Klinefelter syndrome

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LD50.3 Klinefelter syndrome

 ICD-11 LD50.3 Klinefelter syndrome
Klinefelter syndrome defines a group of chromosomal disorders in which there is at least one extra X chromosome compared with the normal 46,XY male karyotype. The effects on physical features and on physical and cognitive development increase with the number of extra X's, and each extra X is associated with an intelligence quotient (IQ) decrease of approximately 15-16 points, with language most affected, particularly expressive language skills.
  • LD50.30 Klinefelter syndrome with karyotype 47,XXY, regular - Karyotype 47 XXY; gonads: testes (hypogonadism) small and firm with decreased spermatogenesis ; phenotype male with associated congenital abnormalities (decreased virilization due to decreased testosterone production, long arms and legs, short trunk, psychosocial problems)
  • LD50.31 Klinefelter syndrome, male with more than two X chromosomes - A disease affecting males, caused by the presence of more than two X chromosomes in each cell. This disease is characterized by impaired sexual development, intellectual disability, distinctive facial features, skeletal abnormalities, poor coordination, and severe problems with speech. This disease may be differentiated from classic Klinefelter syndrome by increased severity of symptoms. Confirmation is through observation of more than two X chromosomes by karyotyping.


Klinefelter syndrome karyotype

Klinefelter syndrome (47,XXY, XXY syndrome or condition, XXY trisomy) affects male physical and cognitive development. The extra copy of genes on the X chromosome interferes with male sexual development and can prevent the normal function of the testis testes, reducing the levels of testosterone. The signs and symptoms vary among affected individuals.

Rare variations include 47,XXY/46,XY (mosaic syndrome) and Poly-X Klinefelter syndrome: 48,XXYY (or tetrasomy), 48,XXXY (or tetrasomy) and 49,XXXXY (or pentasomy).

First described in 1942 by Dr Harry Klinefelter.[1]

Genetic Links: genetic abnormalities | maternal age | Trisomy 21 | Trisomy 18 | Trisomy 13 | Trisomy X | trisomy mosaicism | Monosomy | Fragile X | Williams | Alagille | Philadelphia chromosome | mitochondria | VACTERL | hydatidiform mole | epigenetics | Prenatal Diagnosis | Neonatal Diagnosis | meiosis | mitosis | International Classification of Diseases | genetics

Genital System - Abnormalities

Some Recent Findings

Human X chromosome
  • Onset and progression of puberty in Klinefelter syndrome[2] "Our results suggest that puberty starts within the normal age limits in boys with KS, and testosterone supplementation is not needed for the initial pubertal progression in the majority of patients."
  • Klinefelter syndrome: a multicentre study from KING group.[3] "The prevalence and the etiopathogenesis of thyroid dysfunctions in Klinefelter syndrome (KS) are still unclear. The primary aim of this study was to evaluate the pathogenetic role of hypogonadism in the thyroid disorders described in KS, with the scope to distinguish between patients with KS and hypogonadism due to other causes (Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, iatrogenic hypogonadism and acquired hypogonadotropic hypogonadism after surgical removal of pituitary adenomas) called non-KS. Therefore, we evaluated thyroid function in KS and in non-KS hypogonadal patients. METHODS: This is a case-control multicentre study from KING group: Endocrinology clinics in university-affiliated medical centres. One hundred and seventy four KS, and sixty-two non-KS hypogonadal men were enrolled. The primary outcome was the prevalence of thyroid diseases in KS and in non-KS. Changes in hormonal parameters were evaluated. Exclusion criterion was secondary hypothyroidism. Analyses were performed using Student's t test. Mann-Whitney test and Chi-square test. RESULTS: FT4 was significantly lower in KS vs non-KS. KS and non-KS presented similar TSH and testosterone levels. Hashimoto's thyroiditis (HT) was diagnosed in 7% of KS. Five KS developed hypothyroidism. The ratio FT3/FT4 was similar in both groups. TSH index was 1.9 in KS and 2.3 in non-KS. Adjustment for differences in age, sample size and concomitant disease in multivariate models did not alter the results. CONCLUSIONS: We demonstrated in KS no etiopathogenic link to hypogonadism or change in the set point of thyrotrophic control in the altered FT4 production. The prevalence of HT in KS was similar to normal male population, showing absence of increased risk of HT associated with the XXY karyotype."
More recent papers  
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Search term: Klinefelter syndrome | karyotype 47,XXY

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Klinefelter Syndrome in Childhood: Variability in Clinical and Molecular Findings[4] "Klinefelter syndrome (KS) is the most common (1/500–1/1000) chromosomal disorder in males, but only 10% of cases are identified in childhood. This study aimed to review the data of children with KS to assess the age and presenting symptoms for diagnosis, clinical and laboratory findings, together with the presence of comorbidities. METHODS: Twenty-three KS patients were analyzed retrospectively. Age at admission, presenting symptoms, comorbid problems, height, weight, pubertal status, biochemical findings, hormone profiles, bone mineral density and karyotype were evaluated. Molecular analysis was also conducted in patients with ambiguous genitalia. RESULTS: The median age of patients at presentation was 3.0 (0.04-16.3) years. Most of the cases were diagnosed prenatally (n=15, 65.2%). Other reasons for admission were scrotal hypospadias (n=3, 14.3%), undescended testis (n=2, 9.5%), short stature (n=1, 4.8%), isolated micropenis (n=1, 4.8%) and a speech disorder (n=1, 4.8%). The most frequent clinical findings were neurocognitive disorders, speech impairment, social and behavioral problems and undescended testes. All except two patients were prepubertal at admission. Most of the patients (n=20, 86.9%) showed the classic 47,XXY karyotype. Steroid 5 alpha-reductase 2 gene and androgen receptor gene mutations were detected in two of the three cases with genital ambiguity. CONCLUSION: Given the large number of underdiagnosed KS patients before adolescence, pediatricians need to be aware of the phenotypic variability of KS in childhood. Genetic analysis in KS patients may reveal mutations associated with other forms of disorders of sex development besides KS."


