1 Sydney IVF, 4 O'Connell St, Sydney, NSW, 2000, 2 Royal Prince Alfred Hospital, Camperdown, NSW, 2050, 3 School of Biological Sciences Macquarie University, North Ryde, NSW, 2109, 4 Department of Molecular Genetics, Royal South Sydney Hospital, Zetland, NSW, 2107 and 5 Department of Obstetrics and Gynaecology, University of Sydney, NSW, 2006, Australia
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Abstract |
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Key words: anosmia/gonadal dysgenesis/hypogonadotrophic hypogonadism/Kallmann's syndrome/streak ovaries
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Introduction |
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Clinicopathological report |
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At age 30 years the female proband married and desired pregnancy. She was, however, completely refractory to repeated and prolonged attempts at ovulation induction with firstly pulsatile GnRH (Wyeth-Ayerst HRF®) (Jansen, 1993) and later high dose i.m. gonadotrophins (Pergonal®; Laboratories Serono SA, Aubonne Switzerland). During laparoscopic investigation bilateral `streak ovaries' were noted and ovarian biopsy was performed. The uterus and Fallopian tubes appeared normal. Hysteroscopic examination revealed a normal 7 cm long uterine cavity. Ovarian, antinuclear, mitochondrial, parietal cell, islet of Langerhans cell, adrenocortical, rheumatoid factor, acetylcholinesterase, thyroid microsomal and thyroglobulin serum autoantibodies were not detected. Ultrasound examination revealed normal renal tracts.
The proband conceived at age 34 after the transfer of two frozenthawed embryos, quarantined for the previous 6 months after donor oocyte IVF. Endometrial preparation and support was given with ethinyl oestradiol tablets (Progynon-C; Schering, Berlin, Germany) until 5 weeks after embryo transfer and non-proprietary progesterone pessaries (progesterone powder; Sigma, St Louis, Mo USA) until 7 weeks after the embryo transfer. A healthy female weighing 3395 g was delivered 36 weeks after embryo transfer by elective caesarean section. Vaginal delivery was not attempted due to the clinically contracted pelvis. Hot flushes were experienced a week into the puerperium and hormone replacement therapy was reinstituted.
At presentation it was noted that her brother, age 24 years, had not achieved puberty and had anosmia. The diagnosis of Kallmann's syndrome in the male sibling was supported by endocrine testing: FSH 0.6 IU/l; LH <1.0 IU/l; prolactin 19 nmol/l; total testosterone 1.2 nmol/l and free testosterone 19 pmol/l. The skeletal phenotype was hypogonadal; height 172 cm, arm span 184 cm, with segmental disproportion (upper segment 73 cm, lower segments 79 cm). The hair distribution was fine, bilateral gynaecomastia was observed and the testicular volumes were 8 ml. Seminal fluid analysis revealed azoospermia. Twice weekly injections of human chorionic gonadotrophin (HCG) were then administered for a number of years. Pergonal® treatment initiated spermatogenesis and semen analysis recorded a volume of 4.6 ml, a concentration of 4.6x106 spermatozoa per ml and 50% motility. Sperm morphology was not examined. Androgen replacement therapy was given with s.c. testosterone pellets (Conway et al., 1988). A further attempt at obtaining spermatogenesis was carried out at age 41 years for the purposes of IVF. Using HCG injections in a dose of 2000 units s.c. thrice weekly (Profasi; Laboratories Serono SA, Aubonne Switzerland) and when a serum testosterone concentration of 10 nmol/l was registered 6 weeks later, FSH was introduced in doses of 150 units thrice weekly (Puregon; Organon, Oss The Netherlands). Four months after the FSH was introduced semen analysis recorded 1.5x106 spermatozoa per ml, 64% of spermatozoa exhibited rapid motility and 6% normal morphology. Further analyses over several months recorded similar semen parameters. Spermatozoa were also frozen for long-term storage. Fertilization was obtained with fresh ejaculated semen and intracytoplasmic sperm injection of all five oocytes retrieved after pituitary down-regulation and ovarian stimulation. Semen analyses were performed in accordance with methodology recommended by the World Health Organization (1992). Pregnancy did not ensue from the transfer of two embryos. The three supernumerary embryos are cryostored.
