Presentation
History
Hypogonadism, gynecomastia, and infertility are common symptoms that lead to the diagnostic evaluation of males for Klinefelter syndrome.
Other symptoms include the following:
Tall height with long arms and legs
Delayed or incomplete pubertal development
Sparse facial, body, and sexual hair
Erectile dysfunction
Osteoporosis
Breast malignancy
Speech and language deficits [especially expressive language]
Learning disabilities [lower verbal IQ than performance IQ scores]
Poor self-esteem [increased incidence of anxiety, depression]
Behavioral problems [substance abuse]
Physical
Frequently associated medical disorders
These include the following. [18]
Motor, cognitive, and behavioral dysfunction
Poor muscle tone and strength, as well as impaired gross and fine motor skills, coordination, dexterity, and running ability, are observed. Synkinetic movements and tremor can be seen in early childhood and may persist into adulthood. [19, 20]
Cognitive phenotype is manifested as deficits in the specific domains of language and executive functions. Expressive language is affected more than comprehension or receptive language skills. Problems in understanding complex grammatical constructions, oral language production, word retrieval, and oral narrative construction are observed in these patients. [21] A study by Skakkebæk et al suggested that in persons with KS, the level of social engagement has an impact on executive cognitive functioning and/or vice versa. The study indicated that while lower general intelligence seems to be the principal factor in memory deficits among these individuals, a combination of decreased intelligence and lower social skills produce deficits in executive function. [22]
Schizophrenia, psychosis, and bipolar disorder have been reported in males with Klinefelter syndrome. [23]
Tumors/Cancer
Mediastinal tumors may occur in young patients, presenting as precocious puberty; histologically, these neoplasms are classified as mixed germ cell tumors. Mediastinal tumors in older males present with thorax-associated symptoms, primarily chest pain, dyspnea, and cough; mixed germ cell tumors are more common, but teratomas and other mixed tumors occur. [24]
Breast cancer and testicular cancer are reported, although a clear relationship between Klinefelter syndrome and testicular cancer has not been documented.
Vascular disease
Vascular diseases associated with Klinefelter syndrome include hypostatic ulceration, deep vein thrombosis, pulmonary embolism, and ischemic heart disease.
Endocrine/metabolic and autoimmune diseases
Hypogonadism [pathognomonic] and associated osteoporosis occur. Bone density decreases in 25% of males with Klinefelter syndrome, with this most likely being related to decreased bone formation, increased bone resorption, and/or hypogonadism.
An increased incidence of diabetes mellitus, obesity, hypothyroidism, Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus have been reported in males with Klinefelter syndrome.
Other observations
Growth
Infants and children achieve normal height, weight, and head circumference. Height velocity shows a notable increase between ages 5 and 8 years. Adults with Klinefelter syndrome are usually taller than nonaffected adult males, reaching a mean final height of about 185 cm [73 in]. XXY males [see the image below] also have disproportionately long arms and legs. About 25% of patients have fifth-finger clinodactyly. Some males with Klinefelter syndrome variant 49,XXXXY have short stature.
CNS
Contrary to other genetic syndromes that arise from chromosomal trisomy [eg, Down syndrome, trisomy 18], the overall cognitive abilities of males with Klinefelter syndrome typically are within the range of average intellectual ability. [25] Most males with the 47,XXY karyotype have normal intelligence. Intellectual disability occurs in males with Klinefelter syndrome variants, who have a higher number of X chromosomes.
About 70% of patients have minor developmental and learning disabilities. These may include academic difficulties, delayed speech and language acquisition, diminished short-term memory, decreased data-retrieval skills, reading difficulties, dyslexia, and attention deficit disorder. Evidence for more general impairments in language has been consistent, with the most widely observed deficits having been reported in encoding of verbal information, auditory processing, comprehension, and processing speed. Expressive speech and verbal fluency are also affected. [26]
Behavioral problems and psychological distress are reported and may be due to poor self-esteem, compromised psychosocial development, or an inability to deal with stress. Psychiatric disorders with features of anxiety, depression, neurosis, and psychosis are more common than in the general population.
