SSBP Information Sheet
Kallman Syndrome

Alternative titles: anosmia with hypogonadotropic hypogonadism; dysplasia olfactogenitalis of De Morsier.

First description:
Reports of the association of anosmia and hypogonadism date back to the 1800s.
The familial nature of what is known as Kallmann syndrome was first described by Kallmann et al (1944). De Morsier provided a neuropathologic description of the syndrome (1954).

Syndrome Incidence:
More frequent in males (1:10.000) than in females (1:50.000).
In 46, XY patients with hypogonadism: 1:30.

Genetics:
The syndrome proved to be more frequently X- linked. It may be also autosomal dominant or recessive. According to these different modes of transmission 3 different syndromes have been described: Kallmann syndrome type 1, X linked; Kallmann syndrome type 2, autosomal dominant; Kallmann syndrome type 3, autosomal recessive. Sporadic cases have also been reported.

In Kallmann syndrome type 1, a molecular defect in the Kalig-1 (Kallmann syndrome interval gene 1) located at Xp22.3 causes the neuronal migration defect underlying the syndrome. The Kal gene might promote migration and target recognition of the olfactory axons from the olfactory placode to the hypothalamus. Absence of GnRH secreting cells in the hypothalamus explains the deficiency of this hormone in Kallmann syndrome.

Physical features:
Males with Kallmann syndrome show a defective sense of smell due to developmental abnormalities (partial or complete agenesis) of the olfactory lobes and hypogonadism due to deficiency of GnRH. Both olfactory acuity and identification ability are impaired. Transmitting females have partial or complete anosmia. Affected females have no menses, no breast development and anosmia. The diagnosis may be difficult in prepuberal age. Testis development may be appropriate for age up to puberty, as normal initial amounts of germinal tissue may be present; in other cases, cryptorchidism and micropenis have been reported.

In adults, gynecomastia, genital atrophy and eunuchoidal habitus are present. Most abnormalities have been described in type 1 syndrome (high arched palate, clubfoot, renal agenesis, neurosensorial hearing loss, oculomotor apraxia, colourblindness, cerebellar ataxia, spastic paraplegia ; in 85 % of cases mirror movements of upper limbs are also present ). Type 2 Kallmann syndrome may be associated with congenital heart disease. In type 1 syndrome, a contiguous gene syndrome characterized by ichthyocitosis and chondrodysplasia may be associated. In type 3 syndrome midline cranial abnormalities (cleft palate, cleft lip, choanal atresia) have been signalled.

Life expectancy:
Life expectancy is believed to be normal.

Behavioral characteristics:
During adolescence problems are found in the development of independence (relating to own body image and social functioning) and in identity development.
Patients appear to be low confident and avoidant. They rarely volunteer any information about anosmia, so this symptom has to be inquired about in cases of hypogonadism. In adults, depression and sexual problems, partially reversible with appropriate substitutive therapy, are signalled. Aggressive behavior and anorexia nervosa have also been described in these patients.
Kallmann syndrome and schizophrenia share several clinical features (dysfunctional olfactory abilities, prevalence of affected males and psychiatric presentation) However, the supposed genetic similarity has not been confirmed.

Cognitive characteristics:
IQ is reported borderline to normal. Mild and severe mental retardation have also been reported in association with Kallmann syndrome, but they are considered incidental signs.

Bibliography

Bick D., Franco B.,Sherins RJ., Haye B., Pike L., Crawford J., Maddalena A., Incerti B., Pargliola A., Meitinger T, Ballabio A. Brief report: intragenic deletion of the Kalig-1 gene in Kallmann's syndrome. New England Journal of Medicine, 1992, Jun 326(26): 1752-55

De Morsier G. Etudes sur les dysraphies cranio-encephaliques. I. Agenesie des lobes olfactifs (telencephaloschizis lateral) et des commissures calleuse et anterieure (telencephaloschizis median): la dysplasie olfacto-genitale. Schweizer Archiv fur Neurologie, Neurochirurgie und Psychiatrie, 1954, 74: 309-361

Franco B., Guioli S., Pragliola A., Incerti B., Bardoni B., Tonlorenzi R., Carrozzo R., Maestrini E., Pieretti M., Taillon-Miller P., Brown CJ., Willard H., Lawrence C., Perisco MG., Camerino G., Ballabio A. A gene deleted in Kallmann's sindrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature, 1991, 353: 529-536

Huisman J., Bosch JD., Delemarre v d Waal HA. Personality development of adolescents with hypogonadotropic hypogonadism. Psychological Report, 1996, Dec, 79(3 Pt 2): 1123-6

Kallmann F.J., Schoenfeld W.A., Barrera S.E.. The genetic aspects of primary eunuchoidsm. American Journal of Mental Deficiency, 1944, 48: 203-236

Krams M., Quinton R., Ashburner J., Friston K. J., Frackowiak R.S.J., Bouloux P. M. G., Passingham R.E. Kallmann's syndrome: mirror movements associated with bilateral corticospinal tracts hypertrophy. Neurology, 1999, 52 : 816-822

Layman LC. Genetics of human hypogonadotropic hypogonadism. American Journal of Medical Genetics, 1999, Dec, 89(4): 240-248

Maya-Nunez G., Cuevas-Covarrubias S., Zenteno J.C., Ulloa-Agiurre A., Kofman-Alfaro S., Mendez J.P. Contiguous gene syndrome due to deletion of the first three exons of the Kallmann gene and complete deletion of the steroid sulphatase gene. Clinical Endocrinology (Oxf), 1998, Jun, 48(6): 713-8

Obaydi H., Izmeth M.G.A., Rigby J.C. Kallmann's syndrome and mental handicap. Journal of Intellectual Disability Research, 1992, Oct, 36 (Pt 5):457-60

Parhar I., Pfaff D., Schwanzel-Fukuda M. Genes and behavior as studied through gonadotropin-releasing hormone (GnRH) neurons: comparative and functional aspects. Cellular and Molecular Neurobiology, 1995, Feb, 15: 1107-16

Wiedemann H.-R, Kunze J. Atlas der Klinischen Syndrome fur Klinik und Praxis Stuttgart 1995, 632-633.

Annapia Verri,September 2000