Download PDF
Exp Clin Endocrinol Diabetes 2004; 112(1): 62-67
DOI: 10.1055/s-2004-815728
Case Report

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

A Case of Kallmann Syndrome Associated with Dandy-Walker Malformation

H. Ueno 1 , H. Yamaguchi 1 , H. Katakami 1 , S. Matsukura 1
  • 1The Third Department of Internal Medicine, Miyazaki Medical College, Miyazaki, Japan
Further Information

Publication History

Received: August 30, 2002 First decision: February 20, 2003

Accepted: April 22, 2003

Publication Date:
03 February 2004 (online)

Also available at
    Permissions and Reprints

Abstract

A 19-year-old man was admitted to our hospital for delayed puberty. At birth, he had macrocephalia and showed delayed physical and mental development. At 9 years of age, right cryptorchism was diagnosed. His parents had noticed that he could not recognize any smells since his infancy. Physical examination on admission revealed ocular hypertelorism, high myopia, high arched palate, and intermittent external strabismus. Sense of smell was scaled out by olfactometry. External genitalia were infantile. Neurological examination showed on IQ of 83, and mild truncal ataxia. Magnetic resonance imaging (MRI) showed a cystic distension of the IV ventricle, partial aplasia of the cerebellar vermis, elevation of the tentorium cerebelli, enlargement of the III ventricle, and agenesis of the corpus callosum. These findings revealed that the patient had Dandy-Walker malformation. The basal FSH, LH, and testosterone levels were all low compared with normal adult reference values. The serial LH-RH provocation tests showed stepwise LH and FSH elevation. After the fifth day of LH-RH administration, both LH and FSH responses clearly improved. Olfactory tracts were defective in MRI findings. These findings were consistent with hypogonadotropic hypogonadism of hypothalamic origin with anosmia, and the patient was therefore diagnosed with Kallmann syndrome. Sequence analysis of the KAL1 gene showed no mutation in the coding region. To our knowledge, this is the first case report of the coexistence of Kallmann syndrome and Dandy-Walker malformation in the same patient.

