Case Report doi: 10.4183/aeb.2012.627 A NEW CASE OF TETRASOMY X IN A 8 YEARS OLD GIRL V. Plaiasu1,*, D. Ochiana1, G. Motei1 , I. A. Anca2 1 IOMC Alfred Rusescu - Genetics Department, 2 IOMC Alfred Rusescu, University of Medicine and Pharmacy “Carol Davila” - Pediatrics Department, Bucharest, Romania Abstract Genetic counseling is recommended. Chromosomal aberrations can be Although no cure exists specifically for this generally classified in two main categories: condition, the treatment of the symptoms structural abnormalities (such as can be efficient. Individuals should undergo translocations, deletions or duplications) medical and psychological evaluations. and numerical changes or aneuploidy. Aneuploidies are considered the most Key words: 48,XXXX, polysomy, frequent chromosomal defects occurring in mental deficiency, learning disabilities, humans and the leading cause of mild phenotype, genetic counseling. miscarriage and congenital birth defects. Here we present the case of an 8-year old girl with remarkable prenatal history, low birth weight and length associated with INTRODUCTION increased height in early childhood and developmental delay. On chromosomal Polysomies such as XXXX, XXYY, analysis a rare form of aneuploidy involving XYYY, XXXY, XXXXX, XXXXY are the sex chromosomes has been found in all very rare chromosomal defects. cells: 48, XXXX. Tetrasomy X (48,XXXX) Tetrasomy X (48,XXXX) is a sex is a sex chromosome aneuploidy condition chromosome aneuploidy condition in in which females have two extra X which females have two extra X chromosomes compared to the 46,XX chromosomes compared to the 46,XX karyotype in typical females. There is karyotype in typical females. The first two significant phenotypical variability for females with 48,XXXX have been tetrasomy X syndrome and many cases described by Carr et al. in 1961 (1). escape detection therefore the prevalence Prevalence for tetrasomy X is for tetrasomy X is unknown. This disorder unknown. This disorder is associated with is commonly associated with delayed delayed speech, learning difficulties, speech, learning difficulties, developmental developmental delay and facial delay and facial dysmorphism, reminiscent dysmorphism, reminiscent of Down of Down syndrome. syndrome (2), such as midface *Correspondence to: Vasilica Plaiasu MD, IOMC Alfred Rusescu, Genetics, Bd.Lacul Tei nr.120 sector 2, Bucharest, 20395, Romania, E-mail: [email protected] Acta Endocrinologica (Buc), vol. VIII, no. 4, p. 627-632, 2012 627 V.Plaiasu et al. hypoplasia, mild hypertelorism, cerebral MRI (Magnetic Resonance epichantic folds and mild micrognathia, Imaging) was normal and cardiac with variable phenotypic characteristics. ultrasound revealed a ventricular Mental deficiency appears to be an septal defect. The next step consisted essentially constant feature with IQ range of cytogenetic testing. The following of 30 -70 (3). recommendations involve endocrine evaluations. CASE REPORT MATERIALS AND METHODS A 8-years old girl was referred to our Genetics Department for clinical Peripheral blood lymphocyte cell evaluation because of learning cultures were obtained; after an difficulties. She was the first child of a incubation of 72h at 37°C, the cells non-consanguineous young family at were sacrificed by administering the moment of conception. Prenatal colchicine. GTG banding was history was remarkable, with performed and 30 metaphases were intrauterine growth retardation analyzed. Cytogenetic description was becoming evident at gestational age of performed according to 6 months. The patient was born at 38 recommendations of the international weeks of gestation by cesarean system for nomenclature of delivery. Her birth weight was 2250 g chromosome abnormalities ISCN 2009 (<5th centile) and her birth length was (International System for Human 42 cm (<5th centile). After birth she Cytogenetic Nomenclature) (4). recorded developmental delay: she walked at age of 1 year and 8 months and said first words after age of 3 RESULTS years. On physical examination at actual The standard cytogenetic age she was alert, with behavioral evaluation of the proband showed a problems such as autoagressive hand- rare form of aneuploidy involving tics, moderate mental retardation sexual chromosomes: 48, XXXX in all expressed by learning disorder, with cells, without evidence of mosaicism mild dysmorphism, microcephaly. (Figure 1). Karyotype of the mother Morphometry data were: weight=24 was performed to exclude mosaicism kg (25th centile), height=130 cm (75th and the result was normal. centile), head circumference=47 cm (<5th centile). No other assessments have been DISCUSSION made for this girl until this age due to a mild clinical and behavioral Chromosomal aberrations can be phenotype. Additional