The siblings have normal intelligence and hearing. Ophthalmic examination of the female sibling offered no evidence of ocular albinism type 1 (OA1). There were no skin efflorescences indicative of ichthyosis. Mirror movements were not evoked in the siblings. The mother did not experience premature menopause. Maternal hyposmia was discerned on anamnesis and clinically. Mirror movements were not elicited in either parent. The parents emigrated to Australia from different districts in Sicily. There was no family history of delayed puberty, infertility, consanguinity or anosmia.
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Magnetic resonance imaging |
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Histopathology of the streak ovary biopsy |
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Cytogenetic investigations |
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Molecular genetic investigations |
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PCR using the intragenic KAL1 primers flanking exon 12 resulted in products for both siblings. For the linkage studies the intragenic KAL1 polymorphic locus (Bouloux et al., 1991) was non-informative in the pedigree; however, use of the polymorphic loci, DXS996 and DXS7103, flanking the KAL1 locus, indicated that the siblings have inherited different maternal alleles for these loci (Figure 3
). The likelihood of recombination events between the polymorphic loci, DXS996 and DXS7103, were calculated using centimorgan data, obtained from Cedar Genetics (available on the Internet http://cedar.genetics). DXS996 is stated to be 2.69 centimorgans telomeric to KAL1, while DXS7103 is 3.79 centimorgans centromeric to KAL1. The likelihood of double recombination between these loci was calculated to be 1/981 (or 0.1%).
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Discussion |
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Kallmann syndrome-affected women generally occur sporadically in the population with no other affected relatives (P.M.Bouloux, personal communication). Other conditions have been associated with Kallmann's syndrome, such as mirror movements (bimanual synkinesis), abnormal spatial attention, ocular motor apraxia, unilateral renal dysplasia and more rarely unilateral sensorineural deafness, short clavicles, chorioretinal coloboma, neonatal hydrocephalus, cleft lip/palate, and pes cavus deformity (Hardelin et al., 1993; Quinton et al., 1996a
). Renal dysplasia, in particular, often occurs in X-linked Kallmann syndrome patients (Kirk et al., 1994
) and there is also a high frequency of single kidneys in these affected individuals (Hardelin et al., 1993
). The siblings' renal ultrasound examinations were normal. This finding cannot be used to discount a KAL1 locus. The finding that the siblings did not elicit mirror movements is reliable neurophysiological evidence that the sibship do not possess a mutation of the KAL1 locus (Quinton et al., 1996a
).
It is possible that aberrant cellular interactions might underlie the phenomena of Kallmann's syndrome and renal agenesis. Renal agenesis does not appear to occur in the non-X-linked Kallmann's syndrome (Quinton et al., 1996b). Renal anomalies are observed in 45,X ovarian dysgenesis but without olfactory anomalies (Plouffe and McDonough, 1996
). The metanephros and gonadal ridge develop adjacently and a field defect might suggest aberrant cellular interactions. However, the renal development in the sibship appears to be normal. At the time of gastrulation the primordial germ cells begin migration from the caudal primitive streak/epiblast (Lawson and Hage, 1994
). The epiblast also differentiates to become the neuroectoderm (Larsen, 1997
). Therefore the involvement of germ cells and the olfactory/hypothalamic disorder suggest a possible link at the level of the epiblast development.
There was no evidence in the siblings' examination to suggest involvement of known contiguous gene syndromes. Contiguous gene syndromes have been described where deletions involving the distal short arm of the X-chromosome have resulted in patients with combinations of short stature, chondrodysplasia punctata, mental retardation, steroid sulphatase deficiency (STS) and Kallmann's syndrome (Ballabio et al., 1989). Clinical history and examination excluded the closest adjacent contiguous gene syndromes, STS (ichthyosis) and OA1, flanking the KAL1 locus. PCR amplifications of KAL1 exon 12 and the intragenic KAL1 polymorphism resulted in appropriate products being found for both siblings, and microdeletions of the entire KAL1 locus can therefore be excluded.
Although X-linked transmission of the disorder was not indicated in this family, segregation analysis of the disorder with the KAL1 region of the X chromosome was carried out for confirmation at the molecular level (Firgure 3). In view of the allele segregation findings KAL1 locus involvement would require a double recombination of the maternal allele. The likelihood of a double recombination event was calculated to be 1/981. The denominator, however, is probably underestimated as physical `interference' reduces nearby double recombination frequency (Schmitt et al., 1994; Strachen and Read, 1996
). The likelihood of KAL1 locus involvement is therefore probably less than the centimorgan-derived calculation of 0.1 %.
