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Annales d'Endocrinologie
Volume 71, n° 3
pages 149-157 (mai 2010)
Doi : 10.1016/j.ando.2010.02.005
Clinical genetics of Kallmann syndrome
Syndrome de Kallmann-de Morsier : génétique clinique

C. Dodé a , J.-P. Hardelin b,
a Inserm U1016, département de génétique et développement, institut Cochin, 27, rue du Faubourg-Saint-Jacques, 75679 Paris cedex 14, France 
b Inserm U587, département de neuroscience, Institut Pasteur, 25, rue du Docteur-Roux, 75724 Paris cedex 15, France 

Corresponding author.

Le syndrome de Kallmann-de Morsier associe hypogonadisme hypogonadotrope et anosmie. Il se caractérise par une hétérogénéité à la fois génétique et phénotypique. Les mutations du gène KAL1 , qui code une glycoprotéine de la matrice extracellulaire (anosmine-1), sont responsables de la forme récessive liée au chromosome X de ce syndrome (KAL1). Des mutations de FGFR1 , qui code le premier des quatre récepteurs des facteurs de croissance fibroblastique ou, plus rarement, de FGF8 , qui code l’un de ces facteurs de croissance, sont impliquées dans une forme autosomique dominante à pénétrance incomplète (KAL2). Des mutations de PROKR2 , qui code un des deux récepteurs des prokinéticines, ou de PROK2 , qui code une des deux prokinéticines, sont présentes à l’état hétérozygote, homozygote, ou hétérozygote composite chez certains patients: ces deux gènes sont vraisemblablement impliqués à la fois dans une forme monogénique autosomique récessive (KAL3) et dans des formes digéniques ou oligogéniques du syndrome. Les mutations dans les cinq gènes sus-mentionnés rendent compte de moins de 30% des cas de syndrome de Kallmann, et d’autres gènes restent donc à identifier. Enfin, ce syndrome peut aussi faire partie de maladies pléiotropes du développement, en particulier du syndrome CHARGE, qui résulte dans la plupart des cas de néomutations dans le gène CHD7 codant pour une protéine de liaison à l’ADN.

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The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease (KAL1). Mutations in FGFR1 or FGF8 , encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance (KAL2). Mutations in PROKR2 and PROK2 , encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in autosomal recessive monogenic (KAL3) and digenic/oligogenic KS transmission modes. Mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered. Notably, KS may also be part of pleiotropic developmental diseases including CHARGE syndrome; this disease results in most cases from neomutations in CHD7 that encodes a chromodomain helicase DNA-binding protein.

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Mots clés : Syndrome de Kallmann-de Morsier, Syndrome CHARGE, Hypogonadisme hypogonadotrope, Anosmie, KAL1 , FGFR1 , FGF8 , PROKR2 , PROK2 , CHD7

Keywords : Kallmann syndrome, CHARGE syndrome, Hypogonadotropic hypogonadism, Anosmia, KAL1 , FGFR1 , FGF8 , PROKR2 , PROK2 , CHD7

In brief

Kallman syndrome (KS) is a genetically heterogeneous developmental disease that most often manifests as absent spontaneous puberty combined with a defective sense of smell (hyposmia or anosmia);
some non-reproductive non-olfactory anomalies (e.g., bimanual synkinesis, renal agenesis, cleft lip/palate, hypodontia, hearing impairment…) can also be present, depending on the genetic form of the disease;
KS may also be part of pleiotropic developmental diseases that include the CHARGE syndrome (acronym for coloboma, heart anomalies, choanal atresia, retardation of growth and/or development, genital and ear anomalies);
the prevalence of KS has been roughly estimated at 1:8000 males and 1:40,000 females, but might be underestimated especially in females;
the main differential diagnosis is normosmic congenital hypogonadotropic hypogonadism (HH);
different modes of KS transmission include X chromosome-linked recessive (KAL1), autosomal dominant with incomplete penetrance (KAL2), autosomal recessive (KAL3), and most probably digenic/oligogenic inheritance;
mutations in any of the five known disease genes (KAL1 , FGFR1 , FGF8 , PROKR2 , PROK2 ) have been identified in a relatively small proportion (less than 30%) of the KS patients. In addition, most CHARGE patients carry neomutations in CHD7 ;
as many as 30% of the mutations found in FGFR1 might be de novo mutations, certainly a possibility to be considered before assessing recurrence risk of this genetic form in a family;
genetic testing strategy (Fig. 1) is based on patient’s gender, familial history (if any) and putative mode of disease inheritance, and the presence of additional clinical anomalies that may direct the geneticist towards a particular disease gene or occasionally a contiguous gene syndrome;
treatment of KS is that of the hypogonadism. There is currently no treatment of the olfactory deficit. In both sexes, hormone replacement therapies are used to stimulate the development of secondary sexual characteristics at the time of puberty, and later to induce fertility.

