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Background: 49, XXXXY syndrome is a rare sex chromosomal disorder, occurring in 1 per 85,000-100,000 male births. The classical phenotype is ambiguous genitalia, facial dysmorphism, mental retardation and a combination of cardiac, skeletal and other malformations. Case: A two month-old boy with intrauterine growth restriction (IUGR) and low birth weight, facial dysmorphism, clinodactyly in feet, microphallus, and right undescendent testis were seen by neonatologist. Chromosomal studies via techniques of GTG-banding showed the constitution to be 49,XXXXY in all cells. He was visited by the pediatric cardiologist for congenital heart disease. No obvious malformation and congenital heart disease were seen. Conclusion: In the case, the main presentation of IUGR and low birth weight, clinodactyly with facial dysmorphism and genital abnormalities led to a suspicion of a sex chromosome aneuploidy which was subsequently confirmed by chromosomal analysis.

This paper presents a six-year-old patient with XXXXY syndrome, whose oral findings included a cleft soft palate, hyper- or meso-taurodontism in eight primary molars and in the mandibular permanent first molars, five congenitally missing premolars, and delayed development of the permanent tooth germs. The maxillary and mandibular primary central incisors were in a cross-bite relationship. Cephalometric findings showed a short ramus of the mandible and a short maxilla in the anterio-posterior plane. The anteroposterior jaw relationship was in harmony. The cross-bite was considered to be due to the retroinclination of the maxillary primary incisors. This case emphasises the importance of regular dental care, and monitoring of facial growth and dental development in children with XXXXY syndrome.

Summary We report the case of a 19-year-old boy, presenting several congenital malformations (facial dysmorphisms, cardiac and musculoskeletal abnormalities), mental retardation, recurrent respiratory infections during growth and delayed puberty. Although previously hospitalised in other medical centres, only psychological support had been recommended for this patient. In our department, genetic, biochemical/hormonal and ultrasound examinations were undertaken. The karyotype was 49,XXXXY, a rare aneuploidy with an incidence of 1/85 000–100 000, characterised by the presence of three extra X chromosomes in phenotypically male subjects. The hormonal/biochemical profile showed hypergonadotropic hypogonadism, insulin resistance and vitamin D deficiency. The patient was then treated with testosterone replacement therapy. After 12 months of treatment, we observed the normalisation of testosterone levels. There was also an increase in pubic hair growth, testicular volume and penis size, weight loss, homeostatic model assessment index reduction and the normalisation of vitamin D values. Moreover, the patient showed greater interaction with the social environment and context. Learning points In cases of plurimalformative syndrome, cognitive impairment, recurrent infections during growth and, primarily, delayed puberty, it is necessary to ascertain as soon as possible whether the patient is suffering from hypogonadism or metabolic disorders due to genetic causes. In our case, the diagnosis of hypogonadism, and then of 49,XXXXY syndrome, was unfortunately made only at the age of 19 years. The testosterone replacement treatment, even though delayed, induced positive effects on: i) development of the reproductive system, ii) regulation of the metabolic profile and iii) interaction with the social environment and context. However, earlier and timely hormonal replacement treatment could probably have improved the quality of life of this subject and his family.

49,XXXXY syndrome is a rare sex chromosome aneuploidy and characterized by mental retardation, skeletal defects, craniofacial anomalies and hypogonadism. The increased frequency of diabetes mellitus in patients with Klinefelter syndrome and other types of X-chromosome polysomy has been reported, but no cases of diabetes mellitus in adult with 49,XXXXY syndrome have been reported so far. We report an 18-year-old patient with 49,XXXXY syndrome accompanying diabetes mellitus.

49,XXXXY syndrome is a rare sex chromosome aneuploidy syndrome characterized by mental retardation, severe speech impairment, craniofacial abnormalities, multiple skeletal defects, and genital abnormalities. We describe a 13-year-old boy with 49,XXXXY syndrome, language impairment, seizures, and left-hemisphere magnetic resonance imaging abnormalities and review the distinctive neurologic, cognitive, and behavioral phenotypes associa t e d w i t h t h i s d i s o r d e r. F i n a l l y, w e d i s c u s s testosterone supplementation in the treatment of this syndrome. ( J Child Neurol 2003;18:501—504).