Pedigree information and three translocation reports suggest that there are autosomal forms of Kallmann's syndrome (Best et al., 1990; Casamassima et al., 1993
; McKusick, 1994
; Schinzel et al., 1995
). The diagnosis of Kallmann's syndrome in two of the translocation reports is contestable. Best et al. (1990) have possibly erred in contending that a 7q;12q reciprocal translocation case had Kallmann's syndrome as the gonadotrophin concentrations were actually in the normal range; molecular exclusion of the KAL1 gene was not performed. The case presented by Casamassima et al. (1993) did not exclude involvement of the KAL1 gene with molecular investigations; also the FSH concentration of 3 IU/l is not particularly low, and inconsistent with a Kallmann's syndrome. Schinzel et al. (1995) presented a case in which Southern blot screening did not detect band shifts within the KAL1 gene. Undetected mutations of the KAL1 gene could be present. The basal gonadotrophin concentrations were low, which is consistent with Kallmann's syndrome. In view of the translocation case reported by Schinzel et al. (1995) high-resolution microscopy of the siblings for the distal 1q and 10q regions was performed and an abnormality was not detected. Hypogonadotrophic hypogonadism is also seen in the autosomal recessive BoucherNeuhauser syndrome. However, the sibs do not possess the typical characteristics of chorioretinal dystrophy and cerebellar ataxia (Rump et al., 1997
).
The putative KALP receptor gene, which has not been cloned, has been proposed as a candidate for the autosomal form of Kallmann's syndrome (Quinton et al., 1996a). A recent study considered idiopathic hypogonadotrophic hypogonadism as an alternative manifestation of Kallmann's syndrome and suggested that the X-linked mode of inheritance accounted for only 36% of 106 cases (Waldstreicher et al., 1996
). The investigators also found a low prevalence of KAL1 gene mutation in isolated GnRH deficiency (Georgopoulos et al., 1997
). It has been suggested, however, that Kallmann's syndrome should not be considered together with idiopathic hypogonadotrophic hypogonadism as the latter usually represents a distinct developmental field defect (Dean et al., 1990
; Quinton et al., 1996b
). If so, the proportion of autosomal forms of Kallmann's syndrome is considerably smaller.
In the syndrome of congenital adrenal hypoplasia and hypogonadotrophic hypogonadism the DAX1 gene, at Xp21.3, is mutated (Zanaria et al., 1994). Based upon study of the mouse DAX1 gene, expression is thought to influence gonadal differentiation (Swain et al., 1996
). Although the concurrence of gonadal and hypothalamic effects is fascinating, the DAX1 gene mutation is not, however, known to cause anosmia. Adrenal hypoplasia was not observed in the siblings and an X-linked disorder is unlikely. A DAX-1 gene mutation in the siblings is therefore unlikely.
It has been observed that X-chromosome deletions associated with complete ovarian failure rather than secondary amenorrhoea invariably involve the proximal regions of the X chromosome (Simpson, 1986). These regions are more than likely X-inactivated. If one postulates that the causative locus is within this region then one must assume that the female sibling is a manifesting carrier. This assumption requires the occurrence of a further chance event, such as skewed X-inactivation or uniparental isodisomy. Skewed X-inactivation of a normal allele has been documented to occur in Duchenne muscular dystrophy, but infrequently (Azofeifa et al., 1995
). A homozygous mutated KAL1 status in the woman is most improbable. Uniparental isodisomy in the woman, with a mutated KAL1 gene, can be rejected because of the allele heterozygosity found in the three polymorphic sites KAL1, DXS996 and DXS7103.
Deletions detected from the long arm of the X-chromosome (Xq) are well recognized as a cause of premature ovarian failure (Krauss et al., 1987). The likelihood of contiguous gene deletions in women with ovarian failure accompanying the syndrome of blepharophimosis has been reported (Smith et al., 1989
). Such deletions appear to be autosomal. Linkage studies suggest that blepharophimosisptosisepicanthusinversus syndrome type-1 (BPES1) associated with ovarian dysgenesis has been localized to 3q22-q23 (Small et al., 1995
; Amati et al., 1996
). The BPES1 syndrome has not been associated with Kallmann's syndrome.