Fig. 1

Fig. 1. 

Genetic testing strategy for Kallmann syndrome.

The strategy is based on patient’s gender, familial history (if any) and putative mode of disease inheritance, and the presence of additional clinical anomalies that may direct the geneticist towards a particular disease gene or, occasionally, a contiguous gene syndrome at Xp22.3 [98] or 8p11.2 p12 [7]. The search for KAL1 mutations is restricted to affected males, either isolated cases or patients with a familial history compatible with X-linked recessive mode of inheritance. Mutation screening of the known KS genes (KAL1 , FGFR1 , FGF8 , PROKR2 , PROK2 ) leads to the identification of a mutation in less than one third of the patients. As many as 30% of the mutations found in FGFR1 might be de novo mutations, certainly a possibility to be considered before assessing recurrence risk of this genetic form in a family. In addition, some CHARGE syndrome patients, who usually carry neomutations in CHD7 , may initially present with KS. The main differential diagnosis of KS is isolated (normosmic) congenital HH, which may result from mutations in GNRHR , GNRH1 , TACR3 , TAC3 , or KISS1R .



Maestre de San Juan was probably the first to report, in 1856, the association of the absence of olfactory structures in the brain and the presence of small testes in an individual [1]. The syndrome was identified as a clinical entity in 1944, by an American medical geneticist, Kallmann, who carried out a study on the occurrence of hypogonadism accompanied by anosmia in three affected families [2]. He showed the cosegregation of the anosmia and the hypogonadism in all the affected individuals, and therefore established that this syndrome can be hereditary. In the 1950s, the Swiss anatomist de Morsier further documented the disease by describing the underdevelopment or absence of the olfactory bulbs and tracts in several male patients with hypogonadism [3]. Some years later, the hypogonadism was ascribed to gonadotropin-releasing hormone (GnRH) deficiency [4].

The prevalence of KS is still unknown. It has been roughly estimated at one out of 8000 in boys. In girls, the prevalence was thought to be at least five times lower, but is probably underestimated because some affected females only have mild hypogonadism (see below). Moreover, primary amenorrhea in females often remains unexplored.

Clinical overview

KS typically combines severe HH with a complete absence of the sense of smell (anosmia). The degree of the hypogonadism and that of the smell deficiency can, however, vary significantly, not only between unrelated patients, but also within affected families [5, 6] (and see pedigrees in [7, 8, 9, 10, 11, 12, 13, 14]), even between monozygotic twins [15, 16]. In some families, both typical KS phenotypes and dissociated phenotypes with either hypogonadism or anosmia have been described [7, 10, 13, 14, 17]. In addition, apparent reversal of the hypogonadism after discontinuation of hormonal treatment has been reported in a few KS patients [9, 18, 19]. Finally, a variety of non-reproductive non-olfactory additional anomalies are present in only a fraction of KS patients. These disorders include involuntary upper limb mirror movements (bimanual synkinesis) [17, 20, 21, 22], abnormal eye movements [21, 23], congenital ptosis [24, 25], abnormal visual spatial attention [26], hearing impairment [5, 6, 8, 27, 28, 29], agenesis of the corpus callosum [7, 13], unilateral (occasionally bilateral) renal agenesis [30, 31, 32], cleft lip or palate [5, 6, 33], agenesis of one or several teeth (hypodontia) [7, 24, 33, 34], obesity [6, 10], and other less documented anomalies.