Key words

Kallmann syndrome - KAL1 - Dandy-Walker malformation

References

  • 1 Asai A, Hoffman H J, Hendrick E B, Humphreys R P. Dandy-Walker syndrome: experience at the Hospital for Sick Children, Toronto.  Pediatr Neurosci. 1989;  15 66-73
    CrossrefPubMedGoogle Scholar
  • 48 Ballabio A, Zoghbi H Y. Kallmann syndrome. Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease. Vol. 3. New York; McGraw-Hill 1995: 4549-4557
    Google Scholar
  • 2 Bick D, Franco B, Sherins R J, Heye B, Pike L, Crawford J, Maddalena A, Incerti B, Pragliola A, Meitinger T, Ballabio A. Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome.  N Engl J Med. 1992;  326 1752-1755
    PubMedGoogle Scholar
  • 3 Conrad B, Kriebel J, Hetzel W D. Hereditary bimanual synkinesis combined with hypogonadotropic hypogonadism and anosmia in four brothers.  J Neurol. 1978;  218 263-274
    PubMedGoogle Scholar
  • 4 de Zegher F, Lagae L, Declerck D, Vinckier F. Kallmann syndrome and delayed puberty associated with agenesis of lateral maxillary incisors.  J Craniofac Genet Dev Biol. 1995;  15 87-89
    PubMedGoogle Scholar
  • 5 Dean J C, Johnston A W, Klopper A I. Isolated hypogonadotropic hypogonadism: a family with autosomal dominant inheritance.  Clin Endocrinol. 1990;  32 341-347
    PubMedGoogle Scholar
  • 6 del Castillo, Cohen-Salmon M, Blanchard S, Lutfalla G, Petit C. Structure of the X-linked Kallmann syndrome gene and its homologous pseudogene on the Y chromosome.  Nat Genet. 1992;  2 305-310
    PubMedGoogle Scholar
  • 7 Fischer E G. Dandy-Walker syndrome: an evaluation of surgical treatment.  J Neurosurg. 1973;  39 615-621
    PubMedGoogle Scholar
  • 8 Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Taillon-Miller P, Brown C J, Willard H F, Lawrence C, Persico M G, Camerino G, Ballabio A. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules.  Nature. 1991;  353 529-536
    CrossrefPubMedGoogle Scholar
  • 9 Gardner E, O'Rahilly R, Prolo D. The Dandy-Walker and Arnold-Chiari malformations. Clinical, developmental, and teratological considerations.  Arch Neurol. 1975;  32 393-407
    PubMedGoogle Scholar
  • 10 Georgopoulos N A, Pralong F P, Seidman C E, Seidman J G, Crowley Jr W F, Vallejo M. Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency.  J Clin Endocrinol Metab. 1997;  82 213-217
    CrossrefPubMedGoogle Scholar
  • 11 Gu W X, Colquhoun-Kerr J S, Kopp P, Bode H H, Jameson J L. A novel aminoterminal mutation in the KAL-1 gene in a large pedigree with X-linked Kallmann syndrome.  Mol Genet Metab. 1998;  65 59-61
    CrossrefPubMedGoogle Scholar
  • 12 Guioli S, Incerti B, Zanaria E, Bardoni B, Franco B, Taylor K, Ballabio A, Camerino G. Kallmann syndrome due to a translocation resulting in an X/Y fusion gene.  Nat Genet. 1992;  1 337-340
    PubMedGoogle Scholar
  • 13 Hardelin J P, Levilliers J, Blanchard S, Carel J C, Leutenegger M, Pinard-Bertelletto J P, Bouloux P, Petit C. Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome.  Hum Mol Genet. 1993 a;  2 373-377
    PubMedGoogle Scholar
  • 14 Hardelin J P, Levilliers J, Young J, Pholsena M, Legouis R, Kirk J, Bouloux P, Petit C, Schaison G. Xp22. 3 deletions in isolated familial Kallmann's syndrome.  J Clin Endocrinol Metab. 1993 b;  76 827-831
    CrossrefPubMedGoogle Scholar
  • 15 Hardelin J P. Kallmann syndrome: towards molecular pathogenesis.  Mol Cell Endocrinol. 2001;  179 75-81
    CrossrefPubMedGoogle Scholar
  • 16 Hart M N, Malamud N, Ellis W G. The Dandy-Walker syndrome. A clinicopathological study based on 28 cases.  Neurology. 1972;  22 771-780
    PubMedGoogle Scholar
  • 17 Hermanussen M, Sippell W G. Heterogeneity of Kallmann's syndrome.  Clin Genet. 1985;  28 106-111
