American Journal of Medical Genetics 35:306-309 (1990)
Brief Clinical Report Chromosome Abnormality in Kallmann Syndrome Lyle G. Best, Walter A. Wasdahl, Linda M. Larson, and Jean Sturlaugson Indian Health Service Hospital and University of North Dakota Medical School, Belcourt (L.G.B.) and Department of Pathology, University of North Dakota Medical School, Grand Forks (W.A.W., L.M.L., J.S.)
male and one female half-sibs. All but one half-brother and all full sibs have had a t least two offspring and there are no reports of symptoms or signs of KS in these individuals or their offspring. The full brother without offspring is clearly sexually mature. The patient’s mother reports normal coordination and no other significant medical problems as a child. At age 22 years, the propositus was referred to the University of Minnesota for delayed sexual development. During that evaluation he was noted t o have normal 17-hydroxycorticosteroids and abnormally low 17-ketosteroids and gonadotropin levels. He was Barr body negative, and chromosome analysis of 23 peripheral lymphocytes was normal. He KEY WORDS: chromosome translocation was diagnosed to have hypogonadotropic hypogonad(7q;12q), hypogonadotropic ism. Epiphyseal centers of most long bones and spine hypogonadism, hyposmiai were not yet closed. The bone age of the hand was in the anosmia, steroid sulphatase “neighborhood” of 12 years, and the metacarpals apgene peared shortened and clubbed at their distal ends, especially the 4th right metacarpal. In addition, a sharply outlined foramen in the occipital bone near the internal occipital protuberance was noted. The patient has had INTRODUCTION delayed mental development and tested a t a Wechsler Kallmann syndrome (KS), hypogonadotropic hypo- Adult Intelligence Scale I& of 55 a t age 21 years. gonadism with anosmia (or hyposmia) and occasional Subsequently he has developed type I1 diabetes other anomalies, was first described by Kallmann et al. mellitus, essential hypertension, and chronic alcohol[1944] as an inherited syndrome although DeMorsier ism. He was reevaluated in 1980with similar results. At [19541reported that hypogonadism and defective olfac- this time 17-OH steroids were 17 pg%; 17-keto steroids tion were known to be associated as early as 1850. were 3.9 mg/g of creatinine; and FSH was 6; and LH was The mode of inheritance of KS is still undecided, but 11.Fasting cholesterol and triglycerides were 164 mg% the only cases of cytogenetic abnormalities reported so and 110 mg%, respectively; thyroid function was norfar include ovarian mosaicism (possible trisomy of an mal, and all epiphyses were closed. His examination “F” group chromosome [Jones et al., 19741 and an in- showed a height of 175 cm, weight of 89.5 kg,span of 156 stance of small metacentric chromosome [Ventruto et cm (although difficult to measure accurately secondary al., 19761in the peripheral lymphocytes of a patient and to orthopedic deformity of the upper limbs), upperilower mother. The present case is the first to report a chromo- segment ratio of 0.68, BP of 1lOiS0, no demonstrable some abnormality in the peripheral lymphocytes con- facial hair, no axillary hair, very sparse pubic hair, and cordant with the diagnosis of KS. normal scalp hair. The penis was very small and the testes were approximately 1 cm long and slightly less in CLINICAL REPORT diameter. Intravenous pyelogram was normal. A childThis is a 44-year-old ChippewaiFrench man, oldest of hood injury and a fracture as an adult have lead to five female and one male full sibs and youngest of two flexion deformity at both elbows. Fundi were normal. The patient and parents’ olfaction was tested on a Received for publication January 3,1989; revision received Sep- limited basis according to the method of Henkin and Bartter 119661. The propositus was only vaguely sensitember 8, 1989. tive to 10(- 1) mM pyridine and was unable to detect Address reprint requests to Lyle G. Best, RR1 Box 88, Rolette, 10(- 2 ) mM. The father and mother had detection ND 58366.
We report on an individual with Kallman syndrome (KS)and a balanced de novo translocation (7;12)(q22,q24).None of 6 full sibs, 3 halfsibs, or parents have KS or this chromosome translocation.This is the only known report of KS with a chromosomeabnormality.This may represent a spurious association or genetic heterogeneity vis-a-vis the reported linkage of K S to the steroid sulphatase gene on the X chromosome. The pathophysiology and genetics of KS are discussed.
