Kallmann syndrome type 2 (KS2) is a type of congenital hypogonadotropic hypogonadism with anosmia. It is caused by mutations in the FGFR1 gene and typically manifests in delayed puberty and olfactory impairment. Birth defects such as digital malformations, tooth agenesis, and cleft lip or palate may be observed and facilitate the search for the underlying gene defect. Most KS2 patients respond well to hormonal therapy, develop normal sexual characteristics, and may even have children.
KS2 is generally described as a type of congenital hypogonadotropic hypogonadism with anosmia. As such, symptoms may be present at birth, but diagnoses before puberty are rare in clinical practice. Those cases associated with physical birth defects are the exception to this rule: KS2 may be related to abnormalities of the digital bones, such as such as polydactyly, syndactyly, clinodactyly, or campylodactyly, which are observed in about one-fourth of all cases. Dental agenesis and cleft lip or palate are readily recognizable, too, and are reported in 39 and 11% of KS2 patients, respectively. Hearing loss has been described in a minor share of patients  .
With regard to hypogonadotropic hypogonadism, delayed or absent puberty is the most frequent finding. KS2 interferes with the maturation and activity of the gonads, and the development of secondary sexual characteristics is usually disturbed. Lack of beard growth, absence of voice change, scarce body hair, prepubertal testes, and limited penile growth are often observed in boys. If a growth spurt occurs, they may grow to eunuchoid body proportions with excessively long arms and legs. Poor breast development and primary amenorrhea are most striking in females, who will also miss axillary and pubic hair. Infertility is a common issue in men and women, and in mild cases, it may be the presenting symptom. Of note, KS2 may be related to deficiencies in the development of primary sexual characteristics, too. Corresponding symptoms are mainly noted in males and may comprise micropenis and cryptorchidism .
The disease is commonly related to deficiencies in olfaction, but they don't usually attract the parents' attention. Hyposmia or anosmia may eventually be described by the patients themselves, or may be detected during the diagnostic workup of hypogonadotropic hypogonadism. About 70% of KS2 patients are anosmic, while 30% suffer from hyposmia .
Entire Body System
Proportionate Short Stature
Short Stature/Small for Gestational Age Combined Pituitary Hormone Deficiency, Recessive Tags Green Green List (high evidence) SLC29A3 1 review BIALLELIC, autosomal or pseudoautosomal Sources Emory Genetics Laboratory Expert Review Green Illumina TruGenome [panelapp.genomicsengland.co.uk]
List (high evidence) SLC29A3 1 review BIALLELIC, autosomal or pseudoautosomal Sources Emory Genetics Laboratory Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Histiocytosis-lymphadenopathy [panelapp.genomicsengland.co.uk]
Terms Other Names Learn More: HPO ID 5%-29% of people have these symptoms Agenesis of corpus callosum 0001274 Clinodactyly Permanent curving of the finger 0030084 Ectrodactyly Cleft hand Lobster claw hand [ more ] 0100257 Iris coloboma Cat eye 0000612 Osteopenia [rarediseases.info.nih.gov]
Increased Muscle Mass
They do not show signs of sexual maturation (deepening of their voice, growth of their testes, growth of facial hair, or increased muscle mass) nor do they experience a puberty related growth spurt. [my46.org]
Hyposmia - Anosmia
People with Kallmann also have a diminished to absent sense of smell (hyposmia/anosmia) due to the underdevelopment or absence of their olfactory bulbs in the brain. [my46.org]
Kallmann syndrome is an X-linked disorder that results from disruption of hypothalamic GnRH neuron development and presents with associated olfactory nerve agenesis or hypoplasia, leading to hyposmia/anosmia (16). [jci.org]
Notably, when patients exhibit a diminished/altered sense of smell (hyposmia/anosmia) it is termed Kallmann syndrome (KS). Associated phenotypes occur at highly variable rates. [frontiersin.org]
One patient did not undergo the test because of a cognitive deficit, but reports of hyposmia/anosmia were confirmed by parent testimony. MM, evaluated in all patients, were significantly observed in 9 subjects. [ajnr.org]
KS2 is inherited in an autosomal dominant manner, but incomplete penetrance may hamper the identification of the mode of inheritance . What's more, despite KS2 being a hereditary disorder, positive family histories are rarely documented . The large share of sporadic cases is generally explained by the inherent inability to reproduce; it complicates diagnostic procedures insofar as little data can be obtained from pedigree analyses.
The general diagnosis of Kallmann syndrome is based on clinical findings as described above, endocrine and possibly imaging studies to confirm the nature of hypogonadism, and an assessment of the patient's sense of smell:
- Hypogonadotropic hypogonadism is associated with deficiencies in the release of GnRH, low serum levels of FSH and LH as well as testosterone and estradiol in males and females, respectively. A prolonged stimulated intravenous GnRH test may be carried out if doubts remain as to the site of endocrine dysfunction.
