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National Research Institute for Child Health and Development (N.S., N.K., M.K., T.O.), Tokyo 154-8567; Keio University School of Medicine (T.H., N.H.), Tokyo 160-8582; Toki General Hospital (S.K.), Gifu 509-5122; International Medical Center of Japan (S.M.), Tokyo 113-8655; Kushiro City General Hospital (A.S.), Kushiro 085-0822; Mishuku Hospital (Y.S.), Tokyo 153-0051; Sapporo Medical University (M.Y.), Sapporo 060-8556; Chiba National Hospital (T.Y.), Chiba 260-8606; Niigata Graduate School of Medical and Dental Sciences (K.N.), Niigata 951-8510; Hyogo Prefectural Kobe Children’s Hospital (D.H.), Hyogo 654-0081; Tokyo Metropolitan Kiyose Children’s Hospital (Y.H.), Tokyo 204-8567; Kanagawa Children’s Medical Center (K.T.), Kanagawa 232-8555; and National Center for Child Health and Development (Y.N., R.H., T.T.), Tokyo 154-8535, Japan
Address all correspondence and requests for reprints to: N. Sato or T. Ogata, Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo 154-8567, Japan. E-mail: naoko{at}nch.go.jp or tomogata{at}nch.go.jp.
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Abstract |
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The results suggest the following: 1) KAL1 mutations might be more prevalent in the Japanese patients than previously estimated in the Caucasian patients and can be associated with apparently normal olfactory function; 2) FGFR1 mutations account for approximately 10% of KS patients, as previously reported in the Caucasian patients, and can result in HH and olfactory dysfunction-only phenotype; and 3) renal aplasia, which is characteristic of KAL1 mutations, and cleft palate and dental agenesis, which are characteristic of FGFR1 mutations, can occur in patients without KAL1 and FGFR1 mutations.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The KAL1 gene consists of 14 exons and extends over a distance of 210 kb (10). It encodes an extracellular matrix glycoprotein of approximately 100 kDa termed anosmin-1 and is expressed in multiple embryonic tissues and organs including the primitive olfactory bulb and kidney (11, 12). Anosmin-1 contains a whey acidic protein (WAP)-type four-disulfide core domain, that is found in several protease inhibitors, and four fibronectin type III domains, that show a strong homology to similar motifs in axonal adhesion molecules (10).
Various types of KAL1 gene abnormalities have been reported in patients with KS. They include missense and nonsense mutations, splice site mutations, intragenic deletions, and submicroscopic chromosomal deletions involving the entire KAL1 gene (reviewed in Ref. 13). Clinical features in mutation-positive males include HH, anosmia/hyposmia, mirror movements, and renal abnormalities (13, 14, 15, 16, 17, 18). However, KAL1 mutations have been detected in approximately 60% of patients with familial KS, suggesting an X-linked mode of inheritance, and in only 10–15% of male patients with sporadic KS (13, 14, 15, 16, 17). Furthermore, nearly all mutations have been identified in patients with both HH and olfactory dysfunction of variable extent. In particular, there has been no report documenting a KAL1 mutation-positive patient with normal olfactory function, although two males with apparently normal gonadal function have been identified through familial study of their brothers with typical KS phenotype (16, 18).
The FGFR1 gene consists of 18 coding exons and spans approximately 55 kb (9, 19). It encodes a glycoprotein fibroblast growth factor receptor of about 130 kDa and is expressed in multiple embryonic tissues and organs such as skeletal tissues (20), inner ear (21), and rostral forebrain (22). FGFR1 is required for initial olfactory bulb evagination (22). The FGFR1 protein consists of three extracellular Ig-like domains, one acidic box domain, one transmembrane domain, and two intracellular tyrosine kinase domains (19, 23).