0 1990 Wiley-Liss, Inc.
Kallmann Syndrome: Chromosome Translocation
thresholds 1 and 2 orders of magnitude lower (more sensitive), respectively. These levels were compared to those of ten healthy control adults, all of whom were easily able to detect concentrations of 10( - 3) mM. It should be noted these detection thresholds were higher than those reported by Henkin and Bartter [19661 and Merriam et al. [19771but were consistent with data from Santen and Paulsen “731 for reasons that are not apparent. In addition the patient was tested qualitatively and was unable to detect cinnamon and allspice, although he was capable of detecting ground cloves (albeit misidentifying it as “cinnamon”). In 1984, repeat lymphocyte chromosome studies wcre done and demonstrated a reciprocal translocation (7;12)(q22;q24) (Fig. 1) and a pericentric inversion (9)(p12q13), considered a normal polymorphism. The parents’ cells were difficult to culture but appeared normal with the exception of a paternal pericentric inversion of chromosome 9, as seen in the patient.
a
79- 12
7
b
7
12qt
12
36
I Fig. 1. A Partial karyotype of propositus indicating reciprocal translocation (7;12)(q22;q24).B: Ideogram of normal chromosomes 7 and 12, arrows indicating breakpoints.
307
MATERIALS AND METHODS The culturing technique was the high-resolution method of Yunis [19761. Staining was based on the nypsin-Giemsa method of Seabright 11971). DISCUSSION This patient has manifestations of KS, i.e., hypogonadotropic hypogonadism, deficiency of olfaction, and skeletal anomalies. The chromosome anomaly in this case, a balanced translocation between chromosome 7 and 12, may be a coincidental finding associated with KS, but it may also be an indication of the chromosome location of a gene involved in KS and thus guide more sophisticated linkage analysis in the future. There has been suggested assignment of the KS gene to the X chromosomebecause of the presence of microdeletionsin the steroid sulphatase (STS)gene of the Xp region found in cases with KS and X-linked icthyosis (XLI) [Ballabio et al., 19871. These results were derived from direct DNA analysis, and indeed cytogenetic studies were unable to detect these deletions. The following information needs to be consideredprior to assignment of KS to the X-chromosome LMcKusick, 19871: 1) Kallmann et al. [1944] favored X-linked inheritance in his initial report because of defective color vision seen in a number of his cases and the known X-linked inheritance of these defects. There has been considerable debate since that time, and transmission characteristic of autosomal dominant (with Wegenke et al., 19751 and without [Santen and Paulsen, 19731 sex limitation), autosomal recessive [Lieblich et al., 1982; Juillard, 1978; White et al., 19831, X-linked dominant [Nowakowski and Lenz, 19611, and again X-linked recessive [Wegenke et al., 19751have been proposed. Hermanussen and Sippell [ 19851 described a monozygotic female twin discordant for paternally inherited KS. Although almost by definition, individuals with KS should be infertile, there have been 4 apparent instances of father-son transmission [Hockaday, 1966; Schroffner and f i r t h , 1970; Santen and Paulsen, 1973;Merriam et al., 19771. In some of these cases the only apparent abnormality of the father has been anosmia. The proposed modes of inheritance were recently reviewed by White et al. [19831, Hermanussen and Sippell 119851, and Job et al. [1985]who concluded that there are forms of X-linked KS as well as forms that excluded X-linkage. Hence KS may be linked to more than one locus on one or more chromosomes. A novel possibility [Keitges et al., 19851 is that a single KS gene may be located a t the junction between the pseudoautosomal distal segment of Xp and the more central region subject to lyonization. This could explain both autosomal recessive and X-linked recessive pedigrees, but the autosomal dominant pedigrees would require the presence of at least one additional allele. 2) More standard explanations of genetic heterogeneity such as multiple enzymes required in a biochemical pathway or regulating and controlling genes could also explain the variation in observed inheritance.
308
Best et al.