Seventy-five families with 46,XX ovarian dysgenesis (ODG) have been identified in Finland and some pedigrees suggest the existence of an autosomal recessive gene (Aittomaki, 1994). By systematically searching for linkage in multiplex affected families, a locus for ODG was mapped to chromosome 2p. The follicle-stimulating hormone receptor (FSHR) gene was previously assigned to 2p. A search for mutations identified a C566T transition in exon 7 of FSHR that segregated with the disease phenotype (Aittomaki et al., 1995
). A further study of 22 patients with ovarian dysgenesis and a 566C>>T mutation in the FSH receptor gene suggested a subset of pathogenetically distinct ovarian dysgenesis patients. Possibly because of residual receptor activity these patients can be identified by demonstrating the presence of ovarian follicles and confirmed by mutation analysis (Aittomaki et al., 1996
). Hypogonadotrophism and the development of spermatogenesis experienced after gonadotrophin therapy both suggest that an FSH receptor deficit is unlikely in the sibship.
Autosomal recessive disorders of single gonadotrophin deficit, of either FSH or LH, can frustrate the normal development of puberty and fertility (Weiss et al., 1992; Layman et al., 1993
, 1997
). There is evidence that FSH is not required for spermatogenesis (Kumar et al., 1997
). In isolated FSH deficiency, however, there is no concurrent deficit of LH release, as was observed in the siblings. Males undergo normal virilization, which was not observed in the male proband (Rabin et al., 1972
; Rabin, 1975
). Isolated gonadotrophin deficiency would also not account for the observed ovarian dysgenesis. There is a report of 47,XXY gonadal dysgenesis with Kallmann syndrome (Hazard et al., 1986
). This would possibly indicate a gonosomal gene effecting Kallmann syndrome. It is difficult to assume an X-linked recessive cause such as a KAL1 locus mutation unless the X-chromosome were duplicated. The duplication error might have led to non-disjunction.
The reasons for failure of germ cell persistence in 46,XX gonadal dysgenesis are unknown. A `knock-out' mouse defective for the DNA mismatch repair gene Mlh1 has been noted to have disturbed meiosis control mechanisms and small ovaries with very few follicles (Baker et al., 1996). No endocrine data were reported and Kallmann's syndrome has not been associated with DNA mismatch repair gene disorders. These varied reports suggest that more than one gene encodes for factors necessary for the survival of oocytes through reproductive life. There may well be other women who have Kallmann's syndrome as well as 46,XX gonadal dysgenesis. Such women would be identified by refractory ovulation attempts. There are few reports of ovulation induction and pregnancy results (Sungurtekin et al., 1995
).
This is the first report of male and female siblings with Kallmann's syndrome manifesting concurrently with ovarian dysgenesis. The exclusion of involvement, by linkage analysis, of the KAL1 locus and the presentation of male and female phenotypes suggest that it is highly likely that an autosomal gene is involved. When sufficient pedigrees of females affected with Kallmann's syndrome are obtained, molecular linkage analyses will become possible. Studies might then reveal a gene involved, albeit contiguously, with oocyte survival.
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Acknowledgments |
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Notes |
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References |
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Aittomaki, K., Lucena, J.L., Pakarinen, P. et al. (1995) Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell, 82, 959968.[ISI][Medline]
Aittomaki, K., Herva, R., Stenman, U.H. et al. (1996) Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J. Clin. Endocr. Metab., 81, 37223726.[Abstract]
Amati, P., Gasparini, P., Zlotogora, J. et al. (1996) A gene for premature ovarian failure associated with eyelid malformation maps to chromosome 3q22-q23. Am. J. Hum. Genet., 58, 10891092.[ISI][Medline]
Azofeifa, J., Voit, T., Hubner, C. and Cremer, M. (1995) X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes. Hum. Genet., 96, 167176.[ISI][Medline]