Diagnostic approaches

Most cases are diagnosed at the time of puberty because of the lack of sexual development, identified by small testes and absent virilisation in males or the lack of breast development and primary amenorrhea in females. KS is diagnosed when low serum gonadotropins and gonadal steroids are coupled with a compromised sense of smell. The latter should be ascertained by means of detailed questioning and olfactory screening tests [35, 36, 37] or, ideally, olfactometry [38, 39], because it is rarely mentioned spontaneously. Magnetic resonance imaging (MRI) of the forebrain can be carried out to show the hypoplasia or aplasia of the olfactory bulbs and tracts [40]. MRI is also useful to exclude hypothalamic or pituitary lesions as the cause of HH [41]. The GnRH deficiency can be indirectly assessed by means of endocrinological tests [42].

Notably, KS may also be suspected as early as in infancy in boys, in the presence of cryptorchidism or a micropenis, combined with subnormal LH and FSH concentrations. Indeed, the postnatal surge in FSH, LH, and testosterone in the male infant as a consequence of the continued function of the foetal GnRH pulse generator provides a 6-month window of opportunity to establish the diagnosis of HH [43], and alert the clinician to the possibility of its association with olfactory impairment. In this respect, the usefulness of forebrain MRI in diagnosing the disease in children too young to undergo meaningful testing of olfaction or of the hypothalamo-pituitary-gonadal axis should be emphasized [44, 45], even though normal olfactory bulb images have been reported in a few KS patients [22, 29].

Finally, the presence of non-reproductive non-olfactory additional disorders, including mirror movements, palate anomalies, renal agenesis (ultrasonography), hearing impairment (audiometric testing), and tooth agenesis, should be carefully searched for in the patients and, whenever possible, their first degree relatives, because such anomalies can direct the geneticist towards particular genetic forms of the disease (see below and Fig. 1). In KS-affected families, cleft palate or renal agenesis diagnosed by means of foetal ultrasonography may occasionally reveal the disease before birth.

The complex genetics of KS

Most KS patients present as sporadic cases, but many cases are clearly familial, with three modes of inheritance being reported: X chromosome-linked recessive (OMIM#308700), autosomal dominant (OMIM#147950), and autosomal recessive (OMIM#244200) (omim/). In the autosomal dominant form, incomplete penetrance has been emphasized [5, 46].

Five causal genes have been identified to date, namely, by chronological order of discovery, KAL1 [47, 48, 49], FGFR1 [7], PROKR2 and PROK2 [10], and FGF8 [50]. Various loss-of-function mutations in KAL1 , encoding the extracellular matrix glycoprotein anosmin-1, and in FGFR1 or FGF8 , encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, underlie the X chromosome-linked form (KAL1) and an autosomal dominant form (KAL2) of KS, respectively. The KAL1 and KAL2 genetic forms account for roughly 8 and 10% of all KS cases, respectively. Mutations in KAL1 are mainly nonsense mutations, frameshift mutations, or large gene deletions, whereas the majority of mutations in FGFR1 (i.e. approximately 70%) or FGF8 (all six mutations reported so far) are missense mutations. Notably, as many as 30% of the FGFR1 mutations found in the patients could be de novo mutations [13, 51, 52] (and C. Dodé, unpublished results). Mutations in PROKR2 or PROK2 , encoding prokineticin receptor-2 and prokineticin-2, respectively, have been detected in approximately 9% of the KS patients. Most of these mutations are missense mutations. Many of them have also been found in apparently unaffected individuals, but deleterious effects of these mutations on prokineticin-signalling have been shown in vitro [53, 54]. The finding, for given PROKR2 and PROK2 mutations, of both homozygous or compound heterozygous patients (autosomal recessive form, KAL3) and heterozygous patients [10, 55] is quite remarkable, and argues in favour of a digenic or oligogenic mode of inheritance in heterozygous patients. To date, digenic inheritance of KS has been shown in three such patients, who had monoallelic missense mutations both in PROKR2 and PROK2 [53], KAL1 [10], or FGFR1 [56]. Other patients carrying heterozygous mutations in PROKR2 , PROK2 , or hypomorphic mutations in KAL1 are expected to carry additional mutations in other, as yet unknown, KS genes. Indeed, mutations in the five known genes together account for less than 30% of KS cases, indicating that other genes responsible for the disease remain to be discovered, some of which might also be involved in FGF-signalling or prokineticin-signalling. Notably, recent evidence indicates that the oligogenic mode of inheritance may also apply to patients carrying mutations in FGFR1 or FGF8 . Three patients carrying missense mutations in FGFR1 have indeed been found to also have a monoallelic or a biallelic mutation in FGF8 [50], or a monoallelic mutation in PROKR2 (see above).