Discussions of the pathogenesis of KS have often noted the association of the olfactory defects with the endocrinologic manifestations. Since these two systems are so intimately related both anatomically and physiologically in other species, a single genetic defect might simultaneously affect both systems during embryogenesis. A few authors have hinted that the hypothalamic dysfunction could be secondary t o a primary defect in olfaction, but Hockaday 119661, Netter et al. [1972], and Hermanussen and Sippell [1985] seem to have expressed this possibility the most clearly. There may be a critical period of neuroendocrinologic development (analogous to the postnatal development of the visual cortex) that is forever lost without the proper stimulation of the olfactory lobes during a n early period of life. In favor of this hypothesis would be the selective nature of defects in the gonadotropic system; sparing other hypothalamic endocrine functions affecting adrenocortical function, vasopressin, prolactin, growth hormone, etc. If, as suggested by Wegenke et al. 119751and Cohen [1983], KS represents a mild form of holoprosencephaly with disruption of hypothalamic nuclei involving gonadotropins, i t seems unusual that these other endocrinologic functions would not occasionally be affected given the extremely close physical proximity of these structures. Early direct experimental attempts [Kohne, 19471 to disrupt sexual maturation of the rabbit by ablation of the olfactory lobes were unsuccessful. More recent work cited by Murphy [1976] indicates that olfactory bulb removal does retard development of reproductive organs in 6-week-old rabbits. Murphy [1976] also notes several other studies showing delay in onset of puberty in rats after destruction of olfactory capability. At least one investigation [Sato et al., 19741 concluded that the timing of olfactory disruption was very important with effective lesions produced a t 6 but not a t 20 days of age. The demonstrated effects of the olfactory environment in the acceleration of sexual maturity in mice also gives credance to this concept [Wilson et al., 19801. Weighing against this theory are numerous reports of anosmiai hyposmia without hypogonadism LJob et al., 1985; Santen and Paulsen, 1973; Nowakowski and Lenz. 1961; Lieblich et al., 19821 segregating in families with KS. There is also a n autopsy report by Steenfeldt-Foss [1954] of a female with agenesis of the olfactory lobes but normal-appearing ovaries and no other indication of hypogonadism. Unfortunately only a few of these cases had olfaction tested in a reproducible or sensitive manner. The converse, i.e., hypogonadotropic KS relatives with normal olfactory sense, is apparently rare, with only 2 females and a third case reported [Lieblich et al., 19821. There have been reports of poor pituitary response to LH-RH [Merriam et al., 19771indicating possible pituitary insufficiency as well, but even in these cases LH and FSH were increased 2- to %fold by LH-RH stimulation, which is about the normal proportional response; however, the baseline secretion was so low as to prevent total secretion from being in the normal range. This relative pituitary insufficiency could also be explained by a n early deficient period of stimulation by the olfac-
tory-hypothalamic system, which left the pituitary with too small a population of gonadotropin-producing cells to respond normally in total production but still showing a proportional response to LH-RH. The skeletal anomalies may also be a secondary manifestation of the endocrine anomalies but a t a later date in development when closure of epiphyseal plates is obviously disrupted by lack of normal puberty and yet is still progressing a t a slow pace determined by a n a s yet unknown mechanism. It would be interesting to determine whether these individuals had any shortening of the metacarpalsprior to the usual age of puberty. Shortened metacarpals and abnormal sexual maturation are also occasionally associated in other syndromes such a s in LMBB [Bardin, 1971; Temtamy and McKusick, 19781 and in cases of hypogonadotropism associated with ataxia [Matthews and Rundle, 19641.
ACKNOWLEDGMENTS We extend our sincere appreciation to the members of this family, whose cooperation made this publication possible, and to the Aberdeen Area Indian Health Service (IHS) for their assistance. The opinions expressed in this paper are those of the author and do not necessarily reflect the views of the IHS.