Dental
About 40% of patients have taurodontism, a dental finding characterized by enlargement of the molar teeth by an extension of the pulp. In comparison, the incidence of taurodontism is about 1% in XY males.
Sexual characteristics
Genital abnormalities are not commonly observed in 47,XXY males. This is an important observation because Klinefelter syndrome is considered a cause of genital abnormality or ambiguity. [27] The genital phenotype can include complete sex reversal, true hermaphroditism [eg, ovotestes], testicular feminization, and ambiguous genitalia/undervirilization [eg, hypospadias, micropenis, epispadias, female external genitalia].
Pubertal changes with lack of secondary sexual characteristics are due to decreased androgen production. This results in sparse facial, body, or sexual hair; a high-pitched voice; and body fat distribution as is observed in females. By late puberty, 30-50% of boys with Klinefelter syndrome present with gynecomastia, which is due to elevated estradiol levels and an increased estradiol:testosterone ratio. The risk of developing breast carcinoma in Klinefelter syndrome is at least 20 times higher than in healthy individuals. There is also an increased risk of extragonadal germ cell tumors such as embryonal carcinoma, teratoma, and primary mediastinal germ cell tumor.
Postpubertal males may have testicular dysgenesis [small firm testis; testis size < 10 mL]. Infertility, azoospermia, or both may result from atrophy of the seminiferous tubules. Most males with a 47,XXY karyotype are infertile, but patients with Klinefelter syndrome mosaicism [46,XY/47,XXY] can be fertile. Guidelines for the assessment and treatment of people with fertility problems have been established. [28]
A literature review by Deebel et al indicated that, while azoospermia is a characteristic of Klinefelter syndrome, patients are frequently positive for spermatogonia. Indeed, spermatogonial cells were found in 100% of fetal/infantile patients and in 83%, 42.7%, and 48.5% of prepubertal, peripubertal, and adult patients. In addition, positive spermatogonia results were found in 46.4% of peripubertal/adolescent patients and 24.3% of adult patients, who were negative for spermatozoa. [29]
Cardiac and circulatory problems [30]
Mitral valve prolapse occurs in 55% of patients. Varicose veins occur in 20-40% of patients. The prevalence of venous ulcers is 10-20 times higher than in healthy individuals, and the risk of deep vein thrombosis and pulmonary embolism is increased.
A Swedish study found the standardized incidence ratio for venous thromboembolism [VTE] in Klinefelter syndrome to be 6.43, with a ratio of 12.10 in persons younger than age 30 years and 2.07 in persons aged 70 years or older. Based on the study's findings, an association exists between Klinefelter syndrome and a high risk for VTE. The authors suggest that Klinefelter syndrome could be recognized as a genetic hypercoagulable state. [31]
A study by Chang et al also found the thrombosis risk to be higher in Klinefelter syndrome, with hazard ratios for VTE and total thrombotic death, as measured against a comparison cohort, being 3.95 and 1.76, respectively. The investigators also reported an insignificant decrease in venous thromboembolism and thrombotic deaths in patients who received testosterone treatment. [32]
Klinefelter syndrome variants/sex chromosome aneuploidies
Variants of Klinefelter syndrome are as follows [33] [34] :
48,XXYY variant: Patients typically have intellectual challenges [IQ range 60-80, delayed speech, learning disabilities]; tall stature [adult height >6 feet]; eunuchoid body habitus; sparse body hair; gynecomastia; long, thin legs; hypergonadotropic hypogonadism; and small testes and penis.
48,XXXY variant: Patients typically have intellectual challenges [IQ range 40-60, marked speech delay, slow motor development, poor coordination], average or tall stature, abnormal face [epicanthal folds, ocular hypertelorism, flat nasal bridge], gynecomastia [33-50%], hypergonadotrophic hypogonadism, hypoplastic penis, small testes, fifth-finger clinodactyly, and radioulnar synostosis.
-
49,XXXYY: Patients typically have severe intellectual disabilities; passive, but occasionally aggressive, behavior and temper tantrums; tall stature; dysmorphic facial features; gynecomastia; and hypogonadism.
