American Journal of Medical Genetics 55507-508 (1995)

Letter to the Editor

Is There a Relation Between Klippel-Feil Sequence and Kallmann Syndrome?

To the Editor:

The Klippel-Feil sequence is a well delineated disor- der in which the patients present with congenital block formation of cervical vertebrae. These patients often have associated manifestations in particular invol- untary mirror movements or unilateral renal agenesis (URA) [Helmi and Pruzansky, 19801. These 2 abnor- malities are also common in a completely different ge- netic disorder: X-linked Kallmann syndrome which is characterized by hypogonadotropic hypogonadism and anosmia. The similarity between the associated mani- festations in the two entities suggests the possibility of a similar cause.

KLIPPEGFEIL SEQUENCE Klippel-Feil sequence is a well-delineated disorder

in which the typical patients present with congenital block formation of several cervical vertebrae, short neck, limitation of neck movements, and often addi- tional skeletal defects. Approximatively 50% of the pa- tients with Klippel-Feil sequence have neurological symptoms related, in most cases, to the upper limbs, the head, and the neck [Helmi and Pruzansky, 19801. A common neurological manifestation is synkinesis or mirror movements of the limbs [Baird et al., 19671. Renal anomalies may be found in 70% of the patients with Klippel-Feil sequence including URA [Moore et al., 19751. The genital anomalies found in affected fe- males with the syndrome reflect the failure of Muller- ian duct formation and are almost always present in women with Klippel-Feil sequence with URA. Anom- alies of the male genital tract have been reported and include hypospadias and cryptorchidism. Other associ- ated anomalies include cleft palate, speech defects, and congenital heart malformations [Helmi and Pruzansky, 19801. Most reports of patients with the Klippel-Feil sequence are incomplete as for details concerning synk- inesis and/or renal defects. In addition, large studies do no give details on each individual. Thus, it was not pos- sible to determine whether mirror movements and URA do or do not occur together with an increased fre-

Received for publication April 8, 1994; revision received July 11, 1994.

Address reprint requests to Joel Zlotogora, M.D., W.D., Department of Human Genetics, Hadassah Medical Center. Jerusalem, POB 12000, Israel 91120.

0 1995 Wiley-Liss, Inc.

quency in patients with Klippel-Feil sequence. There is a great need to collect prospective data on those cases and to analyze them causally and pathogenetically.

KALLMA” SYNDROME Kallmann syndrome is defined by the association of

anosmia and hypogonadotropic hypogonadism [Rugarli and Ballabio, 19931. The hypogonadism is of hypothal- amic origin and caused by the deficiency of gonado- tropin releasing hormone (GnRH). X-linked, autosomal recessive or dominant pattern of inheritance of the Kallmann syndrome have been described indicating ge- netic heterogeneity. However, the overall excess of af- fected males over females indicate that the X-linked form is the most frequent. Among the other manifesta- tions present in patients with Kallmann syndrome, mirror movements and genitourinary malformations such as URA and cryptorchidism are frequent. Ataxia, pes cavus, cleft lip/palate, and hearing loss have been also observed.

The pathogenetic basis underlying the association of anosmia and hypogonadism in Kallmann syndrome is explained by the common origin of both olfactory and GnRH secreting neurons. These neurons originate in the olfactory placode and project their axons to the olfactory bulb where they form synapses with the dentrites of mitral cells. During development the GnRH neurons migrate to reach the hypothalamus. The olfac- tory neurons have a short half life and are replaced by new neurons every few weeks. Therefore, migration and targeting are required throughout life. Based on these data it is thought that the gene encodes a factor involved in migration of olfactory and GnRH axons. Re- cently the X-linked Kallmann syndrome gene (KAL) gene has been cloned and mutations and deletions were identified. Mirror movements and URA were present together or alone in 5 out of 9 males from different fam- ilies with identified alterations including point muta- tions of the KAL gene [Hardelin et al., 19931. These findings support the possibility that mirror movements and URA are directly related to the abnormal gene.

IS THERE A RELATION BETWEEN KILPPEL-FEIL SEQUENCE

AND KALLMANN SYNDROME? Mirror movements may be transiently observed in

normal young children. Pathological mirror movements appear as a complication of neurological diseases such as spastic paresis or extrapyramidal disorders. Isolated mirror movements is a very rare disorder which is in-

508 Zlotogora

herited as an autosomal dominant trait [Regli et al., 19671. The only nonneurological disorders in which mirror movements have been reported to be frequent are the Klippel-Feil sequence and Kallmann syn- drome. It is thought that in individuals with mirror movements a single command from one hemisphere is distributed to the motoneurons on both sides. The ori- gin of the mirror movements may then be due to a split- ting of this motor command after it leaves the ipsi- lateral cortical area [Forget et al., 19861. This has be explained by an incomplete pyramidal decussation as it was observed in a pathological study of one patient with Klippel-Feil sequence [Gunderson and Solitaire, 19681. Electrophysiological studies also suggest the possibility that the mirror movements are secondary to a disorder of neuronal outgrowth in the motor system, particularly of inhibitory callosal fibers [Danek et al., 19921.