- Magnetic resonance imaging may reveal arhinencephaly, i.e., the absence of the olfactory bulbs and tracts, or hypoplasia of these structures. The pituitary gland and hypothalamus appear normal.
- There are a number of commercially available, validated kits for the assessment of olfaction, but before quantitative smell testing, patients should be asked to self-report their olfactory function. They may then be evaluated regarding their ability to identify and distinguish odors, and it is also possible to determine detection thresholds . Of note, mutations in the FGFR1 gene have also been determined in patients with normosmic hypogonadotropic hypogonadism. These cases do not fall under the category of Kallmann syndrome, but it should be kept in mind that a normal sense of smell is no exclusion criterion for pituitary disorders due to pathogenic variants of FGFR1 .
The underlying gene defect should be identified to secure the diagnosis, to facilitate the identification of related carriers and possibly allow for prenatal diagnosis. The setup of a straightforward test procedure may pose a major challenge, though, because inactivating variants in several dozen genes may cause Kallmann syndrome . Screening for particular genotypes should thus be prioritized according to the presence of certain clinical features and imaging findings: Digital bone abnormalities have only been observed in patients with KS2 and Kallmann syndrome type 6, and may thus be understood as an indicator of impaired FGF8/FGFR1 signaling. Similarly, dental agenesis and midline facial defects are more commonly seen in KS2 patients. These features may thus be helpful to distinguish KS2 from other types of Kallmann syndrome and to focus genetic studies .
Hormone replacement therapy with GnRH, gonadotropins, androgens or estrogens and progesterone may stimulate the development of primary and secondary sexual characteristics and induce puberty; treatment with GnRH or gonadotropins may also restore fertility. Thus, the treatment plan should be established according to the needs of the individual patient. Sex hormones may be administered initially, until sexual development reaches a satisfying level, and gonadotropins or GnRH may be administered thereafter to gain fertility . Additionally, calcium and vitamin D supplementation should be considered in women at risk for osteoporosis, and if low bone mineral density is confirmed, specific treatment for decreased bone mass may become necessary .
Both males and females with KS2 have been shown to respond well to pulsatile GnRH therapy, with a minor share of males achieving sustained reversal of KS2: About 20% of study participants were able to maintain physiological levels of testosterone after the discontinuation of hormonal therapy  . On the other hand, fertility has successfully been induced in both male and female KS2 patients by gonadotropin therapy . Regardless of fertility, most patients do require lifelong therapy in order to maintain a eugonadal state and to avoid complications like osteoporosis and anemia . Poor compliance may result in relapses, so patients should be thoroughly informed about the significance of their adherence to the recommended course of treatment .
Cleft lip and palate, malformations of the digits, and further birth defects require symptomatic treatment according to the respective guidelines; causal therapy is not available.
KS2 does not diminish life expectancy, but it may still reduce life quality. This is due to the unavailability of therapies for olfactory impairment, which is typically associated with hypogeusia or ageusia. Hypogonadotropic hypogonadism, however, is treatable. Hormonal therapy is safe and effective; it aims at the induction and maintenance of sexual and physical development, growth, and fertility. KS2 patients have been successfully treated with GnRH, gonadotropins, and sex hormones, and have had healthy children   .
KS2 is inherited in an autosomal dominant pattern and has been related to mutations in the FGFR1 gene . This gene is located on the short arm of chromosome 8 and encodes for fibroblast growth factor receptor-1, a cell surface receptor comprising three extracellular immunoglobulin-like domains, a single membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. Pathogenic mutations leading to KS2 have been identified in both the extracellular and intracellular portions of the protein and are mostly missense mutations .
The total prevalence of Kallmann syndrome has been estimated at 1 in 10,000 men and 1 in 50,000 women , with KS2 accounting for up to 10% of these cases and showing similar gender distribution  . While some types of Kallmann syndrome are inherited in an X-linked manner and thus preferentially affect males, this does not apply to KS2. The exact reason for the male predominance in KS2 remains unknown, but underdiagnosis and lower penetrance in females have been discussed as possible causes. With regard to the latter, Dodé and colleagues proposed an interaction between FGFR1 and anosmin-1 as the underlying mechanism. Anosmin-1 is encoded by KAL1, a gene located on the X chromosome, and the expression of KAL1 is naturally expected to be higher in females. If an increased expression of KAL1 was able to compensate for a deficiency of FGFR1, hemizygosity for KAL1 might explain the large share of male patients .
The pathogenesis of anosmia and pituitary gland disorders limited to the gonadotropic axis has long since occupied developmental biologists all over the world. A milestone was reached when it could be demonstrated that the origin of neurons expressing GnRH lies outside the central nervous system, in the olfactory placode of the nasal prominence. These neurons thus share a common origin with olfactory sensory cells, which eventually give rise to the olfactory epithelium .
