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X Chromosome-Linked Kallmann Syndrome: Clinical Heterogeneity in Three Siblings Carrying an Intragenic Deletion of the KAL-1 Gene

Department of Endocrinology and Reproductive Medicine (N.M., J.G., F.K., P.T.), Hôpital Necker, 75743 Paris Cedex 15, France; Department of Biochemistry and Molecular Genetics (C.P., C.D.), Hôpital Cochin, 75014 Paris, France; Department of Oto-Rhino-Laryngology (C.E.), Hôpital Lariboisière, 75010 Paris, France; Department of Radiology (J.-L.B.), Clinique Turin, 75008 Paris, France; and Unité de Génétique des Déficits Sensoriels (J.-P.H.), Institut Pasteur, 75724 Paris Cedex 15, France

Address all correspondence and requests for reprints to: Philippe Touraine, M.D., Ph.D., Department of Endocrinology and Reproductive Medicine, Hôpital Necker, 149 rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: philippe.touraine{at}nck.ap-hop-paris.fr.

	Abstract

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Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3–13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suffered from a severe congenital hearing impairment, a feature that had been reported in KS but had not yet been ascribed unambiguously to the X-linked form of the disease. The variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of the X-linked KS.

	Introduction

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KALLMANN SYNDROME (KS; Ref. 1) is characterized by the association of hypogonadotropic hypogonadism and anosmia. Anosmia is associated with underdevelopment or absence of the olfactory bulbs and tracts (2), and hypogonadism results from impaired secretion of GnRH (3). In the last decade, embryological studies in various animal species, including man, have shed new light on KS by showing the existence of a close, albeit transient, topographical link between GnRH-synthesizing neurons and the developing olfactory system (4, 5, 6). The genetics of KS remains poorly understood. Three different inheritance patterns have been reported in familial cases, namely X chromosome-linked (KAL-1; Ref. 7), autosomal dominant (KAL-2), and autosomal recessive (KAL-3). However, most cases are sporadic. The pathogenesis of the olfactory defect and GnRH deficiency has been partially clarified in the X-linked form of the disease (8, 9). The gene underlying this genetic form, KAL-1 (10, 11), codes for a component of various embryonic extracellular matrices (5). There is a great variety of mutations associated with the X-linked KS: various point mutations (most cases), intragenic deletion (12), complete gene deletion (13), and even larger deletion of the Xp22.3 region associated with a contiguous gene syndrome (KS and ichthyosis; Ref. 14).

Various phenotypic abnormalities have been described either in X-linked form or autosomal form of KS (15): mirror movements, unilateral renal aplasia, deafness, abnormal eye movements, cerebellar dysfunction, shortened fourth metacarpals (brachymetacarpia), and cleft lip palate or high-arched palate. The significant clinical heterogeneity in the X-linked form of KS suggests a diversity in genetic factors involved (16, 17) that are currently unknown. Both inter- and intrafamilial variability have been observed in the X-linked form of KS (18).

Herein, we report the case of three brothers who carry the same intragenic deletion of KAL-1 but present clearly different phenotypes. In particular, one of the affected brothers suffers from profound sensorineural hearing loss, which allowed us to unambiguously ascribe this sensory defect to the X-linked form of the KS.

	Case Reports

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Case 1

An 18-yr-old boy (sibling A) presenting a congenital hearing loss, who was reared in an institution for the deaf and dumb, was referred to our department because of the absence of pubertal development. There was a history of probable KS in the family: a 24-yr-old brother (sibling B) treated with androgens, and a 15-yr-old brother (sibling C) with absence of pubertal development. On physical examination, there was a stunted growth, sparse pubic hair, and absence of gynecomastia. The genitalia were infantile with small testes (approximately 4 ml in volume). Other clinical abnormalities are summarized in Table 1. Audiometry showed a profound bilateral sensorineural hearing loss, with normal scanography of the petrous bone (data not shown). Laboratory tests confirmed hypogonadotropic hypogonadism with low testosterone, low FSH and low LH levels, unresponsive to the GnRH test. The patient, a horticulturist, mentioned that he always had difficulty recognizing odors. The clinical olfactory test confirmed abnormal thresholds for odorant identification. Cranial magnetic resonance imaging (MRI) showed hypoplastic olfactory bulbs and tracts, detailed in Table 2. First, he was given 250 mg testosterone enanthate (Androtardyl, Schering SA, Lys-lez-Lannoy, France) im every 3 wk, and then we added 125 mg/d percutaneous dihydrotestosterone (Andractim, Besins-Icovesco, Paris, France). This was followed by progressive muscular development, deepening of the voice, and development of facial and body hair.

