Kallmann syndrome presents with the following features:

Respiratory: Lack of migration of olfactory neurons from olfactory epithelium leads to complete anosmia. Breathing is rarely affected.

Systemic: Delayed female puberty and secondary sexual characteristics are the chief complaints in Kallmann syndrome.

Urogenital: Delayed menarche and amenorrhea are common presentations of Kallmann syndrome in females and may lead to failure to conceive.

Musculoskeletal: Due to decreased sex hormones which play an important role in bone thickening, growth and muscle mass gain, the bones are usually of decreased density hence easily fractured. Recurring fractures may be a frequent presenting complaint, especially in females. The patients are also usually under weight

Complications

Complications commonly include the following:

Facial deformities: Of these, cleft lip and palate are the most prevalent. This is usually due to faulty migration of neural crest cells during embryonic development.
Auditory defects: In some cases neural hearing defects may also occur. These are rare but occurrence is also due to incomplete or improper migration of the cells of the first pharyngeal pouch.
Renal defects: Anosmin-1 is normally produced by the brain, mesonephros and metanephros. KS may accompany renal agenesis in which the symptoms will be more severe due to complete loss of Anosmin-1. Agenesis if present could be unilateral or bilateral, greatly increasing the mortality rate.
Bone defects: Osteoporosis due to decreased bone density may also be found.

Mortality 

Patients who do not have congenital heart disease or other neurologic manifestations concomitantly with Kallmann syndrome seem to live longer than those who do.

• Developmental Disorder

  CONTEXT: Kallmann syndrome (KS) is a genetically heterogeneous developmental disorder that associates hypogonadotropic hypogonadism and anosmia. [ncbi.nlm.nih.gov]

  Abstract Kallmann's syndrome is a hereditary developmental disorder characterized by anosmia and gonadotropin-releasing hormone (GnRH) deficiency. [repository.upenn.edu]

• Male Hypogonadism

  Male hypogonadism is characterized by impaired testicular function, which can affect spermatogenesis and/or testosterone synthesis. [dnatesting.uchicago.edu]

  Styne, Delayed Puberty and Hypogonadism, Male☆, Reference Module in Biomedical Sciences, 10.1016/B978-0-12-801238-3.04008-3, (2016). [doi.org]

  Establishing the cause of hypogonadism is an important first step to getting appropriate treatment. Causes Male hypogonadism means the testicles don't produce enough of the male sex hormone testosterone. [mayoclinic.org]

  Congenital Hypogonadotropic Hypogonadism (CHH) is a developmental disorder caused by gonadotropin-releasing hormone (GnRH) deficiency leading to a lack of production of sex hormones (testosterone in males and oestrogens in females). [endo-ern.eu]

• Short Stature

  Clinical aspects Highly variable, but characterized by GnRH deficiency with hypogonadotropic hypogonadism, delayed incomplete or absent puberty, short stature, and smelling deficiencies. [accessanesthesiology.mhmedical.com]

  stature Kallmann syndrome: anosmia, absent breast development, uterus is present, syndactyly, cleft palate or lip Prader-Willi syndrome: muscular hypotonia, short stature, facial dysmorphia Gaucher's disease: hepatomegaly, splenomegaly, painful bone [amboss.com]

  Short stature (in some cases). Anosmia (in some cases). Kallmann syndrome symptoms in adults may include: Decreased energy or fatigue. Weight gain. Mood changes. Decrease or loss of menstrual periods in females. Low sex drive in males. Infertility. [my.clevelandclinic.org]

  stature (Laron syndrome, Psychogenic dwarfism) - Multiple endocrine neoplasia (1, 2) - Progeria - Woodhouse-Sakati syndrome de:Kallmann-Syndrom it:Sindrome di Kallmann he:תסמונת קלמן nl:Syndroom van Kallmann fi:Kallmannin oireyhtymä Template:WikiDoc [wikidoc.org]

• Rigor

  Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. [blueprintgenetics.com]