REFERENCES Ballabio A, Sebastio G, Carrozzo R, Parenti G, Piccirillo A, Persico MG, Andria G (1987):Deletions of the steroid sulphatase gene in “classical” X-linked ichthyosis associated withKallmann syndrome. Hum Genet 77:338-341. Bardin WC (1971):Hypogonadotropic hypogonadism in patients with multiple congenital defects. In Bergsma D (ed):“The Clinical Delineation of Birth Defects. The Endocrine Svstem.” Baltimore: Williams and Wilkins Co’., for the National Foundation-March of Dimes, BD:OAS VII(6):175-178. Cohen MM (1983): Craniofacial disorders. In Eimery AEH, Rimoin D (eds): “E’rinciples and Practice of Medical Genetics.” Edinburgh: Churchill-Livingstone Inc., pp 576-578. DeMorsier G 11954): Etudes sur les dysraphies crlnioencephaliques. 1 Agenesie des lobes olfactifs (telencephaloschizislateral) et des commissures calleuse et anterieure (telencephaloschizis median). La dysplasie olfactogenitale. Schweiz Arch Neurol Psychiatr 74:309-361. Henkin RI, Bartter FC (1966): Studies on olfactory thresholds in normal man and in patients with adrenal cortical insufficiency: the role of adrenal cortical steroids and of serum sodium concentration. J Clin Invest 45:1631-1639. Hermanussen M, Sippell WG (1985): Heterogeneity of Kallmann’s syndrome. Clin Genet 28:106-111. Hockaday TDR (1966): Hypogonadism and life-long anosmia. Postgrad Med J 42572-574. Job JC, Naud C, Toublanc J E , Chaussain JL, Canlorbe P (1985): Genetic factors in primary gonadotropic deficiency. In Papadatos CJ, Bartsocas CS (eds): “Endocrine Genetics and Genetics of Growth” New York: Alan R. Liss, Inc., pp 175-183. Jones JR, Kemman E, Cresci J , Solish GI (1974):Anosmia and hypogonadism with ovarian mosaicism. Am J Obstet Gynecol 121:991-994. Juillard E (1978): Considerations genetiques sur le syndrom de Kallmann. Rev Med Suisse Romande 98:237-241. Kallmann FJ, Schoenffeld WA, Barrera SE (1944): The genetic aspects of primary eunuchoidism. Am J Ment Defic 48:203-236. Keitges E, Rivest M, Siniscalco M, Gartler SM (1985): X-linkage of steroid sulphatase in the mouse is evidence for a functional Y-linked allele. Nature 315226, 227.
Kallmann Syndrome: Chromosome Translocation Kohne G (1947): Die Beziehungen des angeborenen Olfactoriusdefekts zum primaren Eunuchoidismus des Mannes (Anatomische und experimentelle Beobachtungen). Virchows Arch [A] 314345-357. Lieblich JM, Rogol AD, White BJ, Rosen SW (1982): Syndrome of anosmia with hypogonadotrophic hypogonadism (Kallmann syndrome). Am J Med 73:506-519. Matthews WB, Rundle AT (1964):Familial cerebellar ataxia and hypogonadlsm. Brain 87:463-468. McKusick VA (1987): The morbid anatomy of the human genome: A review of gene mapping in clinical medicine. Medicine (Baltimore) 66:237-296. Merriam GR, Beitins IZ, Bode HH (1977): Father-to-son transmission of hypogonadism with anosmia, Kallmann’s syndrome. Am J Dis Child 131:1216-~1219. Murphy MR (1976): Olfactory impairment in mammalian olfaction, reproductive processes, and behavior. In Doty RL (ed): “Mammalian Olfaction, &productive Processes, and Behavior.” New York: Academic Press, p 109. Netter A, Gorins A, Millet D (1972):Le syndrome de Morsier-Kallmann ou dysplasie olfacto-ghitale. Nouv Presse Med l:ll9-122. Nowakowski H, Lenz W (1961):Genetic aspects in male hypogonadism. Recent Prog Horm Res 17:53-95. Santen RJ, Paulsen CA (1973): Hypogonadotropic eunuchoidism. I. Clinical study of the mode of inheritance. J Clin Endocrinol Metab 36:47-54. Sat0 N, Haller EW, Powell RD, Henkin RI (1974):Sexual maturation in bulbectomized female rats. J Reprod Fei-ti1 36:301-309.