imaging generally classified in two main investigations were performed: categories: structural abnormalities (such 628 Tetrasomy X Figure 1. G-band karyotype of the patient showing 48,XXXX as translocations, deletions or explains the delay in her diagnosis. duplications) and numerical changes or Most aneuploidy derives form aneuploidy. Aneuploidies are considered maternal meiosis I errors. In oogenesis, the most frequent chromosomal defects the first meiotic division starts in the occurring in humans and the leading fetal ovary and is completed at the time cause of miscarriage and congenital birth of ovulation, some 10-50 years later defects (5). (6). The events that take place during The presence of an extra X prophase of meiosis I are considered to chromosome in the cells is known to be essential for the appropriate have a detrimental defect on growth segregation of chromosomes (7). and development. Females with 48, During this stage meiotic XXXX present a heterogeneous recombination, the mechanism by phenotype, but with recognizable which genetic material is shuffled and features that include hypertelorism, mixed to produce genetic variation in upslanting palpebral features, individuals is the key to the proper epichantal folds and a flat nasal bridge. segregation of homologous Our case presented only mild chromosomes (5). Throughout this dysmorphic features, with process errors can take place that can hypertelorism and microcephaly, which lead to malsegregation of homologues. 629 V.Plaiasu et al. Sex chromosome aneuploidy as get to be expressed despite the overall well as trisomy 21 are known to silencing. It is considered that the increase with maternal age (8,9). abnormal phenotypic features observed Several studies have indicated a for patients with X aneuploidies are possible age-related degradation of the caused by these genes that escape X- cohesion complex that leads to the inactivation (17,18). One such gene is inappropriate separation of SHOX; the SHOX gene is situated on chromosomes (10-12). the short arm of the X chromosome in a Mosaicisms can also occur in region that escapes X inactivation and polysomy X. The most common mosaic is considered to be a key player in limb complement is 46,XX/47,XXX, but development and height determination. 47,XXX/48,XXXX and 48,XXXX/49, The stature reported for patients with XXXXX have been described (13). 48, XXXX syndrome is typically above Other phenotypic anomalies average. Several studies on SHOX gene associated to this chromosomal indicate an additive effect that might anomaly are: heart defects, hip explain the tall stature observed of dysplasia, ovarian dysfunction, skeletal these girls (19-21). anomalies (radioulnar synostosis), There is a paucity of information hypotonia, joint laxity, dental regarding the gonadal function and anomalies. development of secondary sexual Variable intellectual disability is characters for patients with 48,XXXX. characteristic for this chromosomal It has been noted in the few studies disorder (14). A lot of women with available that the 48, XXXX female has tetrasomy X are of low-to-normal or diminished ovarian function (15). borderline intelligence (15). Some Absence of the ovaries was studies report a higher frequency of demonstrated in one case (22). The low schizophrenic symptoms observed for levels of estrogen observed for the the 48,XXXX patients compared with premature ovarian insufficiency (POI) the general population (16). This girl associated with this condition might will be followed on the long-term, also influence the tall stature reported attempting and new learning and social for these females. In the context of the adaptation therapies will be attempted. new identified diagnosis our patient Repeated psychological evaluations will be evaluated also in the next years will be performed. also from an endocrinological point of Our patient presented low birth view, considering growth monitoring weight and length associated with the onset of menarche, puberty and increased height in early childhood. fertility. These morphometric features are In pure tetrasomy X fertility is on indicative for a sex chromosome record in only one case. It appears that abnormality. In 48,XXXX individuals, sterility is common (15), but if the three of the four X chromosomes get to patient has normal ovarian be inactivated. About 5-10% of the development and function it is possible genes on the inactive X chromosome for a female 48,XXXX to reproduce. 630 Tetrasomy X Fertility and normal offspring has been might be useful to join support groups reported for several cases. In the to receive individual and family instance of pregnancy, patients with support. 48,XXXX should undergo prenatal Conflict of interest. investigations to