Kallmann Syndrome


Article Author:
James Sonne


Article Editor:
Wilfredo Lopez-Ojeda


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
2/20/2019 11:29:24 AM

Introduction

Kallmann Syndrome (KS) is a congenital form of hypogonadotropic hypogonadism (HH) that manifests with hypo- or anosmia. This decrease in gonadal function is due to a failure in the differentiation or migration of neurons that arise embryologically in the olfactory mucosa to take up residence in the hypothalamus serving as gonadotropin-releasing hormone (GnRH) neurons. A deficit in the GnRH hormone results in decreased levels of sex steroids leading to a lack of sexual maturity and the absence of secondary sexual characteristics. Typical diagnosis occurs when a child fails to begin puberty. The condition, first described in 1944, is a rare pediatric genetic disease that is estimated to affect 1 in 48,000 individuals [1].  Treatment involves life-long hormone replacement therapy. However, treatment for male infants may include early hormone treatment or surgery to correct undescended testicles [2].  Unfortunately, later in life, these patients have an increased risk for developing osteoporosis due to their decreased sex hormones production and are often prescribed Vitamin D supplementation and bisphosphonates [3]

Kallmann syndrome, like other HH conditions, is characterized by reproductive features centered around a lack of sexual maturation during the years of puberty. These signs can include a lack of testicular development as determined by testicular volume in men, and a failure to start menstruation (amenorrhoea) in women.  Poorly defined secondary sexual characteristics can include a lack of pubic hair and underdeveloped mammary glands.  Micropenis may also be present in a small portion of male cases, while cryptorchidism or undescended testicles may have been present at birth. All of these traits are related to low levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which consequentially results in low testosterone in males and estrogen and progesterone in women [2].

In addition to the reproductive deficits of HH conditions, there will also be the presence of other non-reproductive characteristics which are often defects of embryological origin. KS is defined by its additional presentation of anosmia or hyposmia.  Approximately 60% of patients with GnRH deficiency present with an impaired sense of smell and could be identified as having KS, cleft palate and lip, hypodontia and cleft hand or foot are also frequently present along with unilateral renal agenesis [4]. Cerebral impairments may also be present, including central hearing impairment, mirror movements of the hands (synkinesis) and ataxia. Color-blindness and ocular window defects have also been observed [5][6].

Etiology

Fundamentally, KS is the result of a defect in the GnRH neurons of the hypothalamus or their differentiation and migration to the hypothalamus during embryonic development. The cause of this condition is genetic but can be the result of a multitude of different genetic mutations. Mutations in approximately 40 different genes have been reported to be connected with HH conditions including KS and present with slight variations in secondary features. The most common defects related to KS are in the genes ANOS1 and FGFR1, but approximately 35 to 45% of cases are not explained by the currently identified genetic abnormalities [7].  Clinical genetic testing can be used to determine the specific genes involved in an individual patient. 

One gene of particular interest is the KISS1 gene encoding the kisspeptin signaling molecule. Kisspeptin is a potent initiator of the production of GnRH in the hypothalamus, and its production is known to be impacted by environmental factors [8].

Epidemiology

One study of Kallmann Syndrome in Finland estimated the incidence of the condition within that country to be 1 in 48,000. The condition is genetic and often X-linked, resulting in increased prevalence among males.  Approximately 1 in 30,000 males has the condition compared to 1 in 125,000 females[1][9].

Pathophysiology

The KISS1/Kiss1 gene, which encodes for the kisspeptin hormone, is a well-known regulator of reproductive hormones, specifically acting upstream of GnRH [10][11]. Studies indicate that in some cases of HH, patients present with deletions and point mutations in the KISS1R [12][13]. The kisspeptin neuronal network” (KP) reside within the hypothalamus preoptic (POA) and the infundibular (INF) nuclei, respectively [14][12][13]. This elegant neuronal circuit regulates puberty and human reproductive functions by signaling GnRH secretion, subsequentially controlling FSH And LH. The cranial nerve zero (0) has been described in the literature as an innocuous neuroanatomical structure associated with GnRH and potentially involved in the regulation of human reproductive functions and behaviors[15][16]. Perhaps, the CN0's GnRH axons not only play a critical role in the development and differentiation of the HPA axis but may also trigger conceptually exhilarating endocrinologic responses independently or together with the KP neural circuit[15][16].

History and Physical

Medical history and genetic testing will often reveal many of the primary reproductive features of HH described above, along with non-reproductive features which will assist in differentiating between forms of HH such as KS with its characteristic deficit in the sense of smell. 

Evaluation

Evaluation usually occurs in conjunction with the first complaint of delayed development of adolescent puberty. Constitutionally delayed puberty or constitutional growth delay with prepubertal body proportions can be a normal condition that corrects itself through later onset of puberty and may be caused by some genetic and environmental factors.  During the evaluation of such patients, laboratory tests should be conducted to exclude hormonal deficiencies and other systemic syndromes. Thyroxine and thyroid-stimulating hormone (TSH) levels, along with IGF-1 and gonadotropin levels (LH and FSH) would be normal with skeletal age in constitutionally delayed growth conditions but may be outside of the normal range in patients with a genetic disease. Urinalysis and routine blood work could also be used to screen these patients to identify inflammatory or autoimmune disorders.  Also of note, patients that manage chronic pain with opioids have an increased association with induced hypogonadism later in life[17].

