Reproductive capacity in humans is governed by a few thousand hypothalamic gonadotropin-releasing hormone-secretary (GnRH) neurons. These cells are originally formed outside the central nervous system, although their precise developmental origin remains controversial. The olfactory placode, the anterior pituitary, neural crest cells and the respiratory epithelium are all suggested sources of GnRH neurons Citation[1]. Primitive GnRH neurons migrate to the hypothalamus, using the axons of the developing olfactory neurons as guides. In the hypothalamus, GnRH neurons eventually form a functional unit that secretes GnRH, a decapeptide, into the hypophyseal venous portal system, thereby regulating gonadotropin secretion from the pituitary. Formation of the olfactory system is thus a prerequisite for the migration of GnRH neurons and future fertility.
Kallmann syndrome (KS), a subtype of congenital hypogonadotropic hypogonadism in which patients also have a deficit in their sense of smell due to olfactory bulb abnormalities, is a rare condition with an estimated incidence of 1:30,000 in men and 1:125,000 in women Citation[2]. KS patients typically present with delayed puberty, and the reproductive phenotype may range from genital hypoplasia (i.e., cryptorchidism and/or microphallus) through partial puberty to reversal of hypogonadotropism later in life Citation[2–4]. Although KS is classically attributed to a failure in GnRH neuron migration Citation[5,6], defects in FGF signaling may also affect GnRH neuron specification Citation[7,8]. In 1979, Hall described a series of 17 children with choanal atresia and additional congenital anomalies Citation[9], and Hittner et al. described a syndrome consisting of colobomatous microphtalmia, heart disease, hearing loss and mental retardation Citation[10]. The acronym CHARGE (coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia and ear abnormalities/hearing loss) was proposed 2 years later Citation[11]. The highest incidence of CHARGE syndrome has been estimated at 1:8500 live births Citation[12].
Both KS and CHARGE are clinically highly variable. In 2005, patients with CHARGE were reported to have absent or impaired sense of smell as a result of abnormalities in the olfactory bulb development Citation[13,14]. Additional phenotypic overlap between these syndromes was reported: prepubertal boys with CHARGE accompanied by genital hypoplasia were noted to have low sex steroid levels during the minipuberty of infancy, and five adolescent girls were shown to have absent gonadotropin responses to GnRH stimulation – all findings consistent with congenital hypogonadotropic hypogonadism Citation[13]. CHARGE and KS also overlap genetically: a mutation in the chromodomain helicase-7 gene (CHD7) is found in >75% of CHARGE syndrome patients Citation[15] and in 3–5% of KS patients Citation[16,17]. CHD7 regulates transcription by chromatin remodeling, can form complexes with other proteins Citation[18] and, as suggested by more than 10,000 potential binding sites in the mouse genome, has a multitude of regulatory functions Citation[19]. Additional genetic overlap between CHARGE and KS may also exist, as mutations in class 3 (secreted) semaphorins have been reported in rare cases of both syndromes Citation[20,21]. On the other hand, CHD7 mutations were not identified among well-characterized KS patients without additional (although nonspecific) features pertinent to CHARGE syndrome, such as hearing loss or cleft lip/palate Citation[22]. Conversely, hearing loss can also occur in KS patients with a mutation in KAL1, FGFR1 or FGF8 genes Citation[7,23], and cleft lip/palate is a relatively frequent finding among KS patients with an FGFR1 mutation Citation[23]. It is also now known that KS is genetically heterogeneous, and mutations in at least five different genes (KAL1, FGFR1, FGF8, PROKR2, PROK2) are known to cause it, but typically without the frequent features in CHARGE such as coloboma, cup-shaped ears, semicircular canal hypoplasia or choanal atresia. This suggests that not all KS patients should be considered to represent a mild form of CHARGE.
Mutations in CHD7 are not always fully penetrant for CHARGE. For example, Bergman et al. showed that 14–17% with a CHD7 mutation could not be clinically diagnosed to have CHARGE syndrome Citation[24], and even the same mutation in CHD7 has been described to underlie CHARGE or KS Citation[16]. Similarly, we recently reported a man with a truncating CHD7 mutation, semicircular canal hypoplasia, nonspecific retinal spots and KS, but without full-blown CHARGE Citation[2,4]. He displayed spontaneous testicular growth while on testosterone-replacement therapy, fathered a child following a short course of therapy with human chorionic gonadotropin and sustained adult serum testosterone level and normospermia following cessation of testosterone replacement Citation[4]. The mechanism of gonadotropin secretion recovery, occurring in 8% of KS patients, is currently unknown, but androgen exposure apparently plays a role Citation[4,25]. Chd7 haploinsufficiency in mice leads to genital hypoplasia and delayed puberty, accompanied by decreased expression of Fgfr1 in the olfactory placodal region, reduced number of hypothalamic GnRH neurons, and reduced expression of genes involved in GnRH signaling Citation[26]. These findings thus suggest a link between CHD7 and at least some of the genes implicated in the etiology of isolated KS. Further, Chd7 is known to be one of the key genes for the development of neural crest Citation[18], a suggested source of GnRH neurons in mice Citation[27].
The existing phenotypic and molecular genetic overlap between CHARGE and KS has paved the way toward a better understanding of the ontogeny of the human reproductive system. However, more work is still required. I expect that the rapidly evolving next-generation sequencing techniques will expand our understanding of the molecular genetic overlap between these syndromes. Similarly, disease-modeling with patient-derived, induced pluripotent stem cells will offer new possibilities to investigate the complex relationship between the development of the olfactory system and GnRH neurons. I hope that these lines of investigation will lead to next great steps forward, both in terms of elucidating mechanisms regulating human reproduction and improving patient care.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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