  She gave no history of extreme dieting, sudden weight loss or weight gain, bulimia or rigorous exercise. She was not on any medication. An USG of lower abdomen was done which confirmed presence of uterus and ovaries. [omicsonline.org]

  Suyuti (d. 1505CE) believed that exegesis should be rigorous to avoid misunderstanding. [flickr.com]

• Delayed Female Puberty

  Systemic: Delayed female puberty and secondary sexual characteristics are the chief complaints in Kallmann syndrome. [symptoma.com]

• Anosmia

  Reference article, Radiopaedia.org (Accessed on 28 Mar 2023) https://doi.org/10.53347/rID-6084 Kallmann syndrome is a rare genetic disorder characterized by hypogonadotropic hypogonadism associated with anosmia or hyposmia. [radiopaedia.org]

  However, intrafamilial heterogeneity is also seen.6 The cases reported here showed the main two clinical characteristics, hypogonadism and anosmia.1 A detailed clinical history with a special focus on anosmia suggested the diagnosis. [elsevier.es]

  In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. [genecards.org]

  Our patient had complete anosmia like that of Persson et al [ 22 ]. In a series of 6 patients reported in Jordan 4 had anosmia and 2 had hyposmia [ 25 ]. [omicsonline.org]

• Hyposmia

  In patients with hyposmia, smell tests are often difficult to interpret. [elsevier.es]

  When CHH is accompanied by a defective sense of smell (anosmia or hyposmia), it is termed Kallmann syndrome (KS) and results from incomplete embryonic migration of GnRH-synthesizing neurons. [dnatesting.uchicago.edu]

  OBJECTIVE: Kallmann syndrome (KS) is a genetic disorder with the distinctive features of hyposmia or anosmia and hypogonadotropic hypogonadism. [ncbi.nlm.nih.gov]

• Parosmia

  […] detect air-borne chemicals, and an adenovirus was used to implant a working version of the IFT88 gene into defective cells in the nose, which restored the cilia and allowed a sense of smell. [35] [36] See also [ edit ] Phantosmia Hyperosmia Hyposmia Parosmia [en.wikipedia.org]

• Cryptorchidism

  Occasionally the diagnosis is made earlier due to investigation of other associated anomalies, including: midline defects (e.g. cleft lip and palate) cryptorchidism renal agenesis sensorineural deafness enlarged paranasal sinuses (especially ethmoidal [radiopaedia.org]

  The prevalence of cryptorchidism was high (38.1%) and occurred in patients with different kind of ANOS1 mutations, while the patients with the same mutation did not present with cryptorchidism uniformly. [ncbi.nlm.nih.gov]

  The final diagnosis was made only when they were aged between 17 and 26 (mean 21 years), although they had been seen by several physicians before: 3 for cryptorchidism and 3 for absence of spontaneous puberty; 2 had a positive family history, and 4 of [nature.com]

  On examination we found cryptorchidism, micropenis and absence of secondary sex characteristics. [endocrine-abstracts.org]

• Amenorrhea

  Bone densitometry: It is recommended for all hypogonadal patients, including those with Kallmann syndrome, IHH, or hypothalamic amenorrhea. [flipper.diff.org]

  By contrast, our second patient consulted a doctor at 18 years of age, but the etiology of primary amenorrhea was not investigated at the time, and was simply treated as a symptom. [elsevier.es]

  A 32 yr old woman came to the hospital with a history of treatment for primary amenorrhea once in 2007. Diagnosis of Kallmann syndrome was made based on her complaint of amenorrhea and anosmia. [knepublishing.com]

  These females, aged at 20 and 29-year-old, presented primary amenorrhea with prepubertal estradiol and low gonadotropin levels. No other significant clinical signs were observed. Empty sella was observed on MRI in both cases. [ncbi.nlm.nih.gov]

  Characteristic features in males include testicular hypoplasia, gynecomastia, and absent facial hair growth, while females commonly present with amenorrhea. [amboss.com]

