Variant Of Klinefelter Syndrome Research Articles

An ultra-rare case of 47,XXY/48,XXXY/49,XXXXY mosaic Klinefelter syndrome associated with diabetic ketosis and foot ulcer

Klinefelter syndrome (KS) is the most common chromosome aneuploidy and a common cause of infertility in males. KS patients have at least one extra X chromosome, and about 80% of patients have the karyotype 47,XXY. Twenty percent of KS patients have higher-grade aneuploidies (48,XXXY, 48,XXYY, 49,XXXXY) and exert some clinical manifestation different from those with 47,XXY. Here we report the case of a young man who initially presented with diabetic ketosis and foot ulcer and was later diagnosed as having an extremely rare mosaic variant of KS (47,XXY/48,XXXY/49,XXXXY). Clinical and laboratory features are summarized. The patient developed a severe foot ulcer with an 18-month history of diabetes. Learning disability was noted since early childhood. The patient had typical manifestations of KS, including increased height, sparse beard and body hair, and small penis. He also had some characteristic features of patients with additional sex chromosomes, including epicanthal folds, narrow palpebral fissures, prominent elbows, and undescended testicles. Severe myopia and myopic macular degeneration was also found. Lab tests revealed low testosterone and elevated FSH but normal LH levels. Chromosome analysis on lymphocytes revealed an aberration of 47,XXY/48,XXXY/49,XXXXY. This case provides information on KS patients with the extremely rare karyotype 47,XXY/48,XXXY/49,XXXXY, and also emphasizes the importance of considering KS in the differential diagnosis of a sterile male with diabetes.

Array-CGH revealed gain of Yp11.2 in 49,XXXXY and gain of Xp22.33 in 48,XXYY karyotypes of two rare klinefelter variants.

Klinefelter syndrome (KS) variants often share common features with classical syndrome but some of these variants present with a distinct phenotype. The incidence of sex chromosome tetrasomy and pentasomy are very less and generally diagnosed after prepubertal age. The early diagnosis of complex and unclassified syndromes and it's correlation with genotype is necessary for personalized treatment as well as genetic counselling of the affected families. We describe clinical presentation, and genetic diagnosis of two cases of variant KS. Our first case, a 4 year old male child presented with generalized tonic-clonic seizures (GTCSs), delayed milestones and dysmorphic features while case 2, a-21 years old male who had history of seizures and delayed puberty came to our lab for genetic diagnosis. The chromosomal analysis of case 1 and 2 showed 49,XXXXY and 48,XXYY karyotype respectively. The karyotype results were confirmed with fluorescence in situ hybridization (FISH) and array-CGH analysis. The FISH results were found to be consistent with karyotype but the array-CGH results showed the extra gain of region Yp11.2 in case 1 while the extra gain of region Xp22.33 in case 2. The cases were confirmed as variant KS on the basis of additional sex chromosomes and clinical presentation of deteriorated brain development. The present study suggests that the high doses of sex chromosome linked genes including pseudoautosomal region (PAR) caused the abnormal brain development. The combination of molecular techniques should be utilized for the diagnosis of such complex cases to understand the genotype-phenotype correlation and appropriate genetic counseling.

P28 Marfan syndrome? Think again!