It has been shown that various heterozygous loss-of-function mutations of FGFR1 lead to KS (9), whereas a heterozygous gain-of-function mutation of FGFR1, P252R, results in craniosynostosis (24). The mutations identified in KS include missense and nonsense mutations, splice site mutations, and intragenic insertion and deletion, although a submicroscopic deletion has not been identified (9). The clinical spectrum in mutation-positive patients ranges from typical KS phenotype with or without associated features, such as mirror movements, cleft palate, and dental agenesis, to apparently normal phenotype and includes anosmia-only and dental agenesis-only phenotypes (9). However, FGFR1 mutations have been identified only in approximately 10% of KS patients (9). In addition, it remains to be determined whether cleft palate and dental agenesis, which have been reported in some of the patients with FGFR1 mutations, can also occur in KS patients without FGFR1 mutations.
In this article, we report on the clinical assessment and molecular analysis of KAL1 and FGFR1 in 28 patients with KS.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Twenty-eight Japanese patients (25 males and three females) aged 10–53 yr were studied for clinical features and KAL1 and FGFR1 mutations after informed consent was obtained (Table 1
). Ten males were from five families affected by KS; X-linked recessive inheritance was obvious in families 1 and 5 and obscure in families 2–4 (Fig. 1). The remaining 15 males and three females were sporadic cases. All cases, except for cases 7 and 15, were identified because of the combination of underdeveloped sexual phenotype and hyposmia/anosmia; case 7 was examined through familial study of case 6 with typical KS phenotype, and case 15 was studied because of the combination of underdeveloped sexual phenotype and renal lesion. All the cases had a normal karyotype.
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5 ml) and pubic hair development (Tanner stage II) in his late teens. The three female cases had poor breast development and primary amenorrhea. All cases, except for cases 1, 7, and 15, were afflicted with a severely decreased sense of smell in their daily life; allegedly, case 1 was normosmic until his early twenties and became hyposmic in his late twenties, and cases 7 and 15 had a normal sense of smell. Case 2 received right nephrectomy in the neonatal period because of multiple dysplastic kidney.
Additional features were also identified in 11 of the 28 patients (Table 1
). Case 23 also had intermittent pain at the costochondral joints on the left back. In addition, the mothers of cases 13 and 19 both experienced two miscarriages, and the mother of case 16 had delayed puberty.
Clinical assessment
Clinical assessment was performed for endocrine status, olfactory function, renal lesion, and mirror movement. Endocrine status was examined by a GnRH test (100 µg/m2 bolus iv; blood sampling at 0, 30, 60, 90, and 120 min) for patients of both sexes and by a human chorionic gonadotropin (hCG) test (3000 IU/m2·dose im for 3 consecutive days; blood sampling on d 1–4) for male patients. The hormone levels were assessed by the age-, sex-, and pubertal-tempo matched Japanese reference data (25, 26, 27).
Olfactory acuity was evaluated by a Toyota-Takagi test (28) or by an Alinamin test (29), and olfactory bulb structure was examined by brain magnetic resonance imaging (MRI). For the Toyota-Takagi test, five standard odorous substances, i.e. ß-phenylethyl alcohol (odor of rose), methyl cyclopentenolone (odor of caramel), isovaleric acid (odor of putrid), 
-undercalactone (odor of canned peach), and scatol (odor of vegetable garbage) (Daiichi-Yakuhin, Tokyo, Japan) were given in series of 10-fold dilutions, and the olfactory acuity to each odorant was scored. A score of 0 for a particular odorant indicates a concentration that is detected as a smell of some odorant by 50% of normal subjects (detection threshold) or recognized as a smell of a particular odorant by 50% of normal subjects (recognition threshold), and a score of x indicates that a subject could smell the odorant at a concentration 10x times as high as that for the score of 0. An average score of the five recognition thresholds indicates normosmia for 
+1.0, borderline level for +1.1 to +2.5, hyposmia for +2.6 to +4.0, and anosmia for more than +4.0. For the Alinamin test, 10 mg of the Alinamin (Takeda Chemical Industries, Ltd., Osaka, Japan) was given by bolus iv, and it was examined whether a subject could recognize a smell of garlic (or a mercaptan smell). Normal subjects can recognize the smell of Alinamin around 10 sec after the infusion.
