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Autosomal Recessive Kallmann Syndrome Type 3

Kallmann syndrome type 3 (KS3) is a type of congenital hypogonadotropic hypogonadism with anosmia. It is caused by mutations in the PROKR2 gene and typically manifests in absent puberty and olfactory impairment. Additional symptoms are rare and non-specific, possibly comprising kyphosis or scoliosis, excessive joint mobility, and synkinesia. Most KS3 patients respond well to hormonal therapy, develop normal sexual characteristics, and may even have children.


Presentation

KS3 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 rare exception to this rule: KS3 may be related to a high-arched palate, kyphosis or scoliosis, excessive joint mobility, and pes planus, and the co-occurrence of these anomalies may hint at a hereditary condition. Synkinesia has occasionally been described in all types of Kallmann syndrome, but is more frequently seen in patients with KS3, where about 26% are affected. Hearing loss and epilepsy have been described in a minor share of patients [1] [2]. While obesity and sleeping disorders are non-specific findings, the combination of these symptoms with any of the aforementioned abnormalities should raise suspicion as to a genetic disorder like KS3 [3].

With regard to hypogonadotropic hypogonadism, absent or delayed puberty is the most frequent finding. KS3 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 the rare mild cases, it may be the presenting symptom. Of note, KS3 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 [2].

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 94% of KS3 patients are anosmic, while 6% suffer from hyposmia [2].

High Arched Palate
  • Kallmann syndrome may be associated with additional anomalies, such as a high-arched palate, deviations of the curvature of the spine, excessive joint mobility, involuntary muscle contractions, and sleeping disorders.[symptoma.com]
Hearing Impairment
  • Rare presentations include unilateral (occasionally bilateral and lethal at birth) renal agenesis, hearing impairment, cleft lip or palate, dental agenesis or bimanual synkinesis persisting beyond childhood.[orpha.net]
  • Showing of 16 5%-29% of people have these symptoms Hearing impairment Deafness Hearing defect [ more ] 0000365 Seizures Seizure 0001250 Percent of people who have these symptoms is not available through HPO Anosmia Lost smell 0000458 Autosomal dominant[rarediseases.info.nih.gov]
Short Arm
  • Deletion mapping and positional cloning efforts in the distal short arm of the X chromosome (Xp22.3) led to the isolation of the gene involved in the X-linked type of Kallmann syndrome ( Kallmann syndrome protein or gene symbol, respectively (KAL) ) ([ommbid.mhmedical.com]
  • This gene is located on the short arm of chromosome 20 and encodes for prokineticin receptor 2, an integral membrane protein and G protein-coupled receptor whose activation triggers the mobilization of calcium, phosphoinositide turnover, and p44/p42 MAP[symptoma.com]
Long Arm
  • 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.[symptoma.com]
Hyposmia - Anosmia
  • 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]
Involuntary Movements
  • When involuntary movement of the homologous finger of the other hand was noted, MM was assessed as positive.[ajnr.org]

Workup

KS2 is inherited in an autosomal dominant manner, but incomplete penetrance may hamper the identification of the mode of inheritance [2]. Asymptomatic carriers have been reported on more than one occasion [4] [5], and despite KS3 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 [6]. Of note, mutations in the PROKR2 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 occurrence sense of smell is no exclusion criterion for pituitary disorders due to pathogenic variants of PROKR2.

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 [7]. Screening for particular genotypes should thus be prioritized according to the presence of certain clinical features and imaging findings: Synkinesia, kyphosis or scoliosis, and excessive joint mobility may be observed in patients with distinct types of Kallmann syndrome, but are more commonly reported in those with KS3, Kallmann syndrome type 4, and Kallmann syndrome type 1. These features may thus be helpful to distinguish KS2 from other types of Kallmann syndrome and to focus genetic studies [2].

Treatment

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 [8].

Males and females with KS3 have been shown to respond well to hormone replacement therapy, and fertility has successfully been induced in patients of either sex [2] [5]. Furthermore, at least one patient achieved sustained reversal of KS2, i.e., he was able to maintain physiological levels of testosterone after the discontinuation of hormonal therapy [1] [9]. Notwithstanding, 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.