49,XXXXY variant: Males are severely intellectually challenged [IQ range 20-60]. Patients have short stature and are microcephalic with dysmorphic facial features [ocular hypertelorism, epicanthal folds, flat nasal bridge, prognathism], and a short or broad neck. Other clinical features include severely impaired language, behavioral problems, low birth weight, cleft palate, gynecomastia [rare], congenital heart defects [patent ductus arteriosus is most common], skeletal anomalies [radioulnar synostosis, genu valgus, pes cavus, fifth-finger clinodactyly], muscular hypotonia, hyperextensible joints, hypergonadotropic hypogonadism, hypoplastic genitalia, and cryptorchidism.
Causes
In 1959, Klinefelter syndrome was found to be caused by a supernumerary X chromosome in a male. [35]
The 47,XXY karyotype of Klinefelter syndrome spontaneously arises when paired X chromosomes fail to separate [nondisjunction in stage I or II of meiosis, during oogenesis or spermatogenesis]. [36] Maternal and paternal meiotic nondisjunction each account for approximately 50% of Klinefelter syndrome cases. Seventy-five percent of maternal nondisjunction cases are caused by meiosis I errors, which are associated with increased maternal age. Increased paternal age has been linked to a possible increased risk of Klinefelter syndrome. [37]
Postfertilization nondisjunction is responsible for mosaicism, which is seen in approximately 10% of Klinefelter syndrome patients. Men with mosaicism are less affected and are often not diagnosed. [6]
The androgen receptor [AR] gene encodes the androgen receptor, which is located on the X chromosome.
The AR gene contains a highly polymorphic trinucleotide [CAG] repeat sequence in exon 1, and the length of this CAG repeat is inversely correlated with the functional response of the androgen receptor to androgens. Thus, a short AR CAG repeat sequence correlates with a marked effect of androgens.
In individuals with Klinefelter syndrome, the X chromosome with the shortest AR CAG repeat has been demonstrated to be preferentially inactivated; this process is called skewed or nonrandom X-chromosome inactivation.
Individuals with short AR CAG repeats have been found to respond better to androgen therapy, to form more stable partnerships, and to achieve a higher level of education compared with individuals with long CAG repeats. [38, 39] Conversely, long AR CAG repeat lengths are associated with increased body height and arm span, decreased bone density, decreased testicular volume, and gynecomastia.
Nonrandom X-chromosome inactivation, which preferentially leaves the allele with the longest AR CAG repeat active, may actually contribute to the hypogonadal phenotype found in Klinefelter syndrome and may also explain some of the diverse physical appearances observed in affected individuals.
In boys with Klinefelter syndrome, the paternal origin of the supernumerary X chromosome is associated with later onset of puberty and longer CAG repeats of the androgen receptor, with later pubertal reactivation of the pituitary-testicular axis.
The most common karyotype is 47,XXY, which accounts for 80-90% of all cases. Mosaicism [46,XY/47,XXY] is observed in about 10% of cases. Other variant karyotypes, including 48,XXYY; 48,XXXY; 49,XXXYY; and 49,XXXXY, are rare.
The mosaic forms of Klinefelter syndrome are due to mitotic nondisjunction after fertilization of the zygote. These forms can arise from a 46,XY zygote or a 47,XXY zygote.
Variant forms of Klinefelter syndrome include 48,XXXY; 49,XXXXY; 48,XXYY; and 49,XXXYY.
Klinefelter HF Jr, Reifenstein EC Jr, Albright F. Syndrome characterized by gynecomastia aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone. J Clin Endocr Metabl. 1942. 2:615-24.
Jacobs PA, Strong JA. A case of human intersexuality having possible XXY sex-determining mechanism. Nature. 1959. 2:164-67.
Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006 Oct 24. 1:42. [QxMD MEDLINE Link]. [Full Text].
Schiff JD, Palermo GD, Veeck LL, Goldstein M, Rosenwaks Z, Schlegel PN. Success of testicular sperm extraction [corrected] and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. 2005 Nov. 90 [11]:6263-7. [QxMD MEDLINE Link].
Damani MN, Mittal R, Oates RD. Testicular tissue extraction in a young male with 47,XXY Klinefelter's syndrome: potential strategy for preservation of fertility. Fertil Steril. 2001 Nov. 76[5]:1054-6. [QxMD MEDLINE Link].