Renal structure was assessed by abdominal ultrasounds and/or MRI scans. Intravenous pyelogram and voiding cystourethrography were also performed for case 4 who had recurrent urinary tract infections.
Mirror movement was evaluated clinically, as reported by Mayston et al. (30). In brief, the patients sequentially opposed the tip of each finger to the tip of the thumb, from index to little finger and back again. When involuntary movement of the homologous finger of the other hand was noted, mirror movement was assessed as positive.
Molecular studies
KAL1 and FGFR1 were examined for intragenic mutations and submicroscopic deletions. KAL1 was first investigated in all the cases, and FGFR1 was subsequently analyzed in KAL1 mutation-negative cases. Although KS due to KAL1 mutations is an X-linked recessive disease, female cases were also examined for KAL1 because of possible mutations of both alleles.
Intragenic mutations were examined by sequence determination for the entire coding regions. In brief, leukocyte genomic DNA was PCR-amplified for KAL1 exons 1–14 and FGFR1 exons 2–18, as well as flanking intron sequences. The primer sequences, annealing temperatures, and PCR product sizes for KAL1 are as reported (14), and those for FGFR1 are shown in Table 2. Subsequently, the PCR products were purified and subjected to direct sequencing from both directions on an ABI PRISM 310 autosequencer (Applied Biosystems, Foster City, CA) or on a CEQ 8000 autosequencer (Beckman Coulter, Fullerton, CA). For controls, DNA samples of 100 normal Japanese males were used with permission. When available, the mothers of KAL1 mutation-positive patients were examined for carrier status.
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Results |
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Clinical features are summarized in Table 1. Endocrine studies showed variable degrees of HH in all the 28 patients examined. Furthermore, hCG tests revealed poor testosterone (T) responses in all male patients analyzed, except for case 17 who showed a subnormal T response. The Toyota-Takagi test indicated normal olfactory function in case 15, borderline olfactory function in case 7, and severely impaired olfactory function in the remaining seven cases examined, including case 6 (the elder brother of case 7; Fig. 2, upper part). The Alinamin test resulted in no response in all the 12 cases studied. Brain MRI showed that olfactory bulb was apparently normal in cases 23 and 24, bilaterally hypoplastic in cases 1, 7, 15, and 17, and bilaterally aplastic in the remaining nine cases examined, including case 6 (Fig. 2, lower part; and Fig. 3). Renal MRI or ultrasound studies delineated right renal aplasia in cases 4, 7, 9, 13–15, and 27, together with right renal absence after nephrectomy in case 2. In addition, voiding cystourethrography indicated left vesicoureteral reflux in case 4. Mirror movements were observed in cases 1 and 8–10.
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The results are summarized in Table 3. For KAL1, sequence analysis identified six novel and two recurrent intragenic mutations (17, 35) in familial cases 1–7 and in sporadic cases 12–15 (Fig. 4). The mutations consisted of one missense, three nonsense, and three frameshift mutations, and one splice donor site mutation. The frameshift mutations in cases 4 and 5, 12, and 14 are predicted to result in premature stop codons at nucleotide position 250, 307, and 751, respectively. The splice donor site mutation in case 15 disrupts the conserved GT rule indispensable for normal splicing. All the mutations were absent in the control subjects. These mutations did not disrupt or create a restriction enzyme site. In addition, two previously described polymorphisms, A to G substitution at codon 534 leading to I534V and T to C substitution at codon 611 resulting in I611I (14, 15, 16), were also detected in nine and eight male patients, respectively; of these males, six had both I534V and I611I, three had I534V only, and two had I611I only. Sequence analysis was carried out in the mothers of familial cases 4–7 (families 3 and 4) and three of the five sporadic cases (cases 12, 13, and 15), which showed that the five mothers were heterozygous for the normal and mutant alleles. PCR analysis failed to amplify all the 14 exons of KAL1 in familial cases 8–10 and in one sporadic case (case 11), and further PCR analysis showed submicroscopic deletions involving VCX-A, STS, KAL1, and OA1 in the four cases. In female cases 26–28, FISH analysis delineated two KAL1 signals with a nearly identical signal intensity.