49,XXXXY syndrome which is characterized with the addition of three extra X chromosomes to 46,XY is the rarest sex chromosome aneuploidy syndrome. Its classical findings were defined as a triad of mental retardation, hypogonadism and radioulnar synostosis. In 49,XXXXY syndrome, congenital heart defects like patent ductus arteriosus, atrial septal defect, ventricular septal defect, pulmonary stenosis, Fallot’s tetralogy have been reported. We present a case diagnosed in the newborn stage with low birth weight, short stature, dysmorphic craniofacial findings and hypoplastic male genitalia who was found to have severe pulmonary hypertension and medium patent ductus arteriosus when admitted at 4 months of age with heart failure and who underwent transcathater ductus closure with Amplatzer Duct Occluder I. To our knowledge, our case is the first reported 49,XXXXY syndrome with patent ductus arteriosus closed with the transcathater route. 49,XXXXY sendromu, 46,XY’ye ekstra üç X kromozomu eklenmesi ile karakterize nadir görülen cinsiyet kromozom anöploidi hastalığıdır. Klasik bulguları mental retardasyon, hipogonadizm, radioulnar sinostozis triadı olarak tanımlanmıştır. 49,XXXXY sendromunda patent duktus arteriozus, atriyal septal defekt, ventrikuler septal defekt, pulmoner stenoz, Fallot tetralojisi gibi konjenital kalp defektleri bildirilmiştir. Yenidoğan döneminde düşük doğum ağırlığı, kısa boy, dismorfik kraniyofasiyal bulgular ve hipoplastik erkek genitalya ile tanısını koyduğumuz ve 4 aylık iken kalp yetersizliği kliniği ile kabul edildiğinde ciddi pulmoner hipertansiyonu ve orta büyüklükte patent duktus artriyozusu saptanarak, duktusu transkateter Amplatzer Duktal Okluder I ile kapattığımız olguyu sunuyoruz. Bildiğimiz kadarıyla bu olgu patent duktus artiyozusu transkateter kapatılan ilk 49,XXXXY sendromudur.

Ullrich-Turner syndrome (UTS 45,X), Klinefelter syndrome (47,XXY), XXX, and XYY are the most common sex chromosome aneuploidies. In contrast, trisomy and tetrasomy Y are rare, and they occur predominantly in mosaic form. Dicentric Y-chromosomes are one of the most frequent Y-chromosomal rearrangements [Gersen and Keagle, 1999]. Most (91%) are found in mosaic form, usually a 45,X cell line. Two types of idic(Y) chromosomes can be discerned: those with a break in the short arm have two copies of the long arm and proximal short arm, and those with a break in the long arm have a

49,XXXXY syndrome is a very rare condition that is associated with a considerable more severe phenotype than classic 47,XXY Klinefelter syndrome. We present a patient with 49,XXXXY syndrome, who was first presented to an endocrinological unit at the age of 12.5 years with prepubertal genitalia. He was then lost from follow-up and showed clear clinical and biochemical signs of hypergonadotropic hypogonadism when presenting again at the age of 16 years. The patient was started on testosterone replacement therapy. This case is reported to underline the need for thorough endocrinological follow-up examinations in males with X polysomies.

Pentasomy 49,XXXXY is a rare sex chromosome disorder usually presenting with ambigous genitalia, facial dysmorphism, mental retardation and a combination of cardiac, skeletal and other malformations. The incidence of the condition is estimated to be 1 in 85,000 male births. Previously, this condition was identified as a Klinefelter variant. The condition is suspected in a patient, by a combination of characteristic clinical findings, and the diagnosis is confirmed by chromosome culture and karyotyping. In the case we report here, the main presentation of ambiguous genitalia led to a suspicion of a sex chromosome aneuploidy which was subsequently confirmed by chromosomal analysis.

The developmental history of a 14-year-old male with Klinefelter's syndrome (XXXXY) is described. A review of the XXXXY literature focuses on the physical complications and the mental deficiency associated with this syndrome. This case study describes an individual whose physical development is consistent with many patterns described in the XXXXY literature, although his retardation is not as severe as generally described. His personality and learning style are more similar to descriptions of XXY Klinefelter individuals. A detailed analysis of more XXXXY cases is essential to clarify developmental patterns and learning capacity in individuals with XXXXY syndrome. Severe retardation may no longer need to be the anticipated developmental outcome.

Two patients with the XXXXY syndrome are presented. Both boys are mentally retarded with short stature, muscular hypotonia, and hypogonadism. A constant feature of this syndrome is a varying degree of epiphysial dysplasia probably secondary to hypotonia and growth deceleration.

The XXXXY chromosome abnormality appears to be associated with a clinicallyrecognizable syndrome of severe mental retardation, hypoplastic genitals, multiple skeletal anomalies, and findings suggestive of mongolism. The XXXXY syndrome can be distinguished from mongolism by the examination of the epithelial cells of the buccal smear for chromatin bodies. Another important clue is the roentgenographic demonstration of proximal synostosis of the radius and ulna. The eighth case of this syndrome is reported and the literature reviewed.

