the alpha satellite DNA at the centromeric regions of the X (spectrum green) and Y (spectrum orange) chromosomes, respectively, and the LSI SRY/CEP X probe kit, specific for the SRY gene at Yp11.3 (spectrum orange) and X centromere (spectrum green). FISH was performed as per the procedure followed by Pinkel et al. (1986).
Analysis of more than 200 interphase nuclei revealed two green X centromeric signals, with no detection of Y centromeric signal, thereby excluding the presence of another cell line. An SRY hybridization signal was detected on the distal part of the short arm of one of the X chromosomes, indicating the translocation of the SRY gene to Xp (Fig. 2).
The final karyotype was interpreted as 47,XX,+21.ish XX(SRY+,DXZ1++).
Trisomy 21 (DS) is one of the best-recognized and most common types of viable human aneuploidy, occurring at a frequency of about 1/800 live births (Patterson and Costa, 2005). In Egypt, the incidence of DS has been reported to be one per 1000 births (Abdel Fattah, 1991). Approximately 90–95% of individuals with DS have primary trisomy 21, caused by meiotic nondisjunction of chromosome 21 in one of the parents (Pangalos et al., 1994). In most cases the extra chromosome is of maternal origin with a greatly elevated risk in older mothers and a less pronounced paternal-age effect (Luthardt and Keitges, 2001).
The basis for the age-dependent effect is not fully documented. However, many investigators have tried to address the nature of this biological phenomenon through genomic analyses of extra chromosome 21 using polymorphic markers to determine the frequency or location of crossovers that should ensure faithful chromosome segregation (Sherman et al., 1991; Zittergruen et al., 1995; Kurahashi et al., 2012). Researches have shown that absence of recombination in the prophase of meiosis I predisposes to subsequent nondisjunction, as the chiasmata, which are formed after recombination, are responsible for holding each pair of homologous chromosomes together until subsequent separation occurs in diakinesis (Sherman et al., 1991; Turnpenny and Ellard, 2005). In female patients, recombination occurs before birth and the primary oocytes are then arrested at diplotene. Meiosis continues only at menstruation, which means that proper chromosomal associations must be maintained for decades to promote proper disjunction at any time between 15 and 50 years later. This suggests that at least two factors can be involved in causing nondisjunction, the first being defective recombination between homologous chromosomes in the fetal ovary and the second an abnormality in spindle formation many years later (Turnpenny and Ellard, 2005). Aneuploidy may also arise during mitosis, producing a mosaic pattern of somatic cells including the normal chromosomal complement and the extra chromosome. Mosaicism is present in about 2% of DS patients and may lead to a mild version of the condition. However, this varies according to the type and amount of cells affected (Papavassiliou et al., 2009). DS associated with sex-chromosome aneuploidy or DSD is an extremely rare condition. In the literature, five patients with double aneuploidy including DS associated with XYY or 45,X mosaicism were reported by Schwanitz and Hagner (1978), Zaki et al. (2005), and Parihar et al. (2013).
So far, sex-chromosome discordant chimerism and trisomy 21 have been reported in five patients (Sawai et al., 1994; Hwa et al., 2006; Lucon et al., 2006; Ramsay et al., 2009; Lee et al., 2012) and in a stillborn male fetus with multiple congenital anomalies and a 47, XY, +21/47, XX, +12 karyotype (Wiley et al., 2002).
Many mechanisms have been proposed to explain XX/XY chimerism associated with trisomy 21. Tetragametic chimerism resulting from postzygotic fusion of two distinct embryos, one with a normal karyotype and the other with trisomy 21, was postulated by Danielle et al. (2006). Fertilization of a parthenogenically activated oocyte with two sperms with opposite sex chromosomes, one of which harbored an extra chromosome 21, is another explanation proposed by Lee et al. (2012). Similarly, such chimerism may result when one zygote with trisomy 21 fuses with another zygote formed by a sperm fertilizing with an egg that is empty of genetic material (isodisomic paternal cell lines) (Malan et al., 2006). Postzygotic diploidization and nondisjunction of chromosome 21 of a triploid is another possible mechanism (Lee et al., 2012).
Detailed cytogenetic and FISH analysis of our patient did not reveal any chimerism explaining the discordant sexual development. However, the use of a locus-specific probe for the SRY gene detected a signal on the short arm of one of the X chromosomes, which offers an explanation for the observed phenotype. Accordingly, the diagnosis was established as XX testicular DSD associated with DS.
Approximately 80% of XX testicular DSD patients have a part of the short arm of the Y chromosome translocated to the short arm of the X chromosome (McElreavey and Cortes, 2001). Normally, recombination takes place between X and Y chromosomes during meiosis at two specific regions known as the pseudoautosomal regions (PARs).They are situated at the distal ends of Xp, Yp and Xq, Yq and are termed the pseudoautosomal regions PAR1 and PAR2, respectively (McElreavey and Cortes, 2001; Charchar et al., 2003). As SRY is situated at Yp11.3, very close to PAR1, it may be occasionally translocated to the terminal portion of Xp during male meiosis, resulting in XX testicular DSD (Flaquer et al., 2008). In some cases, XX male development may occur in the absence of the SRY gene as a result of abnormal expression of recessive or X-linked genes involved in the pathway of male development (Rajender et al., 2006; Kojima et al., 2008; Polanco et al., 2009).
Despite the presence of the SRY gene in our patient, he showed atypical presentation, with characteristics that manifested in early childhood in the form of ambiguous genitalia, in addition to the presence of a DS phenotype. A small number of SRY-positive XX male patients present with ambiguous genitalia, and the phenotypic variability observed in them cannot be explained only by the presence or absence of the SRY gene. Other genes either in the sex chromosomes or autosomes must be involved in the definition of the phenotype (Ergun-Longmire et al., 2005).
It was indicated by Link et al. (2013) that Klinefelter’s variants and XX male patients have a higher incidence of obesity and metabolic diseases compared with the general population. They explained in their study that sex chromosome complement – independently from gonadal sex – plays a role in adiposity, feeding behavior, fatty liver, and glucose homeostasis and proposed that potential mechanisms for the effects of sex chromosome complement include differential gene dosage from X chromosome genes that escape inactivation, and distinct genomic imprints on X chromosomes inherited from maternal or paternal parents. This role of sex chromosomes is more influential in the absence of sex hormones as is the case in patients with testicular DSD (Chen et al., 2012). In addition, children with DS are also prone to obesity and an increased risk for developing type 2 diabetes mellitus (Bell and Bhate, 1992; Harris et al., 2003; Fonseca et al., 2005), which further aggravates the risk in our patient and makes him prone to obesity in the future, with the risk of developing metabolic and cardiovascular diseases. Accordingly, it is very important to counsel the parents about the risk factors and establish a prevention and management plan with a regular follow-up.
To our knowledge, this is the first reported patient with combined DS and XX testicular DSD. Most likely, two separate events had resulted in the combined phenotypic and cytogenetic abnormalities in our patient: one occurring during maternal meiosis leading to chromosome 21 nondisjunction and the other due to abnormal terminal X–Y interchange in the father germ cells.
Conflicts of interest
There are no conflicts of interest.
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