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Kallmann syndrome

Kallmann syndrome is an example of hypogonadism (decreased functioning of the sex hormone-producing glands) caused by a deficiency of gonadotropin-releasing hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also known as hypothalamic hypogonadism, familial hypogonadism with anosmia, or gonadotropic hypogonadism, reflecting its disease mechanism. more...

Kallmann syndrome
Kallmann syndrome
Kallmann syndrome
Kallmann syndrome
Kaposi sarcoma
Karsch Neugebauer syndrome
Kartagener syndrome
Kawasaki syndrome
Kearns-Sayre syndrome
Kennedy disease
Keratoconjunctivitis sicca
Keratosis pilaris
Kikuchi disease
Klinefelter's Syndrome
Klippel Trenaunay Weber...
Klippel-Feil syndrome
Klumpke paralysis
Kluver-Bucy syndrome
Kniest dysplasia
Kohler disease
Korsakoff's syndrome
Kostmann syndrome
Seborrheic keratosis

Kallman syndrome was described in 1944 by Franz Josef Kallmann, a German geneticist. However, others had noticed a correlation between anosmia and hypogonadism before this such as the Spanish doctor Aureliano Maestre de San Juan 80 years previously.


Kallmann syndrome is characterized by:

  • Hypogonadotropic hypogonadism (a lack of the pituitary hormones LH and FSH)
  • Congenital (present from birth) anosmia (complete inability to smell) or hyposmia (decreased ability to smell).

It can also be associated with optic problems, such as color blindness or optic atrophy, nerve deafness, cleft palate, cryptorchidism, renal agenesis, and mirror movement disorder. However, it is not clear at this time how or if these other problems have the same cause as the hypogonadism and anosmia and these other problems are more often present in those without Kallmann syndrome.

Males present with delayed puberty and may have micropenis (although congenital micropenis is not present in the majority of male KS cases).

Females present with delayed puberty i.e.primary amenorrhea and lack of secondary sex characteristicd, such as breast development.


The diagnosis is often one of exclusion found during the workup of delayed puberty. The presence of anosmia together with micropenis in boys should suggest Kallmann syndrome (although micropenis alone may have other causes).


Under normal conditions, GnRH travels to the pituitary gland via the tuberoinfundibular pathway, where it triggers production of gonadotropins (LH and FSH). When GnRH is low, the pituitary does not create the normal amount of gonadotropins. The gonadotropins in turn affect the production of hormones in the gonads, so when they are low, the hormones will be low as well.

In Kallmann syndrome, the GnRH neurons do not migrate properly from the olfactory placode to the hypothalamus during development. The olfactory bulbs also fail to form or have hypoplasia, leading to anosmia or hyposmia.

Kallman syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL gene, which maps to chromosome Xp22.3. KAL encodes a neural cell adhesion molecule, anosmin-1. Anosmin-1 is normally expressed in the brain, facial mesenchyme, mesonephros and metanephros. It is required to promote migration of GnRH neurons from the hypothalamus to the pituitary gland. It also allows migration of olfactory neurons from the olfactory bulbs to the hypothalamus.


Treatment is directed at restoring the deficient hormones -- known as hormone replacement therapy (HRT). Males are administered human chorionic gonadotropin (hCG) or testosterone. Females are treated with oestrogen and progestins.


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Testicular neoplasia in cryptorchid boys at primary surgery: case series - Statistical Data Included
From British Medical Journal, 10/2/99 by Dina Cortes

Cryptorchidism is associated with testicular cancer; the lifetime risk of 2-3% is about four times higher than in the general population.[1 2] Some groups of cryptorchid patients may have an especially high risk of testicular cancer.[3] Testicular carcinoma in situ is a well described histological pattern that precedes germ cell tumours[1 4] We investigated whether it is possible at primary surgery to identify cryptorchid boys who have testicular neoplasia and therefore are at high risk of testicular cancer.

Method and results

We examined 1535 consecutive specimens of testicular tissue that were obtained from undescended testes at surgery for cryptorchidism in 1249 boys between 1971 and 1998. Previous reports have described 1026 of the biopsies in detail.[2 4] No patient had fallopian tubes or a uterus.

The table shows the total occurrence of testicular neoplasia at surgery for cryptorchidism. There was one case of invasive germ cell turnout, six cases of testicular carcinoma in situ, and one Sertoli cell tumour. Of the eight testes with neoplasia from seven patients, three neoplasms were diagnosed in intra-abdominal testes (cases 1-3), four occurred in three boys with abnormal external genitalia other than cryptorchidism (cases 4-6), and two were diagnosed in boys with known abnormal karyotype (cases 3 and 7).

Testicular neoplasia in eight undescended testes from seven cryptorchid boys, among 1249 patients who at median age 12.0 years (range 0.1-18.9 years) underwent surgery for cryptorchidism with examination of 1535 specimens of testicular tissue from undescended testes

In total, the risk of testicular neoplasia at surgery for cryptorchidism in childhood was: 7/1249=0.56% (exact 95% confidence interval 0.28% to 1.15%; calculated by solving the exact binomial equations iteratively) per cryptochid, boy, and 8/1535=0.52% (0.27% to 1.02%) per testicular specimen from an undescended testis.