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Schroffner WG, Furth ED (19701: Hypogonadotropic hypogonadism with anosmia (Kallmann’s syndrome) unresponsive to clomiphene citrate. J Clin Endocrinol Metab 31267-270. Seabright M (1971): A rapid banding technique for human chromosomes. Lancet 2:971, 972. Steenfeldt-Foss 0 (1954):Arhinencephaly and imbecility. Acta Psychiatr Scand 29:261-268. Temtamy S, McKusick V (1978):Polydactyly as a part ofsyndromes. In Bergsma D (ed):“The Genetics of Hand Malformations.”New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes, BD:OAS XIV (3):404-408. Ventruto V, Cali A, Farina L, Festa B, Ricciardi I, Sebastio L (19761:A case of hypogonadotrophic hypogonadism with anosmia (Kallmann‘s syndrome) in a male, with familial incidence of a small metacentric chromosome (47,XY,mat?+ ) J Med Genet 13:71-75. Wegenke JD, Uehling DT, Wear JB, Jr. Gordon ES, Bargman JG, Deacon JSR, Herrmann JPR, Opitz J M (1975): Familial Kallman syndrome with unilateral renal aplasia. Clin Genet 7:368-381. White BJ, Rogol AD, Brown KS, Lieblich JM, Rosen SW (1983): The syndrome of anosmia with hypogonadotropic hypogonadism: A genetic study of 18 new families and a review. Am J Med Genet 15:417-435. Wilson MC, Beamer WG: Whitten WK (1980):Puberty acceleration in mice. 1. Dose-response effects and lack of critical time following exposure to male mouse urine. Biol Reprod 22864-872. Yunis JJ (1976): High resolution of human chromosomes. Science 191:1268-1270.
Brief Clinical Report Chromosome Abnormality in Kallmann Syndrome Lyle G. Best, Walter A. Wasdahl, Linda M. Larson, and Jean Sturlaugson Indian Health Service Hospital and University of North Dakota Medical School, Belcourt (L.G.B.) and Department of Pathology, University of North Dakota Medical School, Grand Forks (W.A.W., L.M.L., J.S.)
male and one female half-sibs. All but one half-brother and all full sibs have had a t least two offspring and there are no reports of symptoms or signs of KS in these individuals or their offspring. The full brother without offspring is clearly sexually mature. The patient’s mother reports normal coordination and no other significant medical problems as a child. At age 22 years, the propositus was referred to the University of Minnesota for delayed sexual development. During that evaluation he was noted t o have normal 17-hydroxycorticosteroids and abnormally low 17-ketosteroids and gonadotropin levels. He was Barr body negative, and chromosome analysis of 23 peripheral lymphocytes was normal. He KEY WORDS: chromosome translocation was diagnosed to have hypogonadotropic hypogonad(7q;12q), hypogonadotropic ism. Epiphyseal centers of most long bones and spine hypogonadism, hyposmiai were not yet closed. The bone age of the hand was in the anosmia, steroid sulphatase “neighborhood” of 12 years, and the metacarpals apgene peared shortened and clubbed at their distal ends, especially the 4th right metacarpal. In addition, a sharply outlined foramen in the occipital bone near the internal occipital protuberance was noted. The patient has had INTRODUCTION delayed mental development and tested a t a Wechsler Kallmann syndrome (KS), hypogonadotropic hypo- Adult Intelligence Scale I& of 55 a t age 21 years. gonadism with anosmia (or hyposmia) and occasional Subsequently he has developed type I1 diabetes other anomalies, was first described by Kallmann et al. mellitus, essential hypertension, and chronic alcohol[1944] as an inherited syndrome although DeMorsier ism. He was reevaluated in 1980with similar results. At [19541reported that hypogonadism and defective olfac- this time 17-OH steroids were 17 pg%; 17-keto steroids tion were known to be associated as early as 1850. were 3.9 mg/g of creatinine; and FSH was 6; and LH was The mode of inheritance of KS is still undecided, but 11.Fasting cholesterol and triglycerides were 164 mg% the only cases of cytogenetic abnormalities reported so and 110 mg%, respectively; thyroid function was norfar include ovarian mosaicism (possible trisomy of an mal, and all epiphyses were closed. His examination “F” group chromosome [Jones et al., 19741 and an in- showed a height of 175 cm, weight of 89.5 kg,span of 156 stance of small metacentric chromosome [Ventruto et cm (although difficult to measure accurately secondary al., 19761in the peripheral lymphocytes of a patient and to orthopedic deformity of the upper limbs), upperilower mother. The present case is the first to report a chromo- segment ratio of 0.68, BP of 1lOiS0, no demonstrable some abnormality in the peripheral lymphocytes con- facial hair, no axillary hair, very sparse pubic hair, and cordant with the diagnosis of KS. normal scalp hair. The penis was very small and the testes were approximately 1 cm long and slightly less in CLINICAL REPORT diameter. Intravenous pyelogram was normal. A childThis is a 44-year-old ChippewaiFrench man, oldest of hood injury and a fracture as an adult have lead to five female and one male full sibs and youngest of two flexion deformity at both elbows. Fundi were normal. The patient and parents’ olfaction was tested on a Received for publication January 3,1989; revision received Sep- limited basis according to the method of Henkin and Bartter 119661. The propositus was only vaguely sensitember 8, 1989. tive to 10(- 1) mM pyridine and was unable to detect Address reprint requests to Lyle G. Best, RR1 Box 88, Rolette, 10(- 2 ) mM. The father and mother had detection ND 58366.
