Klinefelter's syndrome

doi:10.1016/S0140-6736(04)16678-6

The Lancet

Volume 364, Issue 9430, 17–23 July 2004, Pages 273-283

https://doi.org/10.1016/S0140-6736(04)16678-6 Get rights and content

Summary

Klinefelter's syndrome is the most common genetic cause of human male infertility, but many cases remain undiagnosed because of substantial variation in clinical presentation and insufficient professional awareness of the syndrome itself. Early recognition and hormonal treatment of the disorder can substantially improve quality of life and prevent serious consequences. Testosterone replacement corrects symptoms of androgen deficiency but has no positive effect on infertility. However, nowadays patients with Klinefelter's syndrome, including the non-mosaic type, need no longer be considered irrevocably infertile, because intracytoplasmic sperm injection offers an opportunity for procreation even when there are no spermatozoa in the ejaculate. In a substantial number of azoospermic patients, spermatozoa can be extracted from testicular biopsy samples, and pregnancies and livebirths have been achieved. The frequency of sex chromosomal hyperploidy and autosomal aneuploidies is higher in spermatozoa from patients with Klinefelter's syndrome than in those from normal men. Thus, chromosomal errors might in some cases be transmitted to the offspring of men with this syndrome. The genetic implications of the fertilisation procedures, including pretransfer or prenatal genetic assessment, must be explained to patients and their partners.

Section snippets

Pathogenesis

The numerical chromosome aberrations in Klinefelter's syndrome arise by non-disjunction either during meiotic divisions occurring in germ-cell development or in early embryonic mitotic cell divisions. Incorrect meiotic divisions are predominant. In autosomal trisomies, paternal non-disjunctions account for only about 10% of all cases; however, paternal errors contribute more frequently to sex-chromosome aneuploidy. The 47,XXY condition has been extensively studied, and about half of all cases

Clinical picture

The clinical picture of patients who come to medical attention varies according to age. Before puberty only discrete physical anomalies may be noticed—eg, slightly lower than normal testicular volume or long-leggedness. Sexual development may be normal before puberty and includes initiation of normal pubertal changes and normal pituitary gonadal function.³⁷ The physical appearance of a pathologically hypogonadal child may not differ clearly from that of a normal prepubertal boy. The evolution

Diagnosis

A suspected diagnosis can be based on the combination of typical clinical findings. The most important of these are very low testicular volume and firm consistency of the testes. However, even this very characteristic symptom may not be present in all cases (figure 3). Testicular size can be assessed by palpation and comparison with testis-shaped models of defined sizes (Prader orchidometer) or more precisely by ultrasonography.⁶² A healthy European man has, on average, a testicular volume of

Management

When testosterone serum concentrations in patients with Klinefelter's syndrome are low, lifelong substitution therapy is indicated and should be started as early as possible to avoid symptoms and sequelae of androgen deficiency.⁷⁵

Early recognition and treatment of Klinefelter's syndrome can significantly improve the patient's quality of life and prevent serious consequences. Early testosterone replacement results in increased masculinity, strength, libido, bone mineral density, and body hair.75

Fertility

Spermatogenesis is present at a very low rate in occasional patients with Klinefelter's syndrome, and very rare cases of spontaneous paternity have been reported (table 3). However, before the introduction of the ICSI technique, the fertility outlook for the vast majority of these patients was hopeless. ICSI offers the opportunity for reproduction even when spermatozoa are not present in the ejaculate, but only in the testis. The successful recovery of spermatozoa from azoospermic men with

Genetic counselling

As in all cases of severe male-factor infertility necessitating ICSI, the genetic risks resulting from this procedure should be discussed with each couple. Preimplantation genetic diagnosis by embryo biopsy offers an efficient tool for embryo selection.¹⁰⁴ To date, 49 healthy children have been born by use of ICSI, and the conception of one 47,XXY fetus has been reported (Table 4, Table 5). Preimplantation genetic diagnosis in couples affected by Klinefelter's syndrome has allowed the

Search strategy and selection criteria

A computer-aided search of PubMed was done with the terms “Klinefelter('s) syndrome”, “hypogonadism”, “XXY”, “male infertility”, “reproduction”, “ICSI”, “TESE”, and “fertility”. For the sections on fertility and genetic counselling, publications from the past 8 years were selected, whereas frequently referenced landmark and highly regarded older publications were included for the earlier sections. References cited in retrieved articles and reviewed articles collected over 35 years were

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