Orthopedic comorbidities and further birth defects require symptomatic treatment according to the respective guidelines; causal therapy is not available.

Prognosis

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. KS3 patients have been successfully treated with GnRH, gonadotropins, and sex hormones, and have had healthy children.

Etiology

KS3 has been related to mutations in the PROKR2 gene. This gene is located on the short arm of chromosome 20 and encodes for prokineticin receptor 2, an integral membrane protein and G protein-coupled receptor whose activation triggers the mobilization of calcium, phosphoinositide turnover, and p44/p42 MAP kinase signaling. Pathogenic mutations of PROKR2 have mainly been identified in exons 1 and 2, are usually missense mutations, and most patients are heterozygous for these gene defects [10]. KS3 has therefore been classified as an autosomal dominant disorder.

Notwithstanding, pedigree analyses have repeatedly put into question the mode of inheritance: Homozygosity has been described in several cases, and heterozygous individuals may be asymptomatic [4] [5]. It should also be noted that mutations in PROKR2 are often found in combination with sequence anomalies in other genes, thus giving rise to mixed-type Kallmann syndrome with oligogenic inheritance [7].

Epidemiology

The total prevalence of Kallmann syndrome has been estimated at 1 in 10,000 men and 1 in 50,000 women. About 5-10% of these cases are attributed to impaired signaling via the PROK2/PROKR2 pathway, which is affected in KS3 and Kallmann syndrome type 4 [8]. Other sources indicate the proportion of KS3 among all cases of Kallmann syndrome as 7 or 4% [10] [11]. The gender distribution in KS3 resembles that of Kallmann syndrome in general [3], but while some types of Kallmann syndrome are inherited in an X-linked manner and thus preferentially affect males, this does not apply to KS3. The exact reason for the male predominance in KS3 remains unknown, but underdiagnosis and lower penetrance in females have been discussed as possible causes.

Sex distribution
Age distribution

Pathophysiology

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.

PROK2/PROKR2 signaling plays a key role in the development of the olfactory bulb and the migration of GnRH and olfactory neurons along the olfactory nerve pathway: Both types of cells are to migrate across the cribriform plate towards the developing olfactory bulb and, in case of neurons expressing GnRH, continue their journey to the arcuate nucleus of the hypothalamus. Accordingly, deficiency for PROKR2 in mice is associated with a dramatic decrease in the GnRH neuron population in the hypothalamus, and these animals show hypogonadotropic hypogonadism [8].

With regard to the underlying molecular mechanisms, PROKR2 mutations identified in KS3 patients could be shown to affect cell surface-targeting of the receptor, coupling to G proteins, and receptor-ligand interaction [10].

Prevention

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.

Summary

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, KS3 is related to mutations in the PROKR2 gene, which encodes for prokineticin receptor 2. The clinical presentation of KS3 is little specific and rather corresponds to the classical picture of Kallmann syndrome:

Patient Information

Kallmann syndrome refers to those types of congenital hypogonadotropic hypogonadism that are associated with deficiencies in the sense of smell:

  • 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 a high-arched palate, deviations of the curvature of the spine, excessive joint mobility, involuntary muscle contractions, and sleeping disorders.

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 5% of cases, mutations in the PROKR2 gene can be identified. The respective patients are diagnosed with Kallmann syndrome type 3.

References

Article

  1. Cole LW, Sidis Y, Zhang C, et al. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab. 2008; 93(9):3551-3559.
  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.
  3. Sarfati J, Guiochon-Mantel A, Rondard P, et al. A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes. J Clin Endocrinol Metab. 2010; 95(2):659-669.
  4. Abreu AP, Trarbach EB, de Castro M, et al. Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab. 2008; 93(10):4113-4118.
  5. Pitteloud N, Zhang C, Pignatelli D, et al. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2007; 104(44):17447-17452.
  6. 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.
  7. Topaloğlu AK. Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism. J Clin Res Pediatr Endocrinol. 2017; 9(Suppl 2):113-122.
  8. 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.
  9. Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007; 357(9):863-873.
  10. Dodé C, Rondard P. PROK2/PROKR2 Signaling and Kallmann Syndrome. Front Endocrinol (Lausanne). 2013; 4:19.
  11. 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.

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Last updated: 2019-07-11 20:38