Paduch DA, Fine RG, Bolyakov A, Kiper J. New concepts in Klinefelter syndrome. Curr Opin Urol. 2008 Nov. 18[6]:621-7. [QxMD MEDLINE Link].
Wikstrom AM, Painter JN, Raivio T, Aittomaki K, Dunkel L. Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome. Clin Endocrinol [Oxf]. 2006 Jul. 65[1]:92-7. [QxMD MEDLINE Link].
Ramasamy R, Ricci JA, Palermo GD, Gosden LV, Rosenwaks Z, Schlegel PN. Successful fertility treatment for Klinefelter's syndrome. J Urol. 2009 Sep. 182[3]:1108-13. [QxMD MEDLINE Link].
Giedd JN, Clasen LS, Wallace GL, et al. XXY [Klinefelter syndrome]: a pediatric quantitative brain magnetic resonance imaging case-control study. Pediatrics. 2007 Jan. 119[1]:e232-40. [QxMD MEDLINE Link]. [Full Text].
van Rijn S, de Sonneville L, Swaab H. The nature of social cognitive deficits in children and adults with Klinefelter syndrome [47,XXY]. Genes Brain Behav. 2018 Feb 6. [QxMD MEDLINE Link].
Seo JT, Lee JS, Oh TH, Joo KJ. The clinical significance of bone mineral density and testosterone levels in Korean men with non-mosaic Klinefelter's syndrome. BJU Int. 2007 Jan. 99[1]:141-6. [QxMD MEDLINE Link].
Rovenský J. Rheumatic diseases and Klinefelter's syndrome. Autoimmun Rev. 2006 Nov. 6[1]:33-6. [QxMD MEDLINE Link].
-
Vorona E, Zitzmann M, Gromoll J, Schuring AN, Nieschlag E. Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab. 2007 Sep. 92[9]:3458-65. [QxMD MEDLINE Link]. [Full Text].
Close S, Fennoy I, Smaldone A, Reame N. Phenotype and Adverse Quality of Life in Boys with Klinefelter Syndrome. J Pediatr. 2015 Sep. 167 [3]:650-7. [QxMD MEDLINE Link].
Carlomagno F, Pozza C, Tenuta M, et al. Testicular Microvascular Flow Is Altered in Klinefelter Syndrome and Predicts Circulating Testosterone. J Clin Endocrinol Metab. 2022 Jan 1. 107 [1]:e236-45. [QxMD MEDLINE Link]. [Full Text].
Skakkebaek A, Moore PJ, Chang S, Fedder J, Gravholt CH. Quality of life in men with Klinefelter syndrome: the impact of genotype, health, socioeconomics, and sexual function. Genet Med. 2018 Feb. 20 [2]:214-22. [QxMD MEDLINE Link].
Paduch DA, Bolyakov A, Cohen P, Travis A. Reproduction in men with Klinefelter syndrome: the past, the present, and the future. Semin Reprod Med. 2009 Mar. 27[2]:137-48. [QxMD MEDLINE Link].
Sokol RZ. It's not all about the testes: medical issues in Klinefelter patients. Fertil Steril. 2012 Aug. 98[2]:261-5. [QxMD MEDLINE Link].
Robinson A, Bender BG, Linden MG, Salbenblatt JA. Sex chromosome aneuploidy: the Denver Prospective Study. Birth Defects Orig Artic Ser. 1990. 26[4]:59-115. [QxMD MEDLINE Link].
Visootsak J, Aylstock M, Graham JM Jr. Klinefelter syndrome and its variants: an update and review for the primary pediatrician. Clin Pediatr [Phila]. 2001 Dec. 40[12]:639-51. [QxMD MEDLINE Link].
Graham JM Jr, Bashir AS, Stark RE, Silbert A, Walzer S. Oral and written language abilities of XXY boys: implications for anticipatory guidance. Pediatrics. 1988 Jun. 81 [6]:795-806. [QxMD MEDLINE Link].
Skakkebaek A, Moore PJ, Pedersen AD, et al. The role of genes, intelligence, personality, and social engagement in cognitive performance in Klinefelter syndrome. Brain Behav. 2017 Mar. 7 [3]:e00645. [QxMD MEDLINE Link]. [Full Text].