Abstract Background A 21 year old male was referred to the adult hypermobility clinic from the local rheumatologist with a suspected diagnosis of Marfan syndrome, based on his body habitus although he had presented to his GP with painful toes. Methods He had a background of autism,learning difficulties and was wearing glasses due to amblyopia. He had a history of dental crowding with two previous teeth extractions. There was no family history of note. On examination, his arm span was not greater than his height, there was no arachnodactyly, his palate was normal, but he had gum hypertrophy. His skin texture was normal, with no abnormal scarring or bruising, but there was presence of striae. His Beighton score was 4/9 and he had flat feet. There was reduced muscle mass and hypotonia, which was felt to be the cause of his hypermobility, rather than increased ligamentous laxity. There was evidence of gynaecomastia and lack of facial hair. The working diagnosis was Klinefelter syndrome due to his tall stature, gynaecomastia and absence of secondary male characteristics. Subsequently, the patient was referred to endocrinology and for genetic testing. Results The endocrinology team recognised the clinical features of male hypogonadism with small phallus (Tanner stage 2/3) and small testes, confirmed also by ultrasound. The patient reported absence of early morning erections. Blood tests confirmed hypergonadotropic hypogonadism (high luteinizing hormone, low testosterone) and the patient was commenced on testosterone therapy. His bone mineral density values lied within the expected range for age. Karyotype analysis confirmed the presence of 48,XXYY which is a chromosomal condition characterized by the presence of an extra X and Y chromosome in males. In terms of management, he attended our Outpatient Hypermobility Exercise Programme and was given advice on footwear. He was provided with extensive written information about this condition by the Rare Chromosome Disorder Support Group, Unique. Conclusion Our case report illustrates the importance of considering 48,XXYY syndrome in patients with typical body habitus and joint hypermobility. Marfanoid habitus is associated with connective tissue diseases, like hypermobile Ehlers-Danlos syndrome and Marfan syndrome, but also described in homocystinuria and Klinefelter syndrome. 48,XXYY was considered previously as a variant of Klinefelter syndrome, but now it is regarded as a separate syndrome with overlapping features with the Klinefelter syndrome. As in our case, the classical phenotypic characteristicsinclude gynaecomastia, small testes and tall stature. Most affected individuals are infertile. This syndrome is also associated with behavioural problems, learning difficulties, congenital heart defects, bone abnormalities, tremor, obesity, type 2 diabetes and/orrespiratory problems. Patients have an essentially normal life expectancy but require regular medical follow-up. Disclosures A. Madenidou None. V. Choida None. V. Reddy None. H. Kazkaz None.

Morbid Obesity and Psychiatric Disorders Hiding a Sex Aneuploidy: A Case of Late Diagnosis of 48,XXYY Syndrome

48,XXYY syndrome is a rare sex chromosomal aneuploidy, with a prevalence of 1:18,000 - 1:50,000 males. Despite it being considered as a variant of Klinefelter syndrome, it is now known to be a distinct entity, differing from the latter due to a greater degree of severity and prevalence of psychiatric disorders and mental deficiency. We present the case of a 37-year-old man with psychiatric disease who attended our department due to morbid obesity, identified as a 48,XXYY genotype. Clinical evaluation and cytogenetic analysis is presented.

48, XXYY Genotype: Case Report of a Rare Clinical Syndrome

Klinefelter Syndrome (KS) is the most common sex chromosomal disorder which occurs in approximately 1 per 500 live born male births [1]. The characteristic clinical features of KS with the classic 47, XXY karyotype is well recognized which includes seminiferous tubule dysgenesis, androgen deficiency, cognitive and behavioral dysfunction, increased risk of autoimmune disorders, thromboembolic disease and cancer [2]. With each additional X chromosome there is progressive divergence from the normal with increased frequency of phenotypic, endocrine and structural abnormalities [3]. Poly X-syndrome, often described in literature as a variant of KS, is much rarely reported with a prevalence of 1:18,000-1:100,000 male births and has more pronounced congenital malformations and associated medical comorbidities [4]. We describe a case of a patient who had a formal diagnosis of classic KS from a very young age of 14, presented with not only behavioral and cognitive impairment but also with a wide spectrum of medical complications and further identified on reassessment as XXYY genotype.

Abstract #918: Rare Variant of Klinefelter Syndrome in a Man Presenting with Suspected Hyperthyroidism

Abstract #918: Rare Variant of Klinefelter Syndrome in a Man Presenting with Suspected Hyperthyroidism

Cognitive, Affective Problems and Renal Cross Ectopy in a Patient with 48,XXYY/47,XYY Syndrome.

Klinefelter syndrome is the most common sex chromosome abnormality (SCA) in infertile patients and 47,XXY genomic configuration constitutes most of the cases. However, additional Xs and/or Y such as 48,XXYY, 48,XXXY, and 47,XYY can occur less frequently than 47,XXY. Those configurations were considered as variants of Klinefelter syndrome. In this report, we present an infertile man with tall stature and decreased testicular volume. Semen analysis and hormonal evaluation supported the diagnosis of nonobstructive azoospermia. Genetic investigation demonstrated an abnormal male karyotype with two X chromosomes and two Y chromosomes consistent with 48,XXYY(17)/47,XYY (13). Additionally, the patient expressed cognitive and affective problems which were documented by psychomotor retardation and borderline intelligence measured by an IQ value between 70 and 80. Systemic evaluation also revealed cross ectopy and malrotation of the right kidney in the patient. The couple was referred to microtesticular sperm extraction (micro-TESE)/intracytoplasmic sperm injection (ICSI) cycles and preimplantation genetic diagnosis (PGD). To the best of our knowledge, this is the first report of combination of XYY and XXYY syndromes associated with cognitive, affective dysfunction and renal malrotation.