A 21-yr-old boy (sibling B) was diagnosed KS because of statural and pubertal delay and partial anosmia. He was given testosterone enanthate im for 12 months, and he then decided to discontinue treatment because of generalized articular pain. Under treatment, partial pubertal development and growth occurred. He was referred to our department when he was 24 yr old. On physical examination, there was no facial and body hair, and genitalia were normal, although the testes were infantile (2 ml). He had erection but no ejaculation. Specific clinical abnormalities are shown in Table 1, and laboratory tests showed hypogonadotropic hypogonadism. Audiometry was normal (Fig. 1). He spontaneously mentioned smell disability that he estimated important and socially bothersome. Olfactometrical tests were extensively abnormal. Cranial MRI is detailed in Table 2 (see Fig. 4 also). Ultrasound scanography showed total absence of the left kidney with prostate and seminal vesicle hypoplasia. Androgen therapy was restarted at a dose of 125 mg testosterone enanthate im every 2 wk.

View larger version (32K): [in this window] [in a new window]   Figure 1. Audiograms of siblings B and C. Air conduction hearing thresholds (in decibels) of the right (circles) and left (squares) ears have been determined for all indicated sound frequencies in siblings B and C.

View larger version (144K): [in this window] [in a new window]   Figure 4. Cranial MRI of the olfactory bulb region in a control man (A and B) and sibling B (C and D). A and B, MRI T2-weighted sequence in coronal plane shows normal olfactory bulb in a control man (A, white arrows), and posterior to the olfactory bulb, good differentiation of the rhinal sulcus (B, white arrows) and the olfactory tracts (B, white arrowheads). C, MRI T2-weighted sequence in coronal plane shows very small olfactory bulb in sibling B (white arrows). On the right side, the rhinal sulcus (white arrowhead) is visible with a good differentiation between right gyrus and orbital gyrus. On the left side, there is no rhinal sulcus (black arrowhead) with no differentiation between the right gyrus and the orbital gyrus. D, MRI T1-weighted sequence in coronal plane, posterior to olfactory bulb, confirms the presence of the rhinal sulcus on the right side (white arrow) with a relatively good differentiation of right gyrus (white arrowhead) and orbital gyrus (black arrowhead), and on the left side no rhinal sulcus (black arrow).

A 15-yr-old boy (sibling C) was referred to our department because of stunted growth and absence of pubertal development. He had an infantile phenotype (testis less than 1 ml) and delayed growth (-2 SD), associated with smell disability that he considered of little social consequence. Laboratory tests showed hypogonadotropic hypogonadism. Phenotype and cranial MRI are summarized in Tables 1 and 2, respectively. Audiometry showed isolated sensorineural defect in high frequencies on the left side (Fig. 1). Olfactometry was abnormal. Androgen therapy was started with 250 mg testosterone enanthate im every 4 wk and 125 mg/d percutaneous dihydrotestosterone. There was progressive growth, as well as development of the genitalia, facial and pubic hair.

The three brothers gave oral and written consent to participate in this genetic study.

Clinical olfactory tests

Endoscopic nasal examination before olfactometry was normal for the three brothers. We used a clinical olfactometer (19) to achieve the measure of detection and identification thresholds for five pure odorants that do not evoke a trigeminal stimulation at the used levels: 1) ß-phenyl ethyl alcohol, similar to flower odor; 2) -undecalactone, similar to fruit odor; 3) isovaleric acid, similar to cheese odor; 4) skatole, similar to stall odor; and 5) cyclotene, similar to caramel odor. Each odorant is presented at eight different concentrations according to a logarithmic scale to cover the range of human olfactory ability (20). The olfactometer is composed of 40 standardized bottles, and each bottle is presented twice during the test, in random order. Patients note differences between detection threshold [i.e. is there any odor in the bottle? (yes/no)] and identification threshold [i.e. what is this odor? (list of odors proposed)]. The olfactory score for each odorant is the geometric mean between the last undetected concentration and the first detected one. Using this standardized method, the three brothers had abnormal olfactory tests, but with variable degrees of severity in the olfactory defect. The olfactory tests of the three brothers are presented in Fig. 2, and thresholds are expressed as percentile of an age-matched male control population. Surprisingly, sibling A had normal detection thresholds, although this was associated with a fast fatigue in smelling. However, quite abnormal identification thresholds were found in this patient. Sibling B showed strongly hyposmic detection thresholds and severe identification disability. Concerning sibling C, detection thresholds were at the upper normal limit, but identification thresholds were quite abnormal.

View larger version (18K): [in this window] [in a new window]   Figure 2. Clinical olfactory tests in three brothers affected by KS. Detection and identification thresholds are expressed for the three brothers for each odorant, as percentile of an age-matched male control population. Odorants: , ß-phenyl ethyl alcohol; , cyclotene; , isovaleric acid; , -undecalactone; and , skatole. The bold black line delimits normal detection thresholds (over) and hyposmia thresholds (under).

All of the techniques used have been previously described (21). Southern blot analysis of the KAL-1 gene, using the KAL-1 cDNA as a probe, indicated the presence of a large deletion in the patients (data not shown). To characterize the deletion, we analyzed each of the KAL-1 14 exons by PCR amplification (Fig. 3). All three brothers carry the same KAL-1 intragenic deletion that encompasses exons 3–13.