Treatment / Management

Kallmann Syndrome is usually treated pharmacologically with steroid replacement therapy such as testosterone or estrogen-progestin supplementation. Fertility can be increased using gonadotropin-based pharmacologic options. Complications of the condition may include osteoporosis, cardiac diseases, and psychological or neurological disorders and consultations with appropriate specialists should be considered if indicated.  Such associated conditions may show the need for dietary supplementation or physical therapy-based rehabilitation, among others.

Differential Diagnosis

Once laboratory testing has identified deviations in hormone levels, a genetic evaluation may narrow down the list of possible hypogonadotropic hypogonadism syndromes.  Kallmann syndrome is unique in that it is a hypogonadotropic hypogonadism syndrome characterized by hyposmia or anosmia.

Prognosis

Kallmann syndrome alone is not associated with decreased life expectancy, but the possible association with heart conditions, osteoporosis, and reduced fertility may impact the patient’s health and longevity separately. 

Complications

A variety of congenital heart disorders are reported in a small subset of KS patients, along with osteoporosis. The developmental of bone malformation is also possible and would be recognized from birth, such as cleft palate. Dry skin is also a potential complication of hypogonadic conditions such as KS. A patient may have had treatment for adrenocortical insufficiency in infancy or childhood.

Deterrence and Patient Education

There are reports of reversal of HH [18], but Kallmann syndrome is a life-long condition requiring steroid replacement therapy.  Adrenocortical insufficiency may impact a patient’s ability to work.  The impact of activity levels is vital in patients with associated heart disease and osteoporosis.

Enhancing Healthcare Team Outcomes

A delay in the initiation of puberty is often first noticed by a child’s parents in consultation with a pediatrician or family practice physician.  In addition to the reproductive features of Kallmann Syndrome, if one or more of the non-reproductive manifestations are present, then a referral to a reproductive endocrinologist should be considered [19].


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Kallmann Syndrome - Questions

Take a quiz of the questions on this article.

Take Quiz
Anosmia is associated with which of the following disorders?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which one of the following is expected in Kallmann syndrome?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Kallmann syndrome is characterized by gonadotropin deficiency. Which other clinical presentations are present?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 17-year-old male is referred to an endocrinologist for evaluation of delayed puberty. The patient gives a history of an impaired sense of smell since childhood. His vital signs are normal. Physical examination reveals sparse facial, pubic, and axillary hair, rounded body contour, and under-developed genitalia. A hormonal assay shows low luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels but normal thyroid hormone levels. What is the most likely diagnosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Kallmann Syndrome - References

References

Laitinen EM,Vaaralahti K,Tommiska J,Eklund E,Tervaniemi M,Valanne L,Raivio T, Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet journal of rare diseases. 2011 Jun 17;     [PubMed]
Boehm U,Bouloux PM,Dattani MT,de Roux N,Dodé C,Dunkel L,Dwyer AA,Giacobini P,Hardelin JP,Juul A,Maghnie M,Pitteloud N,Prevot V,Raivio T,Tena-Sempere M,Quinton R,Young J, Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Nature reviews. Endocrinology. 2015 Sep;     [PubMed]
Iolascon G,Frizzi L,Bianco M,Gimigliano F,Palumbo V,Sinisi AM,Sinisi AA, Bone involvement in males with Kallmann disease. Aging clinical and experimental research. 2015 Oct;     [PubMed]
Balasubramanian R,Crowley WF Jr, Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency 1993;     [PubMed]
Kim SH, Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future. Endocrinology and metabolism (Seoul, Korea). 2015 Dec;     [PubMed]
Lima Amato LG,Latronico AC,Gontijo Silveira LF, Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism. Endocrinology and metabolism clinics of North America. 2017 Jun;     [PubMed]
Vezzoli V,Duminuco P,Bassi I,Guizzardi F,Persani L,Bonomi M, The complex genetic basis of congenital hypogonadotropic hypogonadism. Minerva endocrinologica. 2016 Jun;     [PubMed]
Rhie YJ, Kisspeptin/G protein-coupled receptor-54 system as an essential gatekeeper of pubertal development. Annals of pediatric endocrinology     [PubMed]
McCabe MJ,Bancalari RE,Dattani MT, Diagnosis and evaluation of hypogonadism. Pediatric endocrinology reviews : PER. 2014 Feb;     [PubMed]
AminiLari M,Manjoo P,Craigie S,Couban R,Wang L,Busse JW, Hormone Replacement Therapy and Opioid Tapering for Opioid-Induced Hypogonadism Among Patients with Chronic Noncancer Pain: A Systematic Review. Pain medicine (Malden, Mass.). 2018 May 2;     [PubMed]
Pierzchlewska MM,Robaczyk MG,Vogel I, Induction of puberty with human chorionic gonadotropin (hCG) followed by reversal of hypogonadotropic hypogonadism in Kallmann syndrome. Endokrynologia Polska. 2017;     [PubMed]
Cioppi F,Riera-Escamilla A,Manilall A,Guarducci E,Todisco T,Corona G,Colombo F,Bonomi M,Flanagan CA,Krausz C, Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature. Andrology. 2019 Jan     [PubMed]
Comninos AN,Dhillo WS, Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing. Neuroendocrinology. 2018     [PubMed]
Mills EGA,Dhillo WS,Comninos AN, Kisspeptin and the control of emotions, mood and reproductive behaviour The Journal of endocrinology. 2018 Oct 1     [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Surgery-Urologic. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Surgery-Urologic, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Surgery-Urologic, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Surgery-Urologic. When it is time for the Surgery-Urologic board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Surgery-Urologic.