Neben dem klassischen Klinefelter-Syndrom mit der Chromosomenkonstellation 47,XXY stehen heute eine Reihe von Varianten, deren haufigste 46,XX, 48,XXYY, 48,XXXY und 49,XXXXY sind. Auf Grund seiner unverkennbaren Symptomatologie nimmt das XXXXY-Syndrom unter ihnen eine Sonderstellung ein. Mindestens 79 Falle dieses Karyotyps wurden bis Ende 1972 in der Literatur mitgeteilt. 7 neue Falle dieses seltenen Syndroms werden beschrieben. Haufige Symptome sind die intrauterine Dystrophie, die erhebliche psychomotorische Retardierung, das hypoplastische Genitale, eine eigenartige Facies und Skeletanomalien, die vor allem Unterarm und Hand betreffen (radioulnare Synostose, Klinodaktylie oder Brachyphalangie der 5. Finger, Pseudoepiphysen der Mittelhandknochen). Seltenere Symptome sind Augenfehler und angeborene Vitien, insbesondere ein offener Ductus Botalli. Mit Hilfe der Xg-Blutgruppenanalyse war es mehrfach moglich, den Nachweis zu erbringen, das alle 4 X-Chromosomen mutterlicher Herkunft sein mussen. Als Ursache der Polysomie des X-Chromosoms wird daher in diesen Fallen eine sukzessive Non-disjunction diskutiert.

Bei einem Buben mit dem XXXXY-Syndrom konnte durch Bestimmung der Xga-Blutgruppeneigenschaft die Herkunft der uberzahligen X-Chromosomen bestimmt werden: Der Vater ist Xg (a+), die Mutter ist Xg (a-) und der Bub ist ebenfalls Xg (a-). Das bedeutet, das der Bub alle X-Chromosomen von der Mutter erhalten haben mus. Die verschiedenen Modellvorstellungen fur die Entstehung dieser Uberzahl der X-Chromosomen in der Zygote werden diskutiert.

A boy with 49,XXXXY karyotype is described with only mild mental retardation at 18 months. Physical abnormalities included patent ductus arteriosus, undescended testes, small penis, bilateral epicanthal folds, and incurved 5th digits with small middle phalanges. Literature review showed 7 previous cases of XXXXY patients with congenital heart disease. 23% of buccal cells showed 1 sex chromatin body; 26% showed 2 and 11% 3. Autoradiography demonstrated 3 heavily labelled X chromosomes. The heteropyknotic behavior of X Chromosomes in excess of one may provide some measure of protection against excessive numbers of X chromosomes, bence the relatively normal development of some XXXXY patients.

In 2 adult male patients with 49 chromosomes, an XXXXY sex chromosome constitution was confirmed by trypsin-Giemsa banding sites. Clinical findings as well as fingerprint ridge counts were typical of the syndrome. Primary hypogonadism was documented by finding low serum testosterone and raised serum LH and FSH levels. Several radiological abnormalities, not previously described in this syndrome, were seen in 1 patient.

A second case of fetal XXXXY-syndrome detected by prenatal chromosome analysis is presented. The pathological findings include a facial aspect featuring fetal Down's syndrome, hypogenitalism and hypogonadism with excessive reduction of germ cells and also skeletal abnormalities that may be interpreted as early changes, preceding phalangeal shortening V and radioulnar synostosis.

A case previously described as an XXXxY male has been re-appraised using 3H-thymidine. A balanced translocation probably involving the long arms of chromosomes 4 and 11 was found; all four X chromosomes were normal. Without quantitative autoradiography, this case would not have been correctly evaluated. The translocation was carried only in the balanced form. The translocated segment did not alter its labelling behaviour in its new site. Apart from the propositus, who had XXXXY sex chromosomes and the typical clinical features of the XXXXY syndrome, a brother and the father, both healthy, had the autosomal translocation. Pedigree and blood group studies showed no apparent abnormalities in the family.

The XXXXY syndrome has several distinctive phenotypic features, the most prominent of which are mental retardation and hypogonadism (small penis and small and/or undescended testes). Of the 61 cases of the XXXXY syndrome reviewed, not including the present case, all of the patients had severe mental retardation. Other characteristics include skeletal abnormalities, especially of the elbows and wrists, and clinodactyly of the fifth fingers.1-5 Despite the generally accepted contention that the probability of mental retardation increases proportionately with the number of X chromosomes present,2the 15-month-old XXXXY boy reported here has a normal Gessell adaptive maturity level with only minor motor abnormalities. Report of a Case A male infant of Yugoslavian extraction was born on Nov 9, 1967. He was 8 weeks old when he was referred for evaluation of a peculiar facies and marked redundancy of the skin of the posterior cervical region. The mother was 27

A child with the XXXXY syndrome who had normal intellectual development at 15 months of age was found to have a deceleration of intellectual development and consequent mental retardation at 41 months of age.