Boks MP, de Vette MH, Sommer IE, et al. Psychiatric morbidity and X-chromosomal origin in a Klinefelter sample. Schizophr Res. 2007 Jul. 93[1-3]:399-402. [QxMD MEDLINE Link].
Völkl TM, Langer T, Aigner T, Greess H, Beck JD, Rauch AM, et al. Klinefelter syndrome and mediastinal germ cell tumors. Am J Med Genet A. 2006 Mar 1. 140[5]:471-81. [QxMD MEDLINE Link].
Boada R, Janusz J, Hutaff-Lee C, Tartaglia N. The cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors. Dev Disabil Res Rev. 2009. 15[4]:284-94. [QxMD MEDLINE Link].
Hong DS, Reiss AL. Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol. 2014 Mar. 13[3]:306-18. [QxMD MEDLINE Link].
Lee YS, Cheng AW, Ahmed SF, Shaw NJ, Hughes IA. Genital anomalies in Klinefelter's syndrome. Horm Res. 2007. 68[3]:150-5. [QxMD MEDLINE Link].
[Guideline] Centre for Women's and Children's Health. Fertility: assessment and treatment for people with fertility problems. 2004 Feb. 216. [Full Text].
Deebel NA, Galdon G, Zarandi NP, et al. Age-related presence of spermatogonia in patients with Klinefelter syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2020 Jan 1. 26 [1]:58-72. [QxMD MEDLINE Link].
Salzano A, Arcopinto M, Marra AM, et al. Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives. Eur J Endocrinol. 2016 Jul. 175 [1]:R27-40. [QxMD MEDLINE Link]. [Full Text].
Zöller B, Ji J, Sundquist J, Sundquist K. High Risk of Venous Thromboembolism in Klinefelter Syndrome. J Am Heart Assoc. 2016 May 20. 5 [5]:[QxMD MEDLINE Link].
Chang S, Christiansen CF, Bojesen A, Juul S, Munster AB, Gravholt CH. Klinefelter syndrome and testosterone treatment: a national cohort study on thrombosis risk. Endocr Connect. 2020 Jan. 9 [1]:34-43. [QxMD MEDLINE Link]. [Full Text].
Tartaglia N, Ayari N, Howell S, D'Epagnier C, Zeitler P. 48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatr. 2011 Jun. 100[6]:851-60. [QxMD MEDLINE Link]. [Full Text].
Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006 Oct 24. 1:42. [QxMD MEDLINE Link]. [Full Text].
Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature. 1959 Jan 31. 183[4657]:302-3. [QxMD MEDLINE Link].
Thomas NS, Hassold TJ. Aberrant recombination and the origin of Klinefelter syndrome. Hum Reprod Update. 2003 Jul-Aug. 9[4]:309-17. [QxMD MEDLINE Link]. [Full Text].
Lowe X, Eskenazi B, Nelson DO, Kidd S, Alme A, Wyrobek AJ. Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. Am J Hum Genet. 2001 Nov. 69[5]:1046-54. [QxMD MEDLINE Link]. [Full Text].
Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab. 2004 Dec. 89[12]:6208-17. [QxMD MEDLINE Link].
Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol. 2007 Apr. 4[4]:192-204. [QxMD MEDLINE Link].
Yencilek F, Baykal C. 46 XX male syndrome: a case report. Clin Exp Obstet Gynecol. 2005. 32 [4]:263-4. [QxMD MEDLINE Link].
Allyse M, Minear MA, Berson E, et al. Non-invasive prenatal testing: a review of international implementation and challenges. Int J Womens Health. 2015. 7:113-26. [QxMD MEDLINE Link]. [Full Text].
Samango-Sprouse C, Keen C, Sadeghin T, Gropman A. The benefits and limitations of cell-free DNA screening for 47, XXY [Klinefelter syndrome]. Prenat Diagn. 2017 May. 37 [5]:497-501. [QxMD MEDLINE Link]. [Full Text].
Ottesen AM, Garn ID, Aksglaede L, Juul A, Rajpert-De Meyts E. A simple screening method for detection of Klinefelter syndrome and other X-chromosome aneuploidies based on copy number of the androgen receptor gene. Mol Hum Reprod. 2007 Oct. 13 [10]:745-50. [QxMD MEDLINE Link].