Affects male physical and cognitive development. Small testes that do not produce as much testosterone as usual.

  • delayed or incomplete puberty, breast enlargement (gynecomastia), reduced facial and body hair, and an inability to have biological children (infertility).
  • Some affected individuals also have genital differences - undescended testes (cryptorchidism), (hypospadias), or an unusually small penis (micropenis).
  • Children may have learning disabilities and delayed speech and language development. Tend to be quiet, sensitive, and unassertive, but personality characteristics vary among affected individuals.
  • Older children and adults tend to be taller than their peers.

(Text modified from Genetics Home Reference - Klinefelter syndrome)


Karyotype of a Klinefelter's syndrome patient[5]

Cytogenetics Tests

  • Karyotyping
  • FISH-interphase

Molecular Genetics Tests

  • Detection of homozygosity
  • Deletion/duplication analysis
  • Targeted variant analysis
  • Sequence analysis of the entire coding region

48,XXYY and 48,XXXY

Much less frequent variants

  • 48,XXYY - 1 per 17,000 male births.
    • often tall, may have an eunuchoid habitus with long legs, sparse body hair, small testicles and penis, hypergonadotropic hypogonadism, and gynecomastia. IQ level is in the range of 60–80, with delayed speech.
  • 48,XXXY - 1 per 50,000 male births.
    • prone to hyperactivity, aggression, conduct, and depression compared to males with 47,XXY.


  1. Klinefelter HF. Reifenstein EC. and Albright F. Syndrome characterized by gynecomastia aspermatogenes without A-Leydigism and increased excretion of follicle stimulating hormone. (1942) J Clin Endocrinol Metab. 2:615–627.
  2. Tanner M, Miettinen PJ, Hero M, Toppari J & Raivio T. (2021). Onset and progression of puberty in Klinefelter syndrome. Clin Endocrinol (Oxf) , , . PMID: 34523156 DOI.
  3. Balercia G, Bonomi M, Giagulli VA, Lanfranco F, Rochira V, Giambersio A, Accardo G, Esposito D, Allasia S, Cangiano B, De Vincentis S, Condorelli RA, Calogero A & Pasquali D. (2019). Thyroid function in Klinefelter syndrome: a multicentre study from KING group. J Endocrinol Invest , 42, 1199-1204. PMID: 30912057 DOI.
  4. Akcan N, Poyrazoğlu Ş, Baş F, Bundak R & Darendeliler F. (2018). Klinefelter Syndrome in Childhood: Variability in Clinical and Molecular Findings. J Clin Res Pediatr Endocrinol , 10, 100-107. PMID: 29022558 DOI.
  5. Shamsi MB, Kumar K & Dada R. (2011). Genetic and epigenetic factors: Role in male infertility. Indian J Urol , 27, 110-20. PMID: 21716934 DOI.


Bearelly P & Oates R. (2019). Recent advances in managing and understanding Klinefelter syndrome. F1000Res , 8, . PMID: 30755791 DOI.

Giudice MG, Del Vento F & Wyns C. (2019). Male fertility preservation in DSD, XXY, pre-gonadotoxic treatments - Update, methods, ethical issues, current outcomes, future directions. Best Pract. Res. Clin. Endocrinol. Metab. , , . PMID: 30718080 DOI.

Kanakis GA & Nieschlag E. (2018). Klinefelter syndrome: more than hypogonadism. Metab. Clin. Exp. , 86, 135-144. PMID: 29382506 DOI.

Los E & Ford GA. (2019). Klinefelter Syndrome. , , . PMID: 29493939

Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P & Skakkebæk A. (2018). Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. Endocr. Rev. , 39, 389-423. PMID: 29438472 DOI.

Lanfranco F, Kamischke A, Zitzmann M & Nieschlag E. (2004). Klinefelter's syndrome. Lancet , 364, 273-83. PMID: 15262106 DOI.


Juel Mortensen L, Lorenzen M, Jørgensen N, Andersson AM, Nielsen JE, Petersen LI, Lanske B, Juul A, Hansen JB & Blomberg Jensen M. (2019). Possible link between FSH and RANKL release from adipocytes in men with impaired gonadal function including Klinefelter syndrome. Bone , 123, 103-114. PMID: 30914274 DOI.

Foland-Ross LC, Ross JL & Reiss AL. (2019). Androgen treatment effects on hippocampus structure in boys with Klinefelter syndrome. Psychoneuroendocrinology , 100, 223-228. PMID: 30388596 DOI.

Sakurai T, Iizuka K, Kato T & Takeda J. (2019). Type 1 Diabetes Mellitus and Klinefelter Syndrome. Intern. Med. , 58, 259-262. PMID: 30146555 DOI.

GRIGNON CE & GRIGNON J. (1947). [Not Available]. Union Med Can , 76, 1254. PMID: 18899536

SUSMAN E. (1947). Reifenstein-Klinefelter-Albright syndrome. Med. J. Aust. , 2, 155. PMID: 20344569

BETTINGER HF & ROBINSON B. (1946). The Klinefelter-Reifenstein-Albright syndrome. Med. J. Aust. , 2, 446-9. PMID: 21002506

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Cite this page: Hill, M.A. (2024, April 13) Embryology Klinefelter syndrome. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Klinefelter_syndrome

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