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). The S107X (320C>A) mutation should create a BfaI site, and this was confirmed by BfaI digestion of the PCR product including exon 3. The P745S (2233C>T) mutation should disrupt a BsaI site, and this was confirmed by BsaI digestion of the PCR product encompassing exon 17. Unfortunately, the parents of cases 16 and 17 refused molecular studies. Both mutations were absent in the control subjects. FISH analysis showed two FGFR1 signals with a nearly identical signal intensity in all the KAL1 mutation-negative cases.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Six novel and two recurrent intragenic KAL1 mutations and whole-gene deletions as part of a contiguous gene syndrome were identified. The prevalence of KAL1 mutations was 100% in the familial cases (five of five families), with KAL1 mutations being identified not only in families 1 and 5 with an obvious X-linked recessive inheritance but also in families 2–4 with two affected male siblings only. This suggests that KAL1 mutations are frequent in familial cases. However, because a KAL1 mutation has often been undetected in familial cases of affected male siblings alone (14, 17, 36), the presence of affected male siblings only may not be regarded as a strong indication for a KAL1 mutation. By contrast, the prevalence of KAL1 mutations was 33% in sporadic male cases (five of 15 cases). This implies that KAL1 mutations remain rather infrequent in sporadic KS patients, as has been reported previously (13, 16, 17). However, the frequency of KAL1 mutations in this study is obviously higher than that reported by Izumi et al. (13) (two of 14 Japanese males examined), Georgopoulos et al. (16) (one of 13 Caucasian males analyzed), and Oliveira et al. (17) (four of 38 Caucasian males and females studied). Although the reason for the high prevalence of KAL1 mutations in sporadic cases of this study remains unknown, this may partly be due to an ascertainment bias in the collection of patients, such as the features indicative of a contiguous gene syndrome in case 11 and right renal aplasia in case 15. In addition, the identification of multiple novel mutations appears to be consistent, with mutation hot spot being absent in KAL1 (reviewed in Ref. 13), and the detection of heterozygosity for the normal and mutant alleles in all the five mothers studied would argue for a de novo mutation being rare in KAL1.
Prevalence of FGFR1 mutation
Two novel intragenic mutations were identified for FGFR1 in sporadic cases. By contrast, no submicroscopic deletion was detected by FISH analysis, although a tiny deletion, such as a partial gene deletion, might remain undetected in the present study. Thus, the prevalence of FGFR1 mutations was 11% in the sporadic cases (two of 18 cases) and 9% in the unrelated individuals as a sum of the five probands of familial cases and the 18 sporadic cases (two of 23 probands and sporadic cases). This mutation frequency is comparable to that reported by Dodé et al. (9), who identified 13 mutations in a total of 129 unrelated individuals with KS (10%) after examining intragenic mutations and submicroscopic deletions. In this context, however, it should be pointed out that FGFR1 mutations are accompanied by a wide range of phenotypic spectrum, ranging from apparently normal phenotype to typical KS phenotype with and without associated features (9). This may suggest that the FGFR1 mutation in cases 16 and/or 17 is inherited from a mildly manifesting or nonmanifesting carrier parent(s). In particular, the mother of case 16 allegedly had delayed puberty; therefore, although molecular analysis was not performed because of her refusal, she may also have the S107X mutation.