Azoospermie et tétrasomie 48,XXYY : quelle prise en charge de l’infertilité ?

48,XXYY syndrome is a rare form of sex chromosomal aneuploidy. Usually considered as a variant of Klinefelter syndrome because of shared features (azoospermia, tall stature, hypergonadotropic hypogonadism), it is a separate entity because diagnostic is currently made in prepubertal boy with neuro-psychological disorders. We here report the case of a 48,XXYY patient consulting for adult infertility and the indication to perform testicular sperm extraction is discussed.

Oral Manifestations of 49XXXXY

49XXXXY syndrome was described in1960 as a rare aneuploidy syndrome with an incidence of 1:85,000 male births. Until 1998 it was considered a variant of Klinefelter syndrome, but Peet and colleagues described it as a distinct syndrome presenting a triad composed by mental retardation, radioulnar synostosis, and hypogonadism. Cardiac, circulatory, and respiratory abnormalities can also be observed. Oral manifestations are reported in only four articles. White man, 30, with 49XXXXY syndrome was referred for dental treatment.

Musculoskeletal anomalies in a large cohort of boys with 49, XXXXY

49, XXXXY is a rare aneuploidy and variant of Klinefelter syndrome, occurring in 1 per 80,000-100,000 live births. We present a cohort of 40 affected males, focusing on musculoskeletal problems. Subjects were participants in an annual 49er family support group meeting. Children were examined in a multidisciplinary clinic by a pediatric neurologist and geneticist, a pediatric orthopedist, a neurodevelopmentalist, and two physical therapists. The patient data were collected from this clinic from 2004 to 2012. All patients were required to have karyotypes that confirmed the presence of XXXXY. There was a high prevalence of musculoskeletal disorders, particularly hypotonia (34 patients [85%]), radioulnar synostosis (30 [75%]), pes planus (26 [65%]), asymmetric hip rotation (27 [67.5%]), and clinodactyly (24 [60%]). Other, less common lower-extremity disorders, included, 5 patients (12.5%) with unilateral club foot, 5 boys (12.5%) with pes cavus, 10 patients (25%) genu valgum and 2 children with genu varus (5%). To our knowledge, this is the first large cohort of boys with 49, XXXXY that focuses on musculoskeletal disorders. There was an increased incidence of hypotonia, clubfoot, avascular necrosis of the femoral head, radioulnar synostosis, and pes planus compared to the normative population. Boys with 49, XXXXY would benefit from multidisciplinary evaluations, particularly from pediatric orthopedists, physical therapists, neurologists, and geneticists for appropriate medical care.

Diagnosis of Variant Klinefelter Syndrome in a 21-Year-Old Male Who Presented with Sparse Facial Hair