Genotype-phenotype correlation

For most genetic forms of KS identified so far, the clinical heterogeneity of the disease within affected families clearly indicates that the manifestation of KS phenotypes is dependent on factors other than the mutated gene itself. These factors probably include epigenetic factors and modifier genes, both of which have not yet been identified. In addition, digenic or oligogenic inheritance presumably accounts in part for the long recognized incomplete penetrance of the disease. That said, some general features have emerged from clinical studies in the patients affected by the different genetic forms of KS. For instance, patients carrying biallelic mutations in PROKR2 or PROK2 have uniformly severe reproductive phenotypes before hormone replacement therapies, whereas a greater variability in the degree of hypogonadism has been observed in patients carrying monoallelic mutations in PROKR2 , PROK2 , FGFR1 , or FGF8 [7, 10, 50, 57, 58, 59]. In particular, spontaneously fertile individuals carrying mutations in any of the four autosomal KS genes account for the transmission of the disease over several generations, while the X-linked form of KS is usually transmitted by the female carriers of KAL1 mutations, who are clinically unaffected. By contrast, KAL1 patients (males) usually have severe reproductive phenotypes [59]. Among the variety of non-reproductive and non-olfactory disorders that affect a fraction of the KS patients, some have been reported for specific genetic forms of the disease. For instance, unilateral renal agenesis occurs in approximately 30% of KAL1 patients [31, 32], but has so far not been reported in patients with FGFR1 , FGF8 , PROKR2 or PROK2 mutations. On the other hand, the loss of nasal cartilage, external ear hypoplasia, and skeletal anomalies of the hands or feet, have only been reported in KAL2 patients [7, 13, 52]. By contrast, hearing impairment is common to several genetic forms of KS [7, 8, 13, 23, 24, 29, 50], although it should be noted that the underlying defect (conductive, perceptive, or mixed) is likely to vary between genetic forms. Palate defects should also be considered as one of these shared traits, even though the severity differs between KAL1 (high arched palate) and KAL2 (cleft palate). Cleft lip and/or palate may occur in as many as 25–30% of the KAL2 cases [7, 11, 12, 13, 50, 60]. Lastly, bimanual synkinesis is highly prevalent in KAL1 (maybe >75% of the cases) [17, 22], but seems to be much less common in KAL2 [7, 12]. Additional anomalies have so far not been reported in KS patients carrying mutations in PROKR2 or PROK2 , with the notable exception of a severe sleep disorder and marked obesity in one patient [10], which could be related to the known function of prokineticin-2 signalling in behavioural circadian rhythms, including sleep-wake and ingestive behaviour [61, 62]. The prevalence of sleeping and eating disorders in KS patients, however, remains to be determined. Table 1 displays a comparison of clinical features between the different genetic forms of KS that have been identified so far.

Treatment of the hypogonadism

The treatment of hypogonadism in KS aims firstly to initiate virilisation or breast development, and secondly to develop fertility. Hormone replacement therapy, usually with testosterone for males and combined oestrogen and progesterone for females, is the treatment to stimulate the development of secondary sexual characteristics. For those desiring fertility, either gonadotropins or pulsatile GnRH can be used to obtain testicular growth and sperm production in males or ovulation in females. Both treatments restore fertility in a vast majority of affected individuals [63]. It is still unknown whether transient hormone replacement therapy in affected male infants to simulate the postnatal surge in gonadotropins, could have later impact on their sexual life and reproductive prognosis (see [43]).