Clinical features in patients with KAL1 mutations
Endocrine studies confirmed variable degrees of HH in all the patients. In this regard, two matters are noteworthy. First, case 1 with a missense mutation (C163Y) had relatively well conserved sexual phenotype and hormone values. Because C163Y affects a cysteine residue for a disulfide bond in the WAP domain (37), it would inactivate the WAP domain. Thus, the mild phenotype in case 1 may suggest that the WAP domain is dispensable for some of the biological activities of the KAL1 protein, at least in the GnRH production. This notion may further be supported by the clinical features of three brothers with KS caused by another missense mutation (C172R) affecting a disulfide bond in the WAP domain because all three brothers had normal penile growth and one of them had normal testicular descent (17). Second, the hCG tests resulted in poor or subnormal T responses. This would be ascribed to secondary testicular dysfunction resulting from HH. The poor or subnormal T response would be characteristic of KS and other disorders with true HH because males with delayed puberty usually show a sufficient T response after hCG stimulation (Ref. 38 , and Sato, N., N. Katsumata, R. Horikawa, and T. Tanaka, unpublished observation).
Olfactory studies revealed borderline olfactory function in case 7 and normosmia in case 15. Consistent with this, both cases alleged no olfactory impairment in their daily life. To our knowledge, there has been no report documenting normal to borderline olfactory function in patients with demonstrated KAL1 mutations. Furthermore, KAL1 gene analysis has failed to detect a mutation in a large number of patients with isolated HH lacking anosmia/hyposmia (16, 17). It appears, therefore, that KAL1 mutations almost invariably affect olfactory function and permit apparently normal olfactory function in exceptional cases. Because case 7 had a nonsense mutation and case 15 had a splice site mutation, both mutations would drastically impair the function of KAL1. This suggests that some genetic and/or environmental factors rather than the type of KAL1 mutations play a major role in the preservation of olfactory function in cases 7 and 15. In support of this, Massin et al. (39) have recently reported variable degrees of hyposmia in three brothers with the same intragenic KAL1 mutation. Furthermore, the following several points appear to be notable with respect to olfactory function: 1) cases 7 and 15 were studied for olfactory acuity in their early teens and showed bilaterally hypoplastic, rather than normal, olfactory bulbs on MRI; 2) case 1 was allegedly normosmic until his early twenties and had hyposmia from his late twenties with bilaterally hypoplastic olfactory bulbs on MRI at 33 yr of age; and 3) the previously reported patients with KAL1 mutations, as well as those with isolated HH, have been studied in their pubertal to adult age (16, 17). These findings may imply the presence of a possible age effect on the olfactory function, although this notion awaits further clinical observations, including the olfactory function studies of cases 7 and 15 in their later age.
Renal findings are primarily consistent with those of previous reports (14, 40). Nevertheless, two matters appear to be worth pointing out. First, renal aplasia was exclusively right-sided in the present study. In this regard, renal aplasia is predominantly right-sided in reported patients with proven KAL1 mutations, whereas it is usually left-sided in non-KS patients examined by autopsy (41). This suggests that KS is characterized by right-side dominant renal aplasia, although the underlying mechanism remains to be clarified. Second, multiple dysplastic kidney was detected in the neonatal period of case 2. To our knowledge, multiple dysplastic kidney has not been described in patients with proven KAL1 mutation (42). Thus, our results would expand the spectrum of renal lesion in KS. In addition, renal lesion may be relevant to the recurrent miscarriage in the mother of case 13 because severe renal lesion, if it occurs bilaterally, could result in fetal loss (40, 43).
Mirror movement was observed only in cases 1 and 8–10. The prevalence of mirror movement is quite low compared with that reported in the Caucasian male patients with KAL1 mutations (75%) (30). This may primarily be due to lack of detailed clinical examination. However, because mirror movement has not been detected in a total of 19 Japanese male patients with molecularly confirmed KAL1 mutation (13), the ethnic background might also be involved in the low prevalence of mirror movement in this study.
Other features in mutation-positive patients are compatible with the previous findings, as are intrafamilial phenotypic variations. Ptosis seen in case 3 has occasionally been reported (6), and mental retardation, ichthyosis, and ocular albinism found in cases 8–11 can be explained in terms of a contiguous gene syndrome (31). Phenotypic variations in affected brothers have been reported previously (16, 17, 18, 36, 39, 44, 45), although it may deserve pointing out that intrafamilial variation was also identified for olfactory function (cases 6 and 7).