• Primary Amenorrhea

  By contrast, our second patient consulted a doctor at 18 years of age, but the etiology of primary amenorrhea was not investigated at the time, and was simply treated as a symptom. [elsevier.es]

  These females, aged at 20 and 29-year-old, presented primary amenorrhea with prepubertal estradiol and low gonadotropin levels. No other significant clinical signs were observed. Empty sella was observed on MRI in both cases. [ncbi.nlm.nih.gov]

  Untreated adult females almost always experience primary amenorrhea with absent, little or normal breast development. [orpha.net]

• Delayed Menarche

  Urogenital: Delayed menarche and amenorrhea are common presentations of Kallmann syndrome in females and may lead to failure to conceive. [symptoma.com]

  Among atypical symptoms of CD, disorders of fertility, such as delayed menarche, early menopause, amenorrhea or infertility, and pregnancy complications, such as recurrent abortions, intrauterine growth restriction (IUGR), small for gestational age (SGA [en.wikipedia.org]

A complete work up is necessary before establishing a diagnosis of Kallmann syndrome. This includes the following:

Imaging

X-rays of upper and lower limbs show decreased bone mass and density indicating a probable underlying hormone deficiency. CT scans may indicate delayed bone age.

Hormone evaluation

For narrowing down the underline cause between probable suspects like hypothalamus, pituitary gland and the gonads themselves, hormone evaluation is vital.

Physical examination

A thorough physical examination may reveal micropenis and lack of pubic hair in males and incomplete breast enlargement in females. CT scans may reveal testicular agenesis or cryptorchidism in males and abnormally small ovaries and an immature uterine tract in females.

• Delayed Bone Age

  This includes the following: Imaging X-rays of upper and lower limbs show decreased bone mass and density indicating a probable underlying hormone deficiency. CT scans may indicate delayed bone age. [symptoma.com]

• Testosterone Decreased

  As testosterone decreases, some men may experience symptoms similar to those of menopause in women. [mayoclinic.org]

The treatment plan includes genetic counselling of affected individuals and the family involved, explaining the disease and the accompanying problems they may face. The second step is hormone replacement therapy which, studies show, has been observed to be beneficial [7]. Complications such as facial deformities may be corrected by surgical means.

The disease is present at birth with progressively evident features. Initially there is agenesis of ovaries in females and testes in males with accompanying hypogenesis of external genitalia. As the individual grows, there is marked increase in height and stature due to delayed closure of epiphyseal plates.

Puberty is late in onset and secondary sexual characteristics are poorly defined, for example, lack of facial and axillary hair, enlargement of larynx and deepening of voice, heavier bone structure and increased muscle mass due to lack of testosterone in males and lack of breast enlargement, growth of axillary and pubic hair, widening of hips and increased subcutaneous fat deposition due to decreased estrogen in females.

As the age progresses, more serious effects are seen like erectile dysfunction and oligospermia in males and amenorrhea and infertility in females.

Mutations in various genes play a vital role in the development of Kallmann syndrome, and as the gene in question varies, so does the pattern of inheritance [1] [2] [3] [4] [5].

KAL1 

The first causative gene is the KAL1 gene on locus Xp22.3 which encodes the synthesis of Anosmin-1 which is a neural cell adhesion molecule. This molecule is necessary for the embryonic migration of two chief factors: olfactory neurons and GnRH synthesizing neurons. A mutation in KAL1 results in incomplete migration of olfactory neurons from the olfactory bulbs to the hypothalamus, a defect which leads to slight or usually, complete loss of smell. The external and internal nares as well as the rest of the anatomical structure of the nasal cavity are normal but a lack of sensory neurons cause significant anosmia in both affected males and females.

The second factor promoted by Anosmin-1 is the migration of GnRH synthesizing neurons to the hypothalamus. A mutation in KAL1 causes a migratory defect causing decreased or in severe cases, absent production of GnRH, which in return presents as hypogonadism, late onset of puberty, diminished libido and infertility. KAL1 mutations are inherited by an X-linked recessive pattern, thus affecting males more.