Differential diagnosis: normosmic congenital hypogonadotropic hypogonadism and CHARGE syndrome

Difficulties are encountered at both ends of KS phenotypic spectrum, that is either in the absence of a conspicuous smell deficiency or when non-reproductive non-olfactory additional anomalies are present on top of a typical KS (Fig. 1). Given the variable degree of hyposmia in KS, the clinical distinction between KS and normosmic congenital HH can be difficult, especially since HH patients do not always undergo detailed olfactory testing. There is genetic evidence, however, to suggest that genuine normosmic HH and KS represent distinct pathological entities. Normosmic HH patients may carry biallelic mutations in various genes that include GNRHR , GNRH1 , KISS1R , TACR3 , and TAC3 , encoding the GnRH receptor, GnRH1 hormone, kisspeptin receptor, neurokinin B receptor, and neurokinin B, respectively ([64, 65, 66, 67, 68, 69]). Neurokinin B is produced by the same hypothalamic neurons that also produce kisspeptin and control GnRH neurosecretion [70, 71, 72, 73]. Moreover, GNRH1 , GNRHR and KISS1R do not seem to play a role in the embryonic migration of neuroendocrine GnRH-cells [66, 74], the process defective in KS patients (see below). Therefore, we suggest that normosmic congenital HH should be regarded as a distinct pathological entity that results from a subsequent defect in GnRH neurosecretion (mutations in KISS1R , TACR3 , TAC3, or GNRH1 ), or in the response of pituitary cells to the hormone (mutations in GNRHR ). This is expected to influence genetic counselling practice, because KS, but not genuine normosmic HH, can occur together with other serious developmental anomalies (see above). The report of a family in which deleterious GNRHR and FGFR1 missense mutations cosegregated in the HH individuals indicates, however, that the situation could be more complicated than anticipated [75].

CHARGE syndrome has an estimated birth incidence of 1 in 8500–12,000. The defining features that make the acronym are coloboma, heart anomalies, choanal atresia, retardation of growth and/or development, genital and ear anomalies. It has, however, been claimed that no single feature is universally present or sufficient for the diagnosis of CHARGE syndrome. Other frequently occurring features include characteristic face and hand dysmorphia, hypotonia, facial nerve palsy, semi-circular canal aplasia or hypoplasia (an anomaly that is consistently found in CHARGE patients), hearing impairment, urinary tract anomalies, orofacial clefting, dysphagia, and tracheo-oesophagial anomalies. New diagnostic criteria have been proposed in the past few years [76]. In addition, it has been reported that most if not all CHARGE patients have both olfactory bulb aplasia or hypoplasia and hypogonadotropic hypogonadism [77, 78], that is, the two KS defining features. Moreover, mutations in the CHARGE syndrome gene CHD7 (see below) have been found in some patients who initially presented with KS [79, 80]. Previously reported KS cases associated with congenital heart disease [81] or choanal atresia [82] presumably also represent unrecognized mild CHARGE cases [83]. Notably, CHARGE syndrome shares additional traits with the KAL2 genetic form of KS, including cleft lip or palate, present in 20–35% of CHARGE [84] patients, external ear malformation, noted in virtually all CHARGE patients [84] and a few KAL2 patients [52], agenesis of the corpus callosum, reported in several CHARGE [84] and KAL2 patients [7, 13], and coloboma that is highly prevalent in CHARGE patients [84] and has been reported in at least one KAL2 patient too [7]. Most individuals with CHARGE syndrome are heterozygous for loss-of-function neomutations in CHD7 that encodes a chromodomain (chromatin organization modifier domain) helicase DNA-binding protein [85, 86].