View larger version (33K): [in this window] [in a new window]   Figure 3. Analysis of KAL-1 exons in three brothers affected by KS. PCR amplification products corresponding to each of the 14 KAL-1 exons were analyzed by agarose gel electrophoresis. The results for exons 2, 3, 13, and 14 are presented (ethidium bromide coloration). Lanes 1–5 correspond to siblings A, B, C, a 46 XY normal male, and a negative control with omission of the genomic DNA in the PCR, respectively. Lane M, molecular weight marker. Exons 2 and 14 can be amplified in the four males (lanes 1–4), whereas exons 3 and 13 are amplified only in the control male (lane 4).

Cranial MRI was performed on SIGNA 1.5 tesla-GEMS (General Electric Medical Systems, Waukesha, WI). The examination began by a full exploration of the brain with T1 and T2 spin echo sequences sagittal and axial. The analysis of the olfactory system was performed by coronal contiguous slices of 2- or 2.5-mm thickness, with T1 and T2 spin echo series, focused on the frontoolfactory region, from the posterior border of the frontal sinus to the optic chiasma. The olfactory bulbs, olfactory tracts (22), and the frontoolfactory gyri on both sides of the rhinal sulcus (right gyrus medial and orbital gyrus lateral) were analyzed. The white anterior commissure and, by the end, the temporal lobe (uncus) and the primary olfactory cortex were analyzed. One T1-weighted coronal spin echo sequence after injection of gadolinium completed the exploration of eliminating a tumor of the frontoolfactory region. MRI analysis, detailed in Table 2 and Fig. 4, showed rudimentary or hypoplastic olfactory bulbs in the three siblings. We noted a variable degree of development in olfactory bulbs and tracts.

	Discussion

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We present herein the story of three brothers who have the same clinical and biological expression of hypogonadism. However, the expression of hypogonadism had no similarity with their variable expression of olfactory defect and with development of olfactory bulbs and tracts. They also presented heterogeneity in associated phenotypic abnormalities, which is consistent with both inter- and intrafamilial variability observed in the X-linked form of KS.

Among the various anomalies associated with X-linked KS (9, 21), upper limb mirror movements (bimanual synkinesis) and unilateral renal aplasia are often encountered, because they affect over three fourths and one third of the patients, respectively (23, 24). Moreover, the X-linked form of KS was phenotypically well defined and characterized by upper-limb mirror movements, and unilateral renal agenesis was not observed, to our knowledge, in autosomal KS or normosmic idiopathic hypogonadotropic hypogonadism. They constitute specific phenotypic markers for the X-linked form of the disease (25). In our report, two of the three brothers presented synkinesis and unilateral renal aplasia.

We were interested in other phenotypic abnormalities, namely abnormal eye movements (horizontal nystagmus), and sensorineural deafness. To our knowledge, nystagmus has been described in the autosomal form of KS. But concerning sibling C, we cannot conclude here because only one clinical examination was performed, and no complete neurological and ophthalmic examination was performed. Nystagmus was never observed in the two other siblings.

Meanwhile, the present case report establishes that sensorineural deafness represents real association with X-linked KS, although not specific to this genetic form (26). Sibling A presented a profound bilateral sensorineural deafness and was reared in an institution for deaf and dumb, whereas sibling B presented normal audiometry, and sibling C presented a unilateral sensorineural defect isolated to high frequencies. Hearing loss is reported in 5–10% of KS cases (25), but detailed functional and morphological investigations have been reported in only a small number of patients (27). Hardelin et al. (13) first documented hearing loss associated to familial KS due to a Xp22.3 deletion including the KAL-1 gene: among two brothers with anosmia, only the younger one presented congenital bilateral sensorineural hearing loss, and the older one presented unilateral renal aplasia and ptosis. Hardelin et al. (13) suggested that a distinct contiguous codeleted gene could be responsible for deafness. Quinton et al. (26) also report a sensorineural deafness in an isolated case associated with a stop mutation of exon 12 of KAL-1. Hardelin et al. (5) have shown that KAL-1 is expressed in the inner ear from early developmental stages, suggesting that the defect underlying the hearing loss in X-linked KS occurs during the organogenesis period. In this context, it is noteworthy that medical imaging in affected sibling A did not reveal any structural anomaly of the inner ear.

In conclusion, the developmental failures that lead to the various anomalies of the X-linked KS remain somewhat unclear and must still be clarified. However, phenotypic variability, both qualitatively and quantitatively, in the family reported here further emphasizes the role of putative modifier genes, and/or epigenetic factors, in determining the variable expressivity of the disease.

	Footnotes

 
Abbreviations: KS, Kallmann syndrome; MRI, magnetic resonance imaging.

Received December 18, 2002.

Accepted February 2, 2003.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Massin, N. Articles by Touraine, P. Search for Related Content PubMed PubMed Citation Articles by Massin, N. Articles by Touraine, P.