Dear editor: Klinefelter syndrome (KS) describes a sex chromosomal aneuploidy caused by the addition of at least one extra X chromosome to normal male karyotype, XY. It is the most common disorder of sex chromosomes with a prevalence of one in 600 males1. Variants of KS are characterized by the addition of an extra X or Y chromosome to classic karyotype 47,XXY. Although somatic malformations and mental retardation are more severe in these variants, most cases remain undiagnosed till puberty when the symptoms of androgen deficiency are recognized2,3. A 21-year-old male presented with sparse facial hair since the onset of puberty. His medical history revealed cryptorchidism, delayed neuromotor development, and mild mental retardation recognized in early childhood. His parents were nonconsanguineous, and there was no history of a genetic disease in the family. On physical examination, the facial (Fig. 1A) and axillary hair (Fig. 1B) were sparse whereas other body hair was in normal density. His height and weight were 193 cm and 103 kg, respectively, and the feminine distribution of the adipose tissue was striking on examination (Fig. 1C). He had dysmorphic features consisting of hypodontia, hypoplastic teeth, prognatism, short filtrum (Fig. 1A), gynecomastia (Fig. 1C), clinodactily, and fusiform shaped fingers. Chromosome analysis of a peripheral blood sample disclosed a 48,XXXY karyotype, compatible with the diagnosis of variant KS. Fig. 1 (A) Sparse facial hair, prognatism and short filtrum. (B) Sparse axillary hair. (C) Gynecomastia and feminine distribution of adipose tissue. Detailed hormonal profile analysis revealed a hypergonadotropic hypogonadism, and mild hypothyroidism. Furthermore, scrotal ultrasonography showed small sized testicles. Accordingly, the patient was started on testosterone treatment. Patients with KS may present with a variety of subtle clinical signs of endocrinological, psychological and orthopedic problems. Thus the diagnosis may be quite challenging after birth. In infancy, hypospadias, cryptorchidism or small phallus may be helpful for the diagnosis, while during childhood, speech and language deficits, behavioral and cognitive problems may serve as diagnostic clues1. After puberty, a relative testosterone deficiency becomes evident, and suspicion arises when the development of secondary sexual characteristics is not completed4. The typical male with KS is characterized by eunuchoid body proportions, abnormally long legs and arm span, feminine distribution of adipose tissue, absent or sparse facial, body and sexual hair, small testes and penis. The syndrome may later be diagnosed among adults with azoospermia visiting infertility clinics2. Correct diagnosis needs careful attention as the syndrome is mostly overlooked. One study showed that 10% of the cases were recognized prenatally while 26% were diagnosed in childhood or adult life, leaving 64% of the cases undiagnosed2. The existence of every extra chromosome in KS worsens the clinical manifestation. An average to tall stature, ocular hypertelorism, flat nasal bridge, epicanthic folds, low set ears, prognathism, kyfosis, scoliosis, radioulnar synostosis and clinodactily are common findings of 48,XXXY variant of KS1,3. Prevalence of this disorder is approximately 1:50,0001,3. The rarity of reports may be due to a phenotype identical to the 47,XXY phenotype3. Thus, in the literature, the data for 48,XXXY variants is limited, especially regarding the age of diagnosis and congenital malformations5. Clinicians should pay more attention to this easily overlooked syndrome in order to diagnose more boys with KS at an earlier age. The finding of sparse facial and axillary hair, even though could be familial, is a typical symptom of hypogonadism. Among the most frequent causes of male hypogonadism, KS should come to mind in the presence of eunuchoid body proportions, cognitive or dysmorphic facial features. Unfortunately, our case was left undiagnosed till he visited our clinic with the complaint of sparse facial hair at the age of 21. When his dysmorphic features came to notice during the dermatologic examination, a chromosome analysis was performed and the patient was properly diagnosed as variant KS. In conclusion, KS and its variants can be recognized by even very indefinite findings such as sparse facial hair when combined with a careful detailed physical examination. Thus, we would like to emphasize the importance of a thorough physical examination during dermatological evaluation of a patient that can disclose any underlying systemic illness.

An adolescent with 48,xxyy syndrome with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder and renal malformations

48,XXYY is a rare sex chromosome aneuploidy affecting 1 in 18,000 to 50,000 male births. They present with developmental delay, hypogonadism, gynecomastia, intention tremors, and a spectrum of neurodevelopmental and psychiatric disorders. At one time this condition was considered a variant of Klinefelter syndrome. In clinically suspected cases, 48,XXYY syndrome can be diagnosed by chromosome culture and karyotyping. This patient presented with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder, and renal malformatons. Klinefelter syndrome was clinically suspected. The karyotype confirmed the diagnosis of 48,XXYY syndrome. This is the first reported case of 48,XXYY syndrome from Sri Lanka.

48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome

Sex chromosome tetrasomy and pentasomy conditions occur in 1:18,000-1:100,000 male births. While often compared with 47,XXY/Klinefelter syndrome because of shared features including tall stature and hypergonadotropic hypogonadism, 48,XXYY, 48,XXXY and 49,XXXXY syndromes are associated with additional physical findings, congenital malformations, medical problems and psychological features. While the spectrum of cognitive abilities extends much higher than originally described, developmental delays, cognitive impairments and behavioural disorders are common and require strong treatment plans. Future research should focus on genotype-phenotype relationships and the development of evidence-based treatments. The more complex physical, medical and psychological phenotypes of 48,XXYY, 48,XXXY and 49,XXXXY syndromes make distinction from 47,XXY important; however, all of these conditions share features of hypergonadotropic hypogonadism and the need for increased awareness, biomedical research and the development of evidence-based treatments.