Wikstrom AM, Dunkel L. Testicular function in Klinefelter syndrome. Horm Res. 2008. 69[6]:317-26. [QxMD MEDLINE Link].
Mantovani V, Dondi E, Larizza D, et al. Do reduced levels of steroid 21-hydroxylase confer a survival advantage in fetuses affected by sex chromosome aberrations?. Eur J Hum Genet. 2002 Feb. 10[2]:137-40. [QxMD MEDLINE Link].
Nieschlag E, Ferlin A, Gravholt CH, et al. The Klinefelter syndrome: current management and research challenges. Andrology. 2016 May. 4 [3]:545-9. [QxMD MEDLINE Link].
Samango-Sprouse C, Stapleton EJ, Lawson P, et al. Positive effects of early androgen therapy on the behavioral phenotype of boys with 47,XXY. Am J Med Genet C Semin Med Genet. 2015 Jun. 169 [2]:150-7. [QxMD MEDLINE Link].
Ross JL, Kushner H, Kowal K, et al. Androgen Treatment Effects on Motor Function, Cognition, and Behavior in Boys with Klinefelter Syndrome. J Pediatr. 2017 Mar 10. [QxMD MEDLINE Link].
Tournaye H, Staessen C, Liebaers I, et al. Testicular sperm recovery in nine 47,XXY Klinefelter patients. Hum Reprod. 1996 Aug. 11[8]:1644-9. [QxMD MEDLINE Link]. [Full Text].
Westlander G, Ekerhovd E, Granberg S, Hanson L, Hanson C, Bergh C. Testicular ultrasonography and extended chromosome analysis in men with nonmosaic Klinefelter syndrome: a prospective study of possible predictive factors for successful sperm recovery. Fertil Steril. 2001 Jun. 75 [6]:1102-5. [QxMD MEDLINE Link].
Aboulghar H, Aboulghar M, Mansour R, Serour G, Amin Y, Al-Inany H. A prospective controlled study of karyotyping for 430 consecutive babies conceived through intracytoplasmic sperm injection. Fertil Steril. 2001 Aug. 76[2]:249-53. [QxMD MEDLINE Link].
Van Opstal D, Los FJ, Ramlakhan S, et al. Determination of the parent of origin in nine cases of prenatally detected chromosome aberrations found after intracytoplasmic sperm injection. Hum Reprod. 1997 Apr. 12[4]:682-6. [QxMD MEDLINE Link]. [Full Text].
Bonduelle M, Aytoz A, Van Assche E, Devroey P, Liebars I, VanSteirteghem A. Incidence of chromosomal aberrations in childrenborn after assisted reproduction through intracytoplasmic sperm injection. Hum Reprod. 1998. 13:781-782. [QxMD MEDLINE Link]. [Full Text].
Staessen C, Coonen E, Van Assche E, et al. Preimplantation diagnosis for X and Y normality in embryos from three Klinefelter patients. Hum Reprod. 1996 Aug. 11[8]:1650-3. [QxMD MEDLINE Link]. [Full Text].
Estop AM, Munne S, Cieply KM, Vandermark KK, Lamb AN, Fisch H. Meiotic products of a Klinefelter 47,XXY male as determined by sperm fluorescence in-situ hybridization analysis. Hum Reprod. 1998 Jan. 13[1]:124-7. [QxMD MEDLINE Link]. [Full Text].
Reubinoff BE, Abeliovich D, Werner M, Schenker JG, Safran A, Lewin A. A birth in non-mosaic Klinefelter's syndrome after testicular fine needle aspiration, intracytoplasmic sperm injection and preimplantation genetic diagnosis. Hum Reprod. 1998 Jul. 13[7]:1887-92. [QxMD MEDLINE Link]. [Full Text].
Rosenlund B, Hreinsson JG, Hovatta O. Birth of a healthy male after frozen thawed blastocyst transfer following intracytoplasmic injection of frozen thawed testicular spermatozoa from a man with nonmosaic Klinefelter's syndrome. J Assist Reprod Genet. 2002 Mar. 19[3]:149-51. [QxMD MEDLINE Link].
