Klinefelter's syndrome Q98.40

Prepubertal: no definite symptoms, occasional oligophrenia. On the skin, focal atrophy, pigmentary changes, nodularity.

In puberty or postpuberty: obligatory small testicles with volumes below 3-5 ml in the sense of primary testicular damage with compensatory hypergonadotropic hypogonadism ( FSH strongly increased, LH/ICSH moderately increased or normal), azoospermia or high grade oligozoospermia with mostly irreversible infertility (occasionally paternity has been described); optionally in 30-50% of cases manifest or latent testosterone deficiency with gynoid habitus ( gynecomastia with a possible increased pigmentation of the nipple-areola complex, female fat distribution pattern, female secondary hair, increased voice pitch). Furthermore, there is increased:

• long extremities
• Obesity
• osteoporosis
• Intelligence defects
• vascular dysplasias
• ulcers of the lower legs
• Cutis verticis gyrata (rare)
• Nail dysplasias
• Wart-like papillae of the skin and mucosa (Krause W 2017).

Patients with Klinefelter syndrome have a 50-fold increased risk of developing breast cancer compared to a healthy male (Hultborn R et al 1996).

Molecular genetic examination, family history, clinic

Obligatory reduced testicular volume (below 3-5 ml); azoospermia or high-grade oligozoospermia, hypotestosteronemia, FSH elevation, testicular biopsy with excessive tubular sclerosis and hyperplasia of v. Leydig's intermediate cells, oral mucosal smear with detection of one or more chromatin bodies in the cell nuclei, chromosome analysis.

If the testosterone level is low or the serum LH level > 7 mU/ml, start testosterone substitution therapy at about 11 years of age, see Table 1.

The dosages for children are guidelines which must always be adjusted to the clinical situation (growth in length, ossification, psychosexual development). For monitoring of testosterone substitution, see Kallmann syndrome. The treatment must be carried out for life. A special therapeutic case is formed by patients with criminal convictions, who should receive carefully monitored substitution therapy. If the patient wishes to have children, sperm can be searched for in the testicular tissue and, if necessary, vital sperm can be obtained from a small testicular biopsy for intracytoplasmic sperm injection using the TESE (testicular sperm extraction) technique.

Gynecomastia remains unaffected by testosterone substitution and may need to be addressed surgically. Careful monitoring of these patients as the risk of developing breast carcinoma is increased 20-fold compared to normal men.

Extragonadal germ cell tumors (mediastinal nonseminomatous germ cell tumors, intracerebral germ cell tumors) must be addressed surgically.

Testosterone substitution in Klinefelter syndrome

X-linked genodermatoses

The genes of one of the two X chromosomes in females are usually inactivated (lyonization). X-linked dermatoses that are lethal to male descendants can therefore only be observed in females. These include the following syndromes:

• Incontinentia pigmenti
• Focal dermal hpoplasia
• Conradi-Hünermann-Happle syndrome
• Oral-facial-digital syndrome
• MIDAS (microphthalmia, dermal aplasia, sclerocornea) syndrome.

Other non-lethal x-linked disorders include:

• Hypohidrotic ectodermal dysplasia Christ-Siemens-Touraine
• IFAP syndrome (ichthyosis, follicular alopecia, photophobia)
• Dyskeratosis congenita
• Since 2 or > 2 X chromosomes are present in Klinefelter syndrome, there is a possibility that male children may also survive with one of the syndromes that are lethal to male descendants. Incontinentia pigmenti and focal hypoplasia have been described (Krause W 2017).

1. Amory JK (2000) Klinefelter's syndrome. Lancet 356: 333-335
2. Christiansen P (2003) Longitudinal studies of inhibin B levels in boys and young adults with Klinefelter syndrome. J Clin Endocrinol Metab 88: 888-891
3. De Geyter CH et al (1996): Assisted fertilisation. In: Nieschlag, E., Behre HM (eds.) Andrology - Principles and Clinic of Male Reproductive Health. Springer-Verlag, Berlin, Heidelberg, New York, S. 350-353
4. Hultborn R et al (1997) Prevalence of Klinefelter's syndrome in male breast cancer patients. Anticancer Res 17:4293-4297.
5. Keller K et al (2001) Klinefelter's syndrome and cutis verticis gyrata. At J Med Genet 103: 249-251
6. Klinefelter HF, Reifenstein EC Jr, Albright F Jr (1942) Syndrome characterized by gynaecomastia, aspermatogenesis without A-Leydigism and increased excretion of follicle-stimulating hormones. Journal of Clinical Endocrinology (Baltimore) 2: 615-627

7. Krause W (2017) Skin diseases in Klinefelter's syndrome. Close Dermatology 33:32-35

8. Nieschlag E et al (1996): Disturbances in the area of the tests. In: Nieschlag E, Behre HM (eds.) Andrology - Principles and Clinic of Male Reproductive Health. Springer-Verlag, Berlin, Heidelberg, New York, S. 153-154 and 315-329