Continuing Education Activity

Kallmann Syndrome (KS) is a congenital hypogonadotropic hypogonadism (HH) 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 estimated to affect 1 in 48,000 individuals. Treatment involves life-long hormone replacement therapy. However, treatment for male infants may include early hormone treatment or surgery to correct undescended testicles. 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. This activity reviews the evaluation and treatment of Kallmann syndrome and discusses the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe how Kallmann syndrome typically presents.
• Explain the pathophysiology of Kallmann syndrome.
• Outline the treatment for Kallmann syndrome.
• Summarize the role of the interprofessional team in managing patients with this condition.

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. First described in 1944, the condition is a rare pediatric genetic disease 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 of developing osteoporosis due to decreased sex hormones production and are often prescribed Vitamin D supplementation and bisphosphonates.[3] 

Like other HH conditions, Kallmann syndrome 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 determined by testicular volume in men and a failure to start menstruation (amenorrhea) 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. 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 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 have 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 the 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, patients who 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 separately impact the patient’s health and longevity. 

Complications

A variety of congenital heart disorders are reported in a small subset of patients with KS, 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] Nurses assist with patient evaluation and monitoring. Pharmacists review medications and check for drug interactions. Communication between members of this interprofessional team will improve outcomes. [Level 5]

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References

1.

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 J Rare Dis. 2011 Jun 17;6:41. [PMC free article: PMC3143089] [PubMed: 21682876]

2.

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. Nat Rev Endocrinol. 2015 Sep;11(9):547-64. [PubMed: 26194704]

3.

Iolascon G, Frizzi L, Bianco M, Gimigliano F, Palumbo V, Sinisi AM, Sinisi AA. Bone involvement in males with Kallmann disease. Aging Clin Exp Res. 2015 Oct;27 Suppl 1:S31-6. [PubMed: 26201943]

4.

Balasubramanian R, Crowley WF. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews^® [Internet]. University of Washington, Seattle; Seattle (WA): May 23, 2007. [PMC free article: PMC1334] [PubMed: 20301509]

5.

Kim SH. Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future. Endocrinol Metab (Seoul). 2015 Dec;30(4):456-66. [PMC free article: PMC4722398] [PubMed: 26790381]

6.

Lima Amato LG, Latronico AC, Gontijo Silveira LF. Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism. Endocrinol Metab Clin North Am. 2017 Jun;46(2):283-303. [PubMed: 28476224]

7.

Vezzoli V, Duminuco P, Bassi I, Guizzardi F, Persani L, Bonomi M. The complex genetic basis of congenital hypogonadotropic hypogonadism. Minerva Endocrinol. 2016 Jun;41(2):223-39. [PubMed: 26934720]

8.

Rhie YJ. Kisspeptin/G protein-coupled receptor-54 system as an essential gatekeeper of pubertal development. Ann Pediatr Endocrinol Metab. 2013 Jun;18(2):55-9. [PMC free article: PMC4027097] [PubMed: 24904852]

9.

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;7(1):88-101. [PubMed: 30575316]

10.

Comninos AN, Dhillo WS. Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing. Neuroendocrinology. 2018;106(2):195-202. [PubMed: 28866668]

11.

Mills EGA, Dhillo WS, Comninos AN. Kisspeptin and the control of emotions, mood and reproductive behaviour. J Endocrinol. 2018 Oct 01;239(1):R1–R12. [PubMed: 30306845]

12.

Hrabovszky E. Neuroanatomy of the human hypothalamic kisspeptin system. Neuroendocrinology. 2014;99(1):33-48. [PubMed: 24401651]

13.

Mikkelsen JD, Simonneaux V. The neuroanatomy of the kisspeptin system in the mammalian brain. Peptides. 2009 Jan;30(1):26-33. [PubMed: 18840491]

14.

Lehman MN, Hileman SM, Goodman RL. Neuroanatomy of the kisspeptin signaling system in mammals: comparative and developmental aspects. Adv Exp Med Biol. 2013;784:27-62. [PMC free article: PMC4059209] [PubMed: 23550001]

15.

Sonne J, Reddy V, Lopez-Ojeda W. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 20, 2023. Neuroanatomy, Cranial Nerve 0 (Terminal Nerve) [PubMed: 29083731]

16.

Sonne J, Lopez-Ojeda W. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Dec 9, 2022. Neuroanatomy, Cranial Nerve. [PubMed: 29261885]

17.

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 Med. 2019 Feb 01;20(2):301-313. [PubMed: 29727002]

18.

Pierzchlewska MM, Robaczyk MG, Vogel I. Induction of puberty with human chorionic gonadotropin (hCG) followed by reversal of hypogonadotropic hypogonadism in Kallmann syndrome. Endokrynol Pol. 2017;68(6):692-696. [PubMed: 29022642]

19.

McCabe MJ, Bancalari RE, Dattani MT. Diagnosis and evaluation of hypogonadism. Pediatr Endocrinol Rev. 2014 Feb;11 Suppl 2:214-29. [PubMed: 24683946]

20.

Swee DS, Quinton R, Maggi R. Recent advances in understanding and managing Kallmann syndrome. Fac Rev. 2021;10:37. [PMC free article: PMC8130407] [PubMed: 34046641]

21.

López-Ojeda W, Hurley RA. Cranial Nerve Zero (CN 0): Multiple Names and Often Discounted yet Clinically Significant. J Neuropsychiatry Clin Neurosci. 2022 Spring;34(2):A4-99. [PubMed: 35491548]

22.

Amato E, Taroc EZM, Forni PE. Illuminating the terminal nerve: Uncovering the link between GnRH-1 neuron and olfactory development. J Comp Neurol. 2024 Mar;532(3):e25599. [PMC free article: PMC10958589] [PubMed: 38488687]

23.

Kirsch CFE, Khurram SA, Lambert D, Belani P, Pawha PS, Alipour A, Rashid S, Herb MT, Saju S, Zhu Y, Delman BN, Lin HM, Balchandani P. Seven-tesla magnetic resonance imaging of the nervus terminalis, olfactory tracts, and olfactory bulbs in COVID-19 patients with anosmia and hypogeusia. Front Radiol. 2024;4:1322851. [PMC free article: PMC11473298] [PubMed: 39410969]

24.

Hayes F, Dwyer A, Pitteloud N. Hypogonadotropic Hypogonadism (HH) and Gonadotropin Therapy. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. MDText.com, Inc.; South Dartmouth (MA): Nov 25, 2013. [PubMed: 25905304]

25.

Patti G, Guzzeti C, Di Iorgi N, Maria Allegri AE, Napoli F, Loche S, Maghnie M. Central adrenal insufficiency in children and adolescents. Best Pract Res Clin Endocrinol Metab. 2018 Aug;32(4):425-444. [PubMed: 30086867]

26.

Dwyer AA, Smith N, Quinton R. Psychological Aspects of Congenital Hypogonadotropic Hypogonadism. Front Endocrinol (Lausanne). 2019;10:353. [PMC free article: PMC6624645] [PubMed: 31333578]

Disclosure: James Sonne declares no relevant financial relationships with ineligible companies.

Disclosure: Wilfredo Lopez-Ojeda declares no relevant financial relationships with ineligible companies.