We report on an individual with Kallman syndrome (KS)and a balanced de novo translocation (7;12)(q22,q24).None of 6 full sibs, 3 halfsibs, or parents have KS or this chromosome translocation.This is the only known report of KS with a chromosomeabnormality.This may represent a spurious association or genetic heterogeneity vis-a-vis the reported linkage of K S to the steroid sulphatase gene on the X chromosome. The pathophysiology and genetics of KS are discussed.
0 1990 Wiley-Liss, Inc.
Kallmann Syndrome: Chromosome Translocation
thresholds 1 and 2 orders of magnitude lower (more sensitive), respectively. These levels were compared to those of ten healthy control adults, all of whom were easily able to detect concentrations of 10( - 3) mM. It should be noted these detection thresholds were higher than those reported by Henkin and Bartter [19661 and Merriam et al. [19771but were consistent with data from Santen and Paulsen “731 for reasons that are not apparent. In addition the patient was tested qualitatively and was unable to detect cinnamon and allspice, although he was capable of detecting ground cloves (albeit misidentifying it as “cinnamon”). In 1984, repeat lymphocyte chromosome studies wcre done and demonstrated a reciprocal translocation (7;12)(q22;q24) (Fig. 1) and a pericentric inversion (9)(p12q13), considered a normal polymorphism. The parents’ cells were difficult to culture but appeared normal with the exception of a paternal pericentric inversion of chromosome 9, as seen in the patient.
a
79- 12
7
b
7
12qt
12
36
I Fig. 1. A Partial karyotype of propositus indicating reciprocal translocation (7;12)(q22;q24).B: Ideogram of normal chromosomes 7 and 12, arrows indicating breakpoints.
307
MATERIALS AND METHODS The culturing technique was the high-resolution method of Yunis [19761. Staining was based on the nypsin-Giemsa method of Seabright 11971). DISCUSSION This patient has manifestations of KS, i.e., hypogonadotropic hypogonadism, deficiency of olfaction, and skeletal anomalies. The chromosome anomaly in this case, a balanced translocation between chromosome 7 and 12, may be a coincidental finding associated with KS, but it may also be an indication of the chromosome location of a gene involved in KS and thus guide more sophisticated linkage analysis in the future. There has been suggested assignment of the KS gene to the X chromosomebecause of the presence of microdeletionsin the steroid sulphatase (STS)gene of the Xp region found in cases with KS and X-linked icthyosis (XLI) [Ballabio et al., 19871. These results were derived from direct DNA analysis, and indeed cytogenetic studies were unable to detect these deletions. The following information needs to be consideredprior to assignment of KS to the X-chromosome LMcKusick, 19871: 1) Kallmann et al. [1944] favored X-linked inheritance in his initial report because of defective color vision seen in a number of his cases and the known X-linked inheritance of these defects. There has been considerable debate since that time, and transmission characteristic of autosomal dominant (with Wegenke et al., 19751 and without [Santen and Paulsen, 19731 sex limitation), autosomal recessive [Lieblich et al., 1982; Juillard, 1978; White et al., 19831, X-linked dominant [Nowakowski and Lenz, 19611, and again X-linked recessive [Wegenke et al., 19751have been proposed. Hermanussen and Sippell [ 19851 described a monozygotic female twin discordant for paternally inherited KS. Although almost by definition, individuals with KS should be infertile, there have been 4 apparent instances of father-son transmission [Hockaday, 1966; Schroffner and f i r t h , 1970; Santen and Paulsen, 1973;Merriam et al., 19771. In some of these cases the only apparent abnormality of the father has been anosmia. The proposed modes of inheritance were recently reviewed by White et al. [19831, Hermanussen and Sippell 119851, and Job et al. [1985]who concluded that there are forms of X-linked KS as well as forms that excluded X-linkage. Hence KS may be linked to more than one locus on one or more chromosomes. A novel possibility [Keitges et al., 19851 is that a single KS gene may be located a t the junction between the pseudoautosomal distal segment of Xp and the more central region subject to lyonization. This could explain both autosomal recessive and X-linked recessive pedigrees, but the autosomal dominant pedigrees would require the presence of at least one additional allele. 2) More standard explanations of genetic heterogeneity such as multiple enzymes required in a biochemical pathway or regulating and controlling genes could also explain the variation in observed inheritance.
