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Kallmann syndrome is a congenital form of hypogonadism caused by low levels of hypogonadotropic hormones. In addition to incomplete or delayed puberty and infertility, it characteristically manifests with hyposmia or anosmia from birth. The decrease in gonadal function is due to a failure in the differentiation or migration of neurons that arise embryologically in the olfactory mucosa and normally take up residence in the hypothalamus to serve as gonadotropin-releasing hormone neurons. Although no definitive biomarker is available, a family history of delayed puberty may be present, and case reports have identified genetic differences in patients. Decreased levels of sex steroids result from the deficit in gonadotropin-releasing hormone and lead to the prominent signs and symptoms of 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 the modern era in 1944, is a rare, X-linked genetic disease that is estimated to affect 1 in 48,000 individuals and is 4 times more prevalent in males compared to females. Treatment involves life-long hormone replacement therapy and may include surgery for male patients to correct undescended testicles. Patients have an increased risk of developing osteoporosis later in life due to decreased sexual hormone 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: Compare the typical presentation of Kallmann syndrome with other forms of hypogonadotropic hypogonadism. Determine the pathophysiology of Kallmann syndrome. Select the optimal treatment for Kallmann syndrome to address sexual characteristics and fertility. Implement interprofessional team strategies for improving care coordination and communication for patients with Kallmann syndrome. Access free multiple choice questions on this topic.

Kallmann syndrome is a rare congenital form of hypogonadotropic hypogonadism that manifests with partial or complete anosmia.[1] A deficiency in gonadotropin-releasing hormone (GnRH) results in decreased levels of sex steroids, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH), leading to a lack of sexual development and maturity along with the absence of secondary sexual characteristics. Typically, the diagnosis occurs when a child fails to begin puberty, but it can be identified earlier when associated congenital defects raise suspicion or where there is a family history of delayed puberty that suggests a heritable disorder. The connection between hypogonadism and loss of smell was first noted by Spanish pathologist Aurelian Maestre de San Juan in 1856.[2] However, the condition was named after Franz Josef Kallmann, a German-American geneticist, who first described it as a heritable genetic disorder in 1944 based on findings in 3 family clusters.[3][4] Similar to other hypogonadotropic hypogonadal conditions, Kallmann syndrome is characterized by abnormal or delayed reproductive and sexual characteristics primarily due to a lack of sexual maturation during the typical years of puberty. These signs can include small testicular volume indicative of a lack of testicular development and primary amenorrhea, a failure to start menstruation in women. Poorly defined secondary sexual characteristics can include a lack of pubic hair and underdeveloped mammary glands. Some individuals may also present at birth with micropenis or cryptorchidism (undescended testicles). These traits result from insufficient production of LH and FSH, leading to low levels of testosterone in males and decreased levels of estrogen and progesterone in women.[5] In addition, there are other associated characteristics linked to embryological defects.

Similar to other hypogonadotropic hypogonadal conditions, Kallmann syndrome is characterized by abnormal or delayed reproductive and sexual characteristics primarily due to a lack of sexual maturation during the typical years of puberty. These signs can include small testicular volume indicative of a lack of testicular development and primary amenorrhea, a failure to start menstruation in women. Poorly defined secondary sexual characteristics can include a lack of pubic hair and underdeveloped mammary glands. Some individuals may also present at birth with micropenis or cryptorchidism (undescended testicles). These traits result from insufficient production of LH and FSH, leading to low levels of testosterone in males and decreased levels of estrogen and progesterone in women.[5] In addition, there are other associated characteristics linked to embryological defects. Kallmann syndrome is defined by its additional presentation of anosmia or hyposmia. Approximately 60% of patients with isolated congenital GnRH deficiency present with an impaired sense of smell, which is characteristic of Kallmann syndrome.[6] Additional characteristics may include cleft lip and palate, unilateral renal agenesis, cryptorchidism, and micropenis.[6][7] Cerebral impairments, such as central hearing impairment, mirror movements of the hands (synkinesis), and