Hinney B, Guttenbach M, Schmid M, Engel W, Michelmann HW. Pregnancy after intracytoplasmic sperm injection with sperm from a man with a 47,XXY Klinefelter's karyotype. Fertil Steril. 1997 Oct. 68[4]:718-20. [QxMD MEDLINE Link].
Palermo GD, Schlegel PN, Sills ES, et al. Births after intracytoplasmic injection of sperm obtained by testicular extraction from men with nonmosaic Klinefelter's syndrome. N Engl J Med. 1998 Feb 26. 338[9]:588-90. [QxMD MEDLINE Link].
Ron-El R, Raziel A, Strassburger D, Schachter M, Bern O, Friedler S. Birth of healthy male twins after intracytoplasmic sperm injection of frozen-thawed testicular spermatozoa from a patient with nonmosaic Klinefelter syndrome. Fertil Steril. 2000 Oct. 74[4]:832-3. [QxMD MEDLINE Link].
Crüger D, Toft B, Agerholm I, Fedder J, Hald F, Bruun-Petersen G. Birth of a healthy girl after ICSI with ejaculated spermatozoa from a man with non-mosaic Klinefelter's syndrome. Hum Reprod. 2001 Sep. 16[9]:1909-11. [QxMD MEDLINE Link]. [Full Text].
Tachdjian G, Frydman N, Morichon-Delvallez N, et al. Reproductive genetic counselling in non-mosaic 47,XXY patients: implications for preimplantation or prenatal diagnosis: Case report and review. Hum Reprod. 2003 Feb. 18[2]:271-5. [QxMD MEDLINE Link]. [Full Text].
Close S, Sadler L, Grey M. In the Dark: Challenges of Caring for Sons with Klinefelter Syndrome. J Pediatr Nurs. 2015 May 30. [QxMD MEDLINE Link].
Aguirre D, Nieto K, Lazos M, et al. Extragonadal germ cell tumors are often associated with Klinefelter syndrome. Hum Pathol. 2006 Apr. 37[4]:477-80. [QxMD MEDLINE Link].
Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA,. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005 Aug 17. 97[16]:1204-10. [QxMD MEDLINE Link].
van Rijn S, Swaab H. Vulnerability for psychopathology in Klinefelter syndrome: age-specific and cognitive-specific risk profiles. Acta Paediatr. 2011 Jun. 100[6]:908-16. [QxMD MEDLINE Link].
Horowitz M, Wishart JM, O'Loughlin PD, Morris HA, Need AG, Nordin BE. Osteoporosis and Klinefelter's syndrome. Clin Endocrinol [Oxf]. 1992 Jan. 36 [1]:113-8. [QxMD MEDLINE Link].
Campbell WA, Price WH. Venous thromboembolic disease in Klinefelter's syndrome. Clin Genet. 1981 Apr. 19[4]:275-80. [QxMD MEDLINE Link].
Bardsley MZ, Falkner B, Kowal K, Ross JL. Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. Acta Paediatr. 2011 Jun. 100[6]:866-70. [QxMD MEDLINE Link].
Lahlou N, Fennoy I, Ross JL, Bouvattier C, Roger M. Clinical and hormonal status of infants with nonmosaic XXY karyotype. Acta Paediatr. 2011 Jun. 100 [6]:824-9. [QxMD MEDLINE Link].
Herlihy AS, McLachlan RI, Gillam L, Cock ML, Collins V, Halliday JL. The psychosocial impact of Klinefelter syndrome and factors influencing quality of life. Genet Med. 2011 Jul. 13 [7]:632-42. [QxMD MEDLINE Link].
Adolescent male with gynecomastia and Klinefelter syndrome.
Child with Klinefelter syndrome. Other than a thin build and disproportionately long arms and legs, the phenotype is normal.
G-banded 47,XXY karyotype.
Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair and testicular dysgenesis.
Author
Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center
Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.
Specialty Editor Board
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Chief Editor
Luis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio
Luis O Rohena, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics
Disclosure: Nothing to disclose.
Additional Contributors
Harold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center
Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics
Disclosure: Nothing to disclose.