308
Best et al.
Discussions of the pathogenesis of KS have often noted the association of the olfactory defects with the endocrinologic manifestations. Since these two systems are so intimately related both anatomically and physiologically in other species, a single genetic defect might simultaneously affect both systems during embryogenesis. A few authors have hinted that the hypothalamic dysfunction could be secondary t o a primary defect in olfaction, but Hockaday 119661, Netter et al. [1972], and Hermanussen and Sippell [1985] seem to have expressed this possibility the most clearly. There may be a critical period of neuroendocrinologic development (analogous to the postnatal development of the visual cortex) that is forever lost without the proper stimulation of the olfactory lobes during a n early period of life. In favor of this hypothesis would be the selective nature of defects in the gonadotropic system; sparing other hypothalamic endocrine functions affecting adrenocortical function, vasopressin, prolactin, growth hormone, etc. If, as suggested by Wegenke et al. 119751and Cohen [1983], KS represents a mild form of holoprosencephaly with disruption of hypothalamic nuclei involving gonadotropins, i t seems unusual that these other endocrinologic functions would not occasionally be affected given the extremely close physical proximity of these structures. Early direct experimental attempts [Kohne, 19471 to disrupt sexual maturation of the rabbit by ablation of the olfactory lobes were unsuccessful. More recent work cited by Murphy [1976] indicates that olfactory bulb removal does retard development of reproductive organs in 6-week-old rabbits. Murphy [1976] also notes several other studies showing delay in onset of puberty in rats after destruction of olfactory capability. At least one investigation [Sato et al., 19741 concluded that the timing of olfactory disruption was very important with effective lesions produced a t 6 but not a t 20 days of age. The demonstrated effects of the olfactory environment in the acceleration of sexual maturity in mice also gives credance to this concept [Wilson et al., 19801. Weighing against this theory are numerous reports of anosmiai hyposmia without hypogonadism LJob et al., 1985; Santen and Paulsen, 1973; Nowakowski and Lenz. 1961; Lieblich et al., 19821 segregating in families with KS. There is also a n autopsy report by Steenfeldt-Foss [1954] of a female with agenesis of the olfactory lobes but normal-appearing ovaries and no other indication of hypogonadism. Unfortunately only a few of these cases had olfaction tested in a reproducible or sensitive manner. The converse, i.e., hypogonadotropic KS relatives with normal olfactory sense, is apparently rare, with only 2 females and a third case reported [Lieblich et al., 19821. There have been reports of poor pituitary response to LH-RH [Merriam et al., 19771indicating possible pituitary insufficiency as well, but even in these cases LH and FSH were increased 2- to %fold by LH-RH stimulation, which is about the normal proportional response; however, the baseline secretion was so low as to prevent total secretion from being in the normal range. This relative pituitary insufficiency could also be explained by a n early deficient period of stimulation by the olfac-
tory-hypothalamic system, which left the pituitary with too small a population of gonadotropin-producing cells to respond normally in total production but still showing a proportional response to LH-RH. The skeletal anomalies may also be a secondary manifestation of the endocrine anomalies but a t a later date in development when closure of epiphyseal plates is obviously disrupted by lack of normal puberty and yet is still progressing a t a slow pace determined by a n a s yet unknown mechanism. It would be interesting to determine whether these individuals had any shortening of the metacarpalsprior to the usual age of puberty. Shortened metacarpals and abnormal sexual maturation are also occasionally associated in other syndromes such a s in LMBB [Bardin, 1971; Temtamy and McKusick, 19781 and in cases of hypogonadotropism associated with ataxia [Matthews and Rundle, 19641.
ACKNOWLEDGMENTS We extend our sincere appreciation to the members of this family, whose cooperation made this publication possible, and to the Aberdeen Area Indian Health Service (IHS) for their assistance. The opinions expressed in this paper are those of the author and do not necessarily reflect the views of the IHS.
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