FGF8/FGFR1 signaling plays a key role in the migration of both types of neurons along the olfactory nerve pathway: They are to migrate across the cribriform plate towards the developing olfactory bulb and, in case of GnRH neurons, continue their journey to the arcuate nucleus of the hypothalamus . What's more, dysfunctional FGF8/FGFR1 signaling may interfere with the pre- and postmigratory differentiation of neurons expressing GnRH. Mice deficient for FGFR1 have a decreased total number of GnRH neurons and abnormal projections toward the median eminence, where they should establish a network supporting the coordinated and pulsatile secretion of the releasing hormone .
Affected families may benefit from genetic counseling, whereby the latter should be preceded by a thorough familial workup and genealogical analysis. Precise knowledge regarding the underlying mutation(s) is indispensable to that end.
Kallmann syndrome refers to those forms of congenital hypogonadotropic hypogonadism that are associated with anosmia or hyposmia, a deficiency of the sense of smell. They may be caused by mutations in distinct genes, e.g., genes KAL1, FGFR1, and PROKR2, and the respective types of Kallmann syndrome have been numbered accordingly. Distinct genotypes result in slight phenotypic differences, which may help to make a tentative diagnosis and to prioritize the sequencing of determined genes.
In detail, KS2 is related to mutations in the FGFR1 gene, which encodes for fibroblast growth factor receptor-1. The phenotypic spectrum of KS2 is rather broad:
- In males, hypogonadotropic hypogonadism may be severe, causing micropenis and cryptorchidism, of intermediate severity, delaying puberty, or mild, giving rise to the "fertile eunuch variant" likely to show reversal after androgen therapy. Female patients may show absent or delayed puberty and be infertile .
- Olfactory impairment may be partial or complete, and FGFR1 mutations have even been identified in normosmic patients.
- KS2 may be associated with malformations of the hand skeleton, midface, and teeth.
- The term "hypogonadotropic hypogonadism" describes an endocrine disorder the hypothalamus is largely unable to secrete gonadotropin-releasing hormone (GnRH). GnRH acts on the pituitary to stimulate the release of LH and FSH, which, in turn, induce the synthesis of androgens and estrogens in the adrenal glands and gonads. GnRH, LH, FSH, and the sex hormones are all part of the hypothalamic-pituitary-gonadal axis, which regulates the development of primary and secondary sexual characteristics. Patients with hypogonadotropic hypogonadism have low levels of LH, FSH, androgens, and estrogens, and they most commonly present with delayed or absent puberty. Males don't start shaving, fail to develop body hair, maintain prepubertal testes and a small penis. Females don't show breast development, and there's no onset of menstruation.
- Olfactory impairment is present from birth, but it is hardly noted until the patients themselves describe their inability to smell.
- Kallmann syndrome may be associated with additional anomalies, such as malformations of the digits, cleft lip or palate, and missing teeth.
Kallmann syndrome may be caused by mutations in different genes, and it is increasingly difficult to distinguish the types of Kallmann syndrome based on clinical and laboratory findings. The latter are indispensable to make a general diagnosis of Kallmann syndrome, but comprehensive genetic studies are required to determine the type of the disease. In about 10% of cases, mutations in the FGFR1 gene can be identified. The respective patients are diagnosed with Kallmann syndrome type 2.
- Costa-Barbosa FA, Balasubramanian R, Keefe KW, et al. Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. J Clin Endocrinol Metab. 2013; 98(5):E943-953.
- Zenaty D, Bretones P, Lambe C, et al. Paediatric phenotype of Kallmann syndrome due to mutations of fibroblast growth factor receptor 1 (FGFR1). Mol Cell Endocrinol. 2006; 254-255:78-83.
- Pitteloud N, Meysing A, Quinton R, et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 2006; 254-255:60-69.
- Lewkowitz-Shpuntoff HM, Hughes VA, Plummer L, et al. Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications. J Clin Endocrinol Metab. 2012; 97(1):E136-144.
- Raivio T, Sidis Y, Plummer L, et al. Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2009; 94(11):4380-4390.
- Topaloğlu AK. Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism. J Clin Res Pediatr Endocrinol. 2017; 9(Suppl 2):113-122.
- Sato N, Hasegawa T, Hori N, Fukami M, Yoshimura Y, Ogata T. Gonadotrophin therapy in Kallmann syndrome caused by heterozygous mutations of the gene for fibroblast growth factor receptor 1: report of three families: case report. Hum Reprod. 2005; 20(8):2173-2178.
- Meczekalski B, Podfigurna-Stopa A, Smolarczyk R, Katulski K, Genazzani AR. Kallmann syndrome in women: from genes to diagnosis and treatment. Gynecol Endocrinol. 2013; 29(4):296-300.
- Dodé C, Levilliers J, Dupont JM, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003; 33(4):463-465.
- Wierman ME, Kiseljak-Vassiliades K, Tobet S. Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function. Front Neuroendocrinol. 2011; 32(1):43-52.