Cytogenetic abnormalities and azoospermia factor (AZF)microdeletions in infertile men from Kuwait

Cytogenetic abnormalities and azoospermia factor (AZF)microdeletions in infertile men from Kuwait

Cleft Palate in a Rare Case of Variant Klinefelter Syndrome with 48,XXXY/46,XY Mosaicism

Variant Klinefelter syndrome with 48,XXXY/46,XY mosaicism has been rarely reported, and its phenotypic features, compared with those of the classic type, have not been well delineated. We describe a newborn baby with phenotypic abnormalities, including cleft palate and low-set ears. The cytogenetic analysis of peripheral blood lymphocytes showed a karyotype of 48,XXXY[36]/46,XY[4]. To the best of our knowledge, this is the first case in which 48,XXXY/46,XY mosaicism was related to the congenital anomaly of cleft palate. This case underscores that cytogenetic analysis should be a mandatory workup for the patient with cleft palate and that cleft palate may be a rare clinical presentation of the variant Klinefelter syndrome.

A Variant Klinefelter Syndrome Patient with an XXY/XX/XY Karyotype Studied by GTG-Banding and Fluorescence in Situ Hybridization

Klinefelter syndrome is the first human sex chromosomal abnormality to be reported. The majority of Klinefelter syndrome patients have the XXY karyotype. Approximately 15% of Klinefelter patients, however, are mosaics with variable phenotypes. Among the variant Kline felter genotypes are such karyotypes as XY/XXY and XX/XXY. The variation in phenotypes most likely depends on the number of abnormal cells and their location in body tissues. In this paper we report the case of a 42-year-old patient with Klinefelter syndrome and a rare variant mosaic XXY/XX karyotype initially identified by GTG-banding. This was confirmed by fluorescence in situ hybridization (FISH) using a dual-color X/Y probe. The patient presented with erectile dysfunction and few other physical findings. Thus, this case illustrates a rare variant of Klinefelter syndrome with a relatively mild phenotype. It also illustrates the utility of FISH as an adjunct to conventional cytogenetics in assessing the chromosome copy number in each cell line of a mosaic. In our case, FISH also detected the presence of a small population of cells with the XY karyotype not previously detected in the initial 30-cell GTG-banding analysis. Thus, through a combination of GTG-banding and FISH, the patient was determined to be an XXY/XX/XY mosaic. Given that most individuals with Klinefelter syndrome are infertile, and that these individuals may wish to reproduce with the aid of modern reproductive technology, such as testicular fine needle aspiration and intracytoplasmic sperm injection, it is important that accurate estimation of the frequency of abnormal cells be obtained for accurate risk estimation and genetic counseling, as recent studies in patients with mosaic Klinefelter syndrome revealed that germ cells with sex chromosomal abnormalities were nevertheless capable of completing meiosis.

Screening for connexin 32 mutations in Charcot-Marie-Tooth disease families with possible X-linked inheritance.

The X-linked dominant form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in a gene coding for the gap-junction protein connexin 32 (Cx32). We screened 32 CMT families with a pedigree pattern suggestive of X-linked inheritance for the presence of mutations in the coding region of Cx32 by direct sequencing. Five of the families had a CMT1 diagnosis, 24 had a CMT2 diagnosis and 3 patients had an unspecified CMT. Eight families with a Cx32 point mutation were detected. Five different mutations (four of them published previously) were found in six CMT2 families and one mutation was found in a sporadic CMT1 male patient. One of the mutations, Met194Val, is among the first described in the fourth transmembrane domain of Cx32. Two CMT2 families and the sporadic CMT1 patient had the same mutation, Arg22Gln. An additional, previously unpublished mutation, Arg75Trp, was found in a male patient with unspecified CMT, who subsequently was verified to have a variant Klinefelter syndrome with 48,XXYY karyotype. Our findings show the difficulty in distinguishing CMTX patients from CMT1 and CMT2 patients, and they emphasize the need for Cx32 mutation screening in families previously diagnosed with CMT2.

In Reply: Klinefelter Syndrome and Fire-Setting Behavior

We appreciate the comments of Dr Eberle that provide further anecdotal experience for an association between Klinefelter syndrome and fire-setting behavior. In addition, her observation and Sorenson's observations which she notes provide additional evidence that testosterone may be helpful in individuals with Klinefelter syndrome who have fire-setting behavior or other antisocial behavior including stealing and violence toward others. We have also seen an additional individual with variant Klinefelter syndrome, similar to Dr Eberle's patient.