Most phenotypic anomalies reported in KS may result from developmental failures that occur during the organogenesis period, between four and 10 embryonic weeks (see [87] for review). The disorder leading to the absence (or hypoplasia) of the olfactory bulbs and tracts, and to anosmia in KS is not completely understood. It is likely to involve a failure of the primary contact between olfactory axons and the presumptive olfactory bulbs (see below), but may also involve, in some cases, a later defect in axonal branching of the olfactory bulb output neurons [88]. In the late 1980s, new light was shed on the mechanism of the GnRH deficiency underlying KS hypogonadism, with the discovery of a close topographic link between the peripheral olfactory system and neuroendocrine GnRH-cells during embryonic life [89]. These cells undergo a migration, beginning in the 6th embryonic week, from the olfactory epithelium to the forebrain along the olfactory nerve pathway [90]. This is also when fibres of the olfactory and terminal nerves first come into contact with the rostral forebrain, shortly before the emergence of the olfactory bulbs [91]. In a human foetus carrying a chromosomal deletion at Xp22.3 that included KAL1 , it was shown that GnRH-cells had not migrated normally and had accumulated in the fronto-nasal region, together with entangled fibres of the olfactory and terminal nerves that did not contact the forebrain and formed bilateral neuromas [92]. A similar observation has recently been made in a CHARGE syndrome foetus (Fig. 2). There are presently no pathohistological data to verify that the embryonic migration of GnRH-cells is arrested in individuals affected by other genetic forms of KS, but in Prokr2-null or Prok2-null mice, and in mice carrying Fgfr1 or Fgf8 hypomorphic mutations in the homozygous state, the migration of these cells is disrupted too [14, 50, 93, 94]. The defect of GnRH-cell migration in KS is likely to be a consequence of the early interruption of olfactory nerve and terminal nerve axons, which normally act as guiding cues. This defines a pathological sequence, whereby the primary cause of KS is a developmental disorder of the peripheral olfactory system. Analysis of mouse models, however, suggests that earlier defects in GnRH-cell fate specification or differentiation in the nasal pit, and later defects in their axon elongation or axon targeting to the hypothalamus median eminence may also contribute to the GnRH deficiency, at least in the KAL2 genetic form [94, 95].

Fig. 2

Fig. 2. 

Pathogenesis of Kallmann syndrome: a primary olfactory developmental disorder.

Left panel: Bilateral neuromas in a foetus affected by CHARGE syndrome. Endocranial view of the cribriform plate region of the ethmoid bone in a 23-week old CHARGE foetus. Abnormal spherical structures (arrowheads) formed by entangled fibres of the interrupted olfactory and terminal nerves can be seen on both sides of the crista galli. Scale bar=1mm. (F. Guimiot and L. Teixeira, personal communication).

Right panel: Failed migration of GnRH-cells in a KAL1 foetus. Parasagittal section of the fronto-nasal region in a 19-week-old male foetus affected by the X chromosome-linked form of KS (counterstained with cresyl violet). Clusters of GnRH-immunoreactive cells (in brown) can be seen between the dorsal surface of ethmoid bone cribriform plate (CP) and the meninges (M). No neuroendocrine GnRH-cells were found in the brain of this foetus. Scale bar=100μm. (Reproduced from [92] with permission).


Unresolved questions

Although KS was identified as a hereditary disease more than 60 years ago, its genetics is still incompletely understood, including its higher prevalence in males than in females. Among many unresolved genetic and clinical questions are the following:

what is the actual prevalence of KS, especially in females?
what is the KS phenotypic spectrum, especially with respect to non-reproductive non-olfactory additional anomalies?
could hereditary anosmia without apparent hypogonadism be a clinical form of KS ?
how many different disease genes are involved in KS, and how do they functionally interact in the development of olfactory and GnRH neuroendocrine systems (see [96] for current hypotheses)?
what is the prevalence of the digenic/oligogenic mode of inheritance among KS patients? Indeed, answer to this question is a prerequisite to assess disease recurrence risk in affected families.
why is KS more frequent in males than in females ? Since this cannot be explained by the relatively low prevalence of the X-linked recessive form, could it be that females are to some extent protected against disease occurrence by physiologically higher levels of KAL1 expression during embryonic life compared to males (because KAL1 still partially escapes the X-chromosome inactivation process in humans [47], presumably as a reminder of the gene ancestral location in the pseudoautosomal region of sex chromosomes in lower primates [97])?


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