    PubMedGoogle Scholar
  • 18 Hill J, Elliott C, Colquhoun I. Audiological, vestibular and radiological abnormalities in Kallman's syndrome.  J Laryngol Otol. 1992;  106 530-534
    PubMedGoogle Scholar
  • 19 Hirsch J F, Pierre-Kahn A, Renier D, Sainte-Rose C, Hoppe-Hirsch E. The Dandy-Walker malformation. A review of 40 cases.  J Neurosurg. 1984;  61 515-522
    PubMedGoogle Scholar
  • 20 Incerti B, Guioli S, Pragliola A, Zanaria E, Borsani G, Tonlorenzi R, Bardoni B, Franco B, Wheeler D, Ballabio A, Camerino G. Kallmann syndrome gene on the X and Y chromosomes: implications for evolutionary divergence of human sex chromosomes.  Nat Genet. 1992;  2 311-314
    PubMedGoogle Scholar
  • 21 Izumi Y, Tatsumi K, Okamoto S, Hosokawa A, Ueno S, Fukui H, Amino N. A novel mutation of the KAL1 gene in Kallmann syndrome.  Endocr J. 1999;  46 651-658
    PubMedGoogle Scholar
  • 22 Izumi Y, Tatsumi K, Okamoto S, Ogawa T, Hosokawa A, Matsuo T, Kato Y, Fukui H, Amino N. Analysis of the KAL1 gene in 19 Japanese patients with Kallmann syndrome.  Endocr J. 2001;  48 143-149
    PubMedGoogle Scholar
  • 23 James H E, Kaiser G, Schut L, Bruce D A. Problems of diagnosis and treatment in the Dandy-Walker syndrome.  Childs Brain. 1979;  5 24-30
    PubMedGoogle Scholar
  • 49 Jones J, Kemmann E. Olfacto-genital dysplasia in the female.  Obstet Gynecol Annu. 1976;  5 443-445
    PubMedGoogle Scholar
  • 50 Kaiser G, Schut L, James H E, Bruce D A. Problems of diagnosis and treatment in the Dandy-Walker syndrome.  Mod Probl Paediatr. 1976;  18 123-4
    PubMedGoogle Scholar
  • 51 Kallmann F J, Schoenfeld W A, Barrera S E. The genetic aspects of primary eunuchoidism.  Am J Ment Deficiency. 1944;  XLVIII 203-236
    PubMedGoogle Scholar
  • 24 Kertzman C, Robinson D L, Sherins R J, Schwankhaus J D, McClurkin J W. Abnormalities in visual spatial attention in men with mirror movements associated with isolated hypogonadotropic hypogonadism.  Neurology. 1990;  40 1057-1063
    PubMedGoogle Scholar
  • 25 Knorr J R, Ragland R L, Brown R S, Gelber N. Kallmann syndrome: MR findings.  Am J Neuroradiol. 1993;  14 845-851
    PubMedGoogle Scholar
  • 26 Kumar R, Jain M K, Chhabra D K. Dandy-Walker syndrome: different modalities of treatment and outcome in 42 cases.  Childs Nerv Syst. 2001;  17 348-352
    CrossrefPubMedGoogle Scholar
  • 27 Legouis R, Hardelin J P, Levilliers J, Claverie J M, Compain S, Wunderle V, Millasseau P, Le Paslier D, Cohen D, Caterina D, Bougueleret L, de Waal H D, Lutfalla G, Weissenbach J, Petit C. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules.  Cell. 1991;  67 423-435
    CrossrefPubMedGoogle Scholar
  • 28 Lieblich J M, Rogol A D, White B J, Rosen S W. Syndrome of anosmia with hypogonadotropic hypogonadism (Kallmann syndrome): clinical and laboratory studies in 23 cases.  Am J Med. 1982;  73 506-519
    CrossrefPubMedGoogle Scholar
  • 29 Matsuo T, Okamoto S, Izumi Y, Hosokawa A, Takegawa T, Fukui H, Tun Z, Honda K, Matoba R, Tatsumi K, Amino N. A novel mutation of the KAL1 gene in monozygotic twins with Kallmann syndrome.  Eur J Endocrinol. 2000;  143 783-787
    CrossrefPubMedGoogle Scholar
  • 30 Maya-Nunez G, Zenteno J C, Ulloa-Aguirre A, Kofman-Alfaro S, Mendez J P. A recurrent missense mutation in the KAL gene in patients with X-linked Kallmann's syndrome.  J Clin Endocrinol Metab. 1998 a;  83 1650-1653
    CrossrefPubMedGoogle Scholar
  • 31 Maya-Nunez G, Cuevas-Covarrubias S, Zenteno J C, Ulloa-Aguirre 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.  Clin Endocrinol. 1998 b;  48 713-718
    CrossrefPubMedGoogle Scholar