(*) This biopsy from a scrotal testis was not included in the material of 1535 specimens of testicular tissue from undescended testes.

All the case reports were reviewed. In the 97 boys (124 specimens) with intra-abdominal testes, three had known abnormal karyotype; 46,XY/47,XYY (case 3), 46,XYdel(11p), and 46,XY,13/20 unbalanced translocation; five had abnormal external genitalia, two with hypospadias, one with epispadias, and two with small penis and scrotum. Furthermore, 28 patients (38 specimens) had abnormal external genitalia but no intra-abdominal testes: 14 with hypospadias, two with epispadias, two with some ambiguity of the external genitalia (cases 4 and 5), two with hypoplastic scrotum, and eight with small penis and scrotum, of whom four had Kallmann's syndrome and one had testicular neoplasia (case 6). Moreover, 10 patients (14 specimens) had known abnormal karyotype: seven with 47,XXY; one with 45,X/46,XY (case 7); one with 46,XX; and one with 47,XYY.

At surgery for cryptorchidism the risk of testicular neoplasia was 7/135 (5.2%) in patients with intraabdominal testis, abnormal external genitalia other than cryptorchidism, or diagnosed abnormal karyotype. In contrast, no case of testicular neoplasia occurred in 1114 patients without these characteristics. The figures are significantly different (Fischer's exact test, P [is less than] 0.001).

At surgery the risk of testicular neoplasia was 4/286 (1.4%) in the 286 patients operated on for bilateral cryptorchidism, which is not significantly different from 3/963 (0.3%) in the 963 patients with unilateral cryptorchidism (P=0.10). However, intra-abdominal testis, abnormal external genitalia, or abnormal karyotype were reported in 42 (14.7%) patients operated on for bilateral cryptorchidism, compared with 93 (9.7%) patients with unilateral cryptorchidism (P [is less than] 0.05).


All seven boys with testicular neoplasia at surgery for cryptorchidism had intra-abdominal testis, abnormal external genitalia, or known abnormal karyotype. No case of testicular neoplasia was found in patients without these characteristics. To our knowledge, this information is new, but it is not inconsistent with the literature.[1 4 5] At operation for cryptorchidism the surgeon may elect to request a biopsy of testes with a high risk of neoplasia. This bias may explain the conflicting interpretation of our previously published results[2] and the results published by Swerdlow et al.[3] In clinical practice, we recommend a testicular biopsy at surgery for cryptorchidism if the boy has intra-abdominal testis, abnormal external genitalia, or known abnormal karyotype. These abnormalities were more common in patients with bilateral than with unilateral cryptorchism. The suggested procedure may diagnose testicular neoplasia at surgery for cryptorchidism and some patients may be treated for testicular neoplasia before invasive cancer develops.

Contributors: JV verified the pathological data and contributed to interpretation and reporting. HM contributed to interpretation and reporting. JT verified the clinical data and contributed to study design, interpretation, and reporting. DC took the initiative in this study, verified the pathological and clinical data, and was responsible for interpreting the results and drafting the paper. All authors are guarantors.

Funding: No specific funding.

Competing interests: None declared.

[1] Cortes D. Cryptorchidism--aspects of pathogenesis, histology and treatment. Scand J Urol Nephrol 1998;32(suppl 196):1-54.

[2] Moller H, Cortes D, Engholm G, Thorup J. Risk of testicular cancer with cryptorchidism and with testicular biopsy: cohort study. BMJ 1998; 317:729.

[3] Swerdlow AJ, Higgins CD, Pike MC. Risk of cancer in cohort of boys with cryptorchidism. BMJ 1997;314:1507-11.

[4] Cortes D, Thorup J, Frisch M, Moller H, Jacobsen GK, Beck BL. Examination for intratubular germ cell neoplasia (ITGCN) at operation for undescended testis in boys. A follow-up study. J Urol 1994;151:722-5.

[5] Muller J, Skakkebaek NE, Ritzen M, Ploen L, Petersen KE. Carcinoma in situ of the testis in children with 45,X/46,XY gonadal dysgenesis. J Pediatr 1985;106:431-6.

(Accepted 12 May 1999)

Department of Paediatric Surgery, 4072, Rigshospitalet, DK-2100 Copenhagen O, Denmark

Dina Cortes registrar

Jorgen Thorup consultant paediatric surgeon

Department of Pathology, Rigshospitalet

Jakob Visfeldt professor

Centre for Research in Health and Social Statistics, Danish National Research Foundation, DK-2100 Copenhagen O, Denmark

Henrik Moller head

Correspondence to: J Thorup

BMJ 1999;319:888-93

COPYRIGHT 1999 British Medical Association
COPYRIGHT 2000 Gale Group

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