'The association of genitourinary malformations and fusion of the cervical vertebrae has been explained in Klippel-Feil sequence by the embryonic development of these organs. A n insult in the region of the 7th and 14th somites, the area from which the cervical spine develops, may cause the faulty development of the spine and in some cases of the pronephros and the pronephrotic ducts because of the intimate spatial rela- tionship. This may lead to renal and other anomalies in the female genital tract since the Mullerian ducts orig- inate from the pronephrotic duct.

Explanations implicating a local insult in the patho- genesis of mirror movements and URA cannot be ap- plied to Kallmann syndrome. It is probable that the KAL protein has an important role in areas responsible for inhibition of mirror movement as well as for the nor- mal development of the kidneys. Such a function of the KAL protein is supported by the distribution of the transcripts of the gene in the chick embryo. In situ hy- bridization demonstrated the presence of transcripts in the mitral cells of the olfactory bulbs, in stria1 neurons, Purkinje cells of the cerebellum, retinal neurons and in isolated neurons of the brain stem and spinal cord. In addition, transcripts were also observed in mesenchy- ma1 derivatives [Legouis et al., 19931.

I would like to propose that the Klippel-Feil se- quence may be, at least in some cases, secondary to a developmental defect due to the mutation of a molecule with some functional similarity to the KAL protein, a molecule most probably encoded by an autosome and not by the X chromosome as for the KAL protein. This would then explain why the same combination of traits

may be present in both entities. Klippel-Feil sequence is most frequently observed as a sporadic disorder with multiple causes; however, autosomal dominant and re- cessive forms have been reported [Da Silva, 1982; Gunderson et al., 19671. It may be that the sequence is in some cases secondary to an insult during embryoge- nesis while in others it is due to an inherited mutation in a protein related the KAL protein. In order to try to determine whether this hypothesis is valid as men- tioned above, data are needed on patients with Klip- pel-Feil with mirror movements and URA and every- one willing to collaborate on such analysis is invited to contact me.

REFERENCES Baird PA, Robinson GC, Buckler WJ (1967): Klippel-Feil syndrome. A

study of mirror movement detected by electromyography. Am J Dis Child 113:546-551.

Danek A, Heye B, Schroedter R (1992): Cortically evoked motor re- sponses in patients with Xp22.3-linked Kallmann's syndrome and in female gene carriers. Ann Neurol31:299-304.

Da Silva EO (1982): Autosomal recessive Klippel-Feil sequence. J Med Genet 19:130-134.

Forget R, Boghen D, Attig E, Lamare (1986): Electromyographic stud- ies of congenital mirror movements. Neurology 36:1316-1322.

Gunderson CH, Greenspan RH, Glaser GH, Lubs HA (1967): The Klippel-Feil syndrome: genetic and clinical reevaluation of cervi- cal fusion. Medicine 46:491-512.

Gunderson CH, Solitaire GB (1968): Mirror movements in patients with the Klippel-Feil syndrome. Neuropathologic observations. Arch Neurol 18:675-679.

Hardelin JP, Levilliers J, Blanchard S, Care1 JC, Leuteneger M, Pinard-Bertelletto JP, Bouloux P, Petit C (1993): Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. Hum Mol Genet 2:373-377.

Helmi C, Pruzansky S (1980): Craniofacial and extracranial malfor- mations in the Klippel-Feil syndrome. Cleft Palate J 17:65-88.

Legouis R, Ayer-Le Lievre C, Leibovici M, Lapointe F (1993): Expres- sion of the KAL gene in multiple neuronal sites during chicken development. Proc Natl Acad Sci USA 90:2461-2465.

Moore WB, Matthews TJ, Rabinowitz R (1975): Genitourinary ano- malies associated with Klippel-Feil syndrome. J Bone Joint Surg 57A355-357.

Regli F, Filippa G, Wiesendanger M (1967): Hereditary mirror move- ments. Arch Neurol16:620-623.

Rugarli EI, Ballabio A (1993): Kallmann syndrome from genetics to neurobiology. JAMA 270:2713-2716.

Joel Zlotogora Department of Human Genetics Hadassah Hospital and Medical School Hebrew University Jerusalem, Israel