KAL2 

The second mutation that may cause Kallmann syndrome (KAL2) occurs in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene on chromosome 8. The pattern of inheritance is autosomal dominant. This presentation is rare, evident in only 10% of cases.

KAL3 

Another extremely uncommon autosomal dominant form of Kallmann syndrome (KAL3) is a result of mutations in the Prokineticin receptor-2 gene (PROK2). However, a slight variation in symptoms has been observed in this form.

Others 

Defects in some other ligands like TAC3, LEP, GnRH1 etc have also been indicated in the pathogenesis of Kallmann syndrome.

Kallmann syndrome is a rare genetic disorder which shows a predisposition in male children affecting 1:8000 males and 1:40.000 females. In strictly familial Kallmann syndrome, the male-to-female ratio is 2.5:1.

A decrease in GnRH from the hypothalamus causes diminished synthesis and release of Luteinising hormone and Follicle stimulating hormone from the pituitary gland. A decrease in these hormones cause delayed onset of puberty, small non-functional gonads leading to decreased levels of sex hormones, lack of secondary sexual characters, prolonged and sometimes abnormal growth, decreased bone density and muscle mass. Affected patients are infertile [6].

Kallmann syndrome is the result of a genetic defect. To prevent mutations, life style changes may be advised such as avoidance of harmful radiation, exposure to radioactive substances and in the case of pregnant females, safeguarding against teratogens.

Kallmann syndrome is a congenital disease associated with complete absence or partial decrement of Gonadotropin releasing hormone (GnRH) from the hypothalamus. This isolated GnRH deficiency results in hypogonadism and consequent infertility.

Major symptoms also include partial or complete anosmia. The anosmia is due to a defect in the development of olfactory bulbs leading to progressive decrease in perception of smell. This disease, although present from birth, may not be evident at first but can be suspected in the case of abnormally small genitalia, as observed in male infants.

Definition 

Kallmann syndrome is a genetic disease which results in loss of smell, delayed puberty, bone and muscle weakness and infertility.

Types

Kallmann syndrome is of 3 major types of which the first one, known as KAL1, is the most common. It is inherited from parent to son, having a chance of 1 in 4 children of being affected.

Prevention

As the defect lies in the mutated genes, prevention is essential. Protecting and safeguarding oneself from harmful radiation, radioactive substances, high exposure to ultra violet light and toxic chemicals can prevent the occurrence of Kallmann syndrome.

KS and pregnancy

Special care should be taken by pregnant women to avoid mutations occurring in the fetus. Some drugs like tetracyclines, aminoglycosides, etc should be avoided as well as alcohol intake, exposure to radiation and other toxic substances.

Treatment

The disease itself can be managed with symptomatic treatment. Hormone therapy is initiated to treat the delayed, and often incomplete, attaining of puberty. Administration of sex hormones can reverse the infertility in both males and females, leading to successful conception. Vitamins may be given to strengthen bones and muscles.

Summary

Kallmann syndrome is treatable but not curable. This disease occurs at birth and persists for life. Male infants are especially vulnerable to it. However, its negative effects may be reversed or at least significantly improved by regular treatment and counselling.

1. Dode C, Levilliers J, Dupont JM, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. Apr 2003;33(4):463-5
2. Monnier C, Dode C, Fabre L, et al. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling-activity. Hum Mol Genet. Sep 29 2008
3. Canto P, Munguía P, Söderlund D, et al. Genetic analysis in patients with Kallmann syndrome: coexistance of mutations in prokineticin receptor 2 and KAL1. J Androl. Aug 21 2008
4. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. Oct 23 2003;349(17):1614-27
5. Trarbach EB, Silveira LG, Latronico AC. Genetic insights into human isolated gonadotropin deficiency. Pituitary. 2007;10(4):381-91
6. Layman LC. The molecular basis of human hypogonadotropic hypogonadism. Mol Genet Metab. Oct 1999;68(2):191-9
7. Hoffman AR, Crowley WF Jr. Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med. Nov 11 1982;307(20):1237-41