Baker, S.M., Plug, A.W., Prolla, T.A. et al. (1996) Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nature Genet., 13, 336342.[ISI][Medline]
Ballabio, A., Bardoni, B., Carrozzo, R. et al. (1989) Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc. Natl. Acad. Sci. USA, 86, 1000110005.[Abstract]
Best, L.G., Wasdahl, W.A., Larson, L.M. and Sturlaugson, J. (1990) Chromosome abnormality in Kallmann syndrome. Am. J. Med. Genet., 35, 306309.[ISI][Medline]
Bick, D., Franco, B., Sherins, R.J. et al. (1992) Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome. N. Engl. J. Med., 326, 17521755.[ISI][Medline]
Bouloux, P.M., Hardelin, J.P., Munroe, P. et al. (1991) A dinucleotide repeat polymorphism at the Kallmann locus (Xp22.3). Nucleic Acids Res., 19, 5453
Budowle, B., Chakraborty, R., Giusti, A.M. et al. (1991) Analysis of the VNTR locus D1S80 by the PCR followed by high-resolution PAGE. Am. J. Hum. Genet., 48, 137144.[ISI][Medline]
Casamassima, A.C., Wilmot, P.L., Vibert, B.K. and Shapiro, L.R. (1993) Kallmann syndrome associated with complex chromosome rearrangement. Am. J. Med. Genet., 45, 539541.[ISI][Medline]
Conway, A.J., Boylan, L.M., Howe, C. et al. (1988) Randomized clinical trial of testosterone replacement therapy in hypogonadal men. Int. J. Androl., 11, 247264.[ISI][Medline]
Dean, J.C., Johnston, A.W. and Klopper, A.I. (1990) Isolated hypogonadotrophic hypogonadism: a family with autosomal dominant inheritance. Clin. Endocr., 32, 341347.[ISI][Medline]
Franco, B., Guioli, S., Pragliola, A. et al. (1991) A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature, 353, 529536.[ISI][Medline]
Georgopoulos, N.A., Pralong, F.P., Seidman, C.E. et al. (1997) Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency. J. Clin. Endocr. Metab., 82, 213217.
Hardelin, J.P., Levilliers, J., delCastillo, I. et al. (1992) X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene. Proc. Natl. Acad. Sci. USA, 89, 81908194.[Abstract]
Hardelin, J.P., Levilliers, J., Blanchard, S. et al. (1993) Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. Hum. Mol. Genet., 2, 373377.[Abstract]
Hazard, J., Rozenberg, I., Perlemuter, L. et al. (1986) Gonadotropin responses to low dose pulsatile administration of GnRH in a case of anosmia with hypogonadotropic hypogonadism associated with gonadal dysgenesis 47 XXY. Acta Endocrinol., 113, 593597.[ISI][Medline]
Jansen, R.P.S. (1993) Pulsatile intravenous gonadotrophin releasing hormone for ovulation induction: determinants of follicular and luteal phase responses. Hum. Reprod., 8 (Suppl. 2), 193196.[Abstract]
Jones, J.R. and Kemmann, E. (1976) Olfacto-genital dysplasia in the female. Obstet. Gynecol. Ann., 5, 443466.[Medline]
Kirk, J.M., Grant, D.B., Besser, G.M. et al. (1994) Unilateral renal aplasia in X-linked Kallmann's syndrome. Clin. Genet., 46, 260262.[ISI][Medline]
Krauss, C.M., Turksoy, R.N., Atkins, L. et al. (1987) Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome. N. Engl. J. Med., 317, 125131.[Abstract]
Kumar, T.R., Wang, Y., Lu, N. and Matzuk, M.M. (1997) Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nature Genet., 15, 201204.[ISI][Medline]
Larsen, W.J. (1997) Human Embryology, 2nd edn. Churchill Livingstone, New York.
Lawson, K.A. and Hage, W.J. (1994) Clonal analysis of the origin of primordial germ cells in the mouse. Ciba Foundn Symp., 182, 6884.
Layman, L.C., Lee, E.-J., Peak, D.B. et al. (1997) Brief report: delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone ß-subunit gene. N. Engl. J. Med., 337, 607611.
Layman, L.C., Shelley, M.E., Huey, L.O. et al. (1993) Follicle-stimulating hormone beta gene structure in premature ovarian failure. Fertil. Steril., 60, 852857.[ISI][Medline]
Legouis, R., Hardelin, J.P., Levilliers, J. et al. (1991) The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell, 67, 423435.[ISI][Medline]
McKusick, V.A. (1994) 308700 Kallmann syndrome. In McKusick, V.A. (ed.), Mendelian Inheritance in Man, 11th edn. Johns Hopkins University Press, Baltimore.
Meitinger, T., Heye, B., Petit, C. et al. (1990) Definitive localization of X-linked Kallman syndrome (hypogonadotropic hypogonadism and anosmia) to Xp22.3: close linkage to the hypervariable repeat sequence CRI-S232 Am. J. Hum. Genet., 47, 664669. [Published erratum appears in Am. J. Hum. Genet., 47, 883.]