Clinical features in patients with FGFR1 mutations
Cases 16 and 17 had HH and anosmia and lacked other features such as renal lesion, mirror movement, cleft palate, and dental agenesis. This indicates that FGFR1 mutations can result in HH and anosmia-only phenotype in some patients. Consistent with this, Dodé et al. (9) reported that seven of the 12 patients with heterozygous FGFR1 mutations had HH and anosmia/hyposmia-only phenotype.
For FGFR1 mutations, it seems noteworthy that endocrine function and olfactory bulb formation were better preserved in case 17 with P745S than in case 16 with S107X. In this context, S107X is unlikely to have a residual FGFR1 protein activity because it results in the formation of severely truncated FGFR1 protein missing two of the three extracellular Ig-like domains, the acidic box domain, the transmembrane domain, and the two intracellular tyrosine kinase domains (19). By contrast, P745S might be a hypomorphic mutation with a residual FGFR1 protein activity because it occurs at the second intracellular tyrosine kinase domain residing in the 3' end of the FGFR1 protein (19). This may be, more or less, relevant to the phenotypic difference between cases 16 and 17, although the presence of intra- and interfamilial phenotypic variations in individuals with FGFR1 mutations suggest that other genetic and environmental factors also contribute to the phenotypic variations (9).
Clinical features in patients without KAL1 and FGFR1 mutations
The remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations had both HH and defective smelling sense. It should be pointed out, however, that cases 23 and 24 had apparently normal olfactory bulbs on MRI, despite obviously impaired olfactory dysfunction. Such discordance between function and structure has been described in KAL1 mutation-positive and -negative patients (36). Although the reason for the apparently normal olfactory bulb structure remains unknown, it might be possible that the primary lesion in cases 23 and 24 lies in some region other than the olfactory bulbs (36). It might also be possible that the young age in cases 23 and 24 contributed to the preservation of the olfactory bulbs, as discussed in the section of clinical features in patients with KAL1mutations.
Several findings are also notable with respect to the associated features in KS. Case 27 had right renal aplasia, which is frequently observed in patients with KAL1 mutations (14, 40) and remains unidentified in patients with FGFR1 mutations. Cases 18, 23, and 25 had cleft palate or dental agenesis, which is often present in patients with FGFR1 mutations (9) and remains undetected in patients with KAL1 mutations, and cases 23 and 25 also manifested perceptive deafness, which has been identified in a single case with homozygous FGFR1 mutation (9). These findings imply that renal lesion is characteristic of but not specific to KAL1 mutations, as has been described previously (36, 45), and that cleft palate and dental agenesis, and possibly perceptive deafness as well, are characteristic of but not unique to FGFR1 mutations.
Conclusion
Clinical assessment and molecular analysis of KAL1 and FGFR1 were carried out in a total of 28 Japanese patients with KS. On the basis of the present results, we suggest the following: 1) KAL1 mutations might be more prevalent in the Japanese KS patients than previously estimated in the Caucasian KS patients and can be associated with apparently normal olfactory function; 2) FGFR1 mutations account for approximately 10% of KS patients as previously reported in the Caucasian KS patients (9) and can be accompanied by HH and olfactory dysfunction-only phenotype; and 3) renal aplasia, reported in approximately 30% of the patients with KAL1 mutations (40), and cleft palate and dental agenesis, reported in several patients with FGFR1 mutations (9), can occur in patients with no KAL1 or FGFR1 mutations.
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Acknowledgments |
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Footnotes |
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Abbreviations: FISH, Fluorescence in situ hybridization; FGFR1, fibroblast growth factor receptor 1; hCG, human chorionic gonadotropin; HH, hypogonadotropic hypogonadism; KAL1, Kallmann syndrome 1; KS, Kallmann syndrome; MRI, magnetic resonance imaging; T, testosterone; WAP, whey acidic protein.
Received March 18, 2003.
Accepted November 12, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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