  • 32 Molsted K, Kjaer I, Giwercman A, Vesterhauge S, Skakkebaek N E. Craniofacial morphology in patients with Kallmann's syndrome with and without cleft lip and palate.  Cleft Palate Craniofac J. 1997;  34 417-424
    PubMedGoogle Scholar
  • 52 Naftolin F, Harris G W, Bobrow M. Effect of purified luteinizing hormone releasing factor on normal and hypogonadotrophic anosmic men.  Nature. 1971;  232 496-7
    PubMedGoogle Scholar
  • 33 Ohaegbulam S C, Afifi H. Dandy-Walker syndrome: incidence in a defined population of Tabuk, Saudi Arabia.  Neuroepidemiology. 2001;  20 150-152
    CrossrefPubMedGoogle Scholar
  • 34 O'Neill M J, Tridjaja B, Smith M J, Bell K M, Warne G L, Sinclair A H. Familial Kallmann syndrome: a novel splice acceptor mutation in the KAL gene.  Hum Mutat. 1998;  11 340-342
    PubMedGoogle Scholar
  • 35 Pascual-Castroviejo I, Velez A, Pascual-Pascual S I, Roche M C, Villarejo F. Dandy-Walker malformation: analysis of 38 cases.  Childs Nerv Syst. 1991;  7 88-97
    PubMedGoogle Scholar
  • 36 Quinton R, Duke V M, de Zoysa P A, Platts A D, Valentine A, Kendall B, Pickman S, Kirk J M, Besser G M, Jacobs H S, Bouloux P M. The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis.  J Clin Endocrinol Metab. 1996;  81 3010-3017
    CrossrefPubMedGoogle Scholar
  • 37 Raimondi A J, Sato K, Shimoji T. Dandy-Walker Syndrome. Basel; Karger 1984: 1-82
    Google Scholar
  • 38 Rugarli E I, Lutz B, Kuratani S C, Wawersik S, Borsani G, Ballabio A, Eichele G. Expression pattern of the Kallmann syndrome gene in the olfactory system suggests a role in neuronal targeting.  Nat Genet. 1993;  4 19-26
    CrossrefPubMedGoogle Scholar
  • 39 Rugarli E I, Ghezzi C, Valsecchi V, Ballabio A. The Kallmann syndrome gene product expressed in COS cells is cleaved on the cell surface to yield a diffusible component.  Hum Mol Genet. 1996;  5 1109-1115
    CrossrefPubMedGoogle Scholar
  • 40 Sawaya R, McLaurin R L. Dandy-Walker syndrome. Clinical analysis of 23 cases.  J Neurosurg. 1981;  55 89-98
    PubMedGoogle Scholar
  • 41 Schwankhaus J D, Currie J, Jaffe M J, Rose S R, Sherins R J. Neurologic findings in men with isolated hypogonadotropic hypogonadism.  Neurology. 1989;  39 223-226
    PubMedGoogle Scholar
  • 42 Soussi-Yanicostas N, Hardelin J P, Arroyo-Jimenez M M, Ardouin O, Legouis R, Levilliers J, Traincard F, Betton J M, Cabanie L, Petit C. Initial characterization of anosmin-1, a putative extracellular matrix protein synthesized by definite neuronal cell populations in the central nervous system.  J Cell Sci. 1996;  109 1749-1757
    PubMedGoogle Scholar
  • 43 Tal Y, Freigang B, Dunn H G, Durity F A, Moyes P D. Dandy-Walker syndrome: analysis of 21 cases.  Dev Med Child Neurol. 1980;  22 189-201
    PubMedGoogle Scholar
  • 44 Vogl T J, Stemmler J, Heye B, Schopohl J, Danek A, Bergman C, Balzer J O, Felix R. Kallman syndrome versus idiopathic hypogonadotropic hypogonadism at MR imaging.  Radiology. 1994;  191 53-57
    PubMedGoogle Scholar
  • 45 Wegenke J D, Uehling D T, Wear Jr J B. Gordon ES, Bargman JG, Deacon JS, Herrmann JP, Opitz JM. Familial Kallmann syndrome with unilateral renal aplasia.  Clin Genet. 1975;  7 368-381
    PubMedGoogle Scholar
  • 46 White B J, Rogol A D, Brown K S, Lieblich J M, Rosen S W. The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review.  Am J Med Genet. 1983;  15 417-435
    CrossrefPubMedGoogle Scholar
  • 47 Zusho H, Asaka H, Okamoto M. Diagnosis of olfactory disturbance.  Auris Nasus Larynx. 1981;  8 19-26
    PubMedGoogle Scholar

M. D. Hiroaki Ueno PhD.

Third Department of Internal Medicine · Miyazaki Medical College

5200, Kihara, Kiyotake

Miyazaki, 889-1692

Japan

Phone: + 81985859246

Fax: + 81 9 85 85 75 91

Email: intron@med.miyazaki-u.ac.jp

      >