Miller, S.A., Dykes, D.D. and Polesky, H.F. (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res., 16, 1215[ISI][Medline]
Plouffe Jr, L. and McDonough, P.G. (1996) Ovarian agenesis and dysgenesis. In Adashi, E.Y., Rock, J.A. and Rosenwaks, Z. (eds), Reproductive Endocrinology, Surgery, and Technology. Lippincott-Raven, Philadelphia, pp. 13661384.
Quinton, R., Duke, V.M., De Zoysa, P.A. and Bouloux, P.M.G. (1996a) The neurobiology of Kallmann's syndrome. J. Br. Fertil. Soc., 1, 121127.
Quinton, R., Duke, V.M., de, Z.P., Platts, A.D. et al. (1996b) The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis J. Clin. Endocr. Metab., 81, 30103017. [Published erratum appears in J. Clin. Endocrinol. Metab., 81, 3614].
Rabin, D. (1975) The syndromes of isolated gonadotropin deficiency. Birth Defects: Original Article Series, 11, 7380.
Rabin, D., Spitz, I., Bercovici, B. et al. (1972) Isolated deficiency of follicle-stimulating hormone. Clinical and laboratory features. N. Engl. J. Med., 287, 13131317.[ISI][Medline]
Rugarli, E.I., Ghezzi, C., Valsecchi, V. and Ballabio, A. (1996) The Kallmann syndrome gene product expressed in COS cells is cleaved on the cell surface to yield a diffusible component. Hum. Mol. Genet., 5, 11091115.
Rugarli, E.I., Lutz, B., Kuratani, S.C. et al. (1993) Expression pattern of the Kallmann syndrome gene in the olfactory system suggests a role in neuronal targeting. Nature Genet., 4, 1926.[ISI][Medline]
Rump, P., Hamel, B.C.J., Pinckers, A.J.L.G. and vanDop, P.A. (1997) Two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia: BoucherNeuhauser syndrome. J. Med. Genet., 34, 767771.[Abstract]
Schinzel, A., Lorda-Sanchez, I., Binkert, F. et al. (1995) Kallmann syndrome in a boy with a t(1;10) translocation detected by reverse chromosome painting. J. Med. Genet., 32, 957961.[Abstract]
Schmitt, K., Lazzeroni, L.C., Foote, S. et al. (1994) Multipoint linkage map of the human pseudoautosomal region, based on single-sperm typing: do double crossovers occur during male meiosis? Am. J. Hum. Genet., 55, 423430.[ISI][Medline]
Simpson, J.L. (1986) Phenotypickaryotypic correlations of gonadal determinants: current status and relationship to molecular studies. In Sperling, K. and Vogel, F. (eds), Proceedings 7th International congress on Human Genetics Berlin, 1986. Springer-Verlag, Heidelberg, pp. 224232.
Small, K.W., Stalvey, M., Fisher, L. et al. (1995) Blepharophimosis syndrome is linked to chromosome 3q. Hum. Mol. Genet., 4, 443448.[Abstract]
Smith, A., Fraser, I.S., Shearman, R.P. and Russell, P. (1989) Blepharophimosis plus ovarian failure: a likely candidate for a contiguous gene syndrome. J. Med. Genet., 26, 434438.[Abstract]
Soussi-Yanicostas, N., Hardelin, J.P., Arroyo-Jiminez, M.M. et al. (1996) Initial characterisation of anosmin-1, a putative extracellular matrix protein synthesized by definite neuronal cell populations in the central nervous system. J. Cell Sci., 109, 17491757.
Strachen, T. and Read, A.P. (1996) Human Molecular Genetics. Bios, Oxford, p. 329.
Sungurtekin, U., Fraser, I.S. and Shearman, R.P. (1995) Pregnancy in women with Kallmann's syndrome. Fertil. Steril., 63, 494499.[ISI][Medline]
Swain, A., Zanaria, E., Hacker, A. et al. (1996) Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nature Genet., 12, 404409.[ISI][Medline]
Waldstreicher, J., Seminara, S.B., Jameson, J.L. et al. (1996) The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J. Clin. Endocr. Metab., 81, 43884395.[Abstract]
Weiss, J., Axelrod, L., Whitcomb, R.W. et al. (1992) Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone. N. Engl. J. Med., 326, 179183.[ISI][Medline]
Zanaria, E., Muscatelli, F., Bardoni, B. et al. (1994) An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature, 372, 635641.[ISI][Medline]
Submitted on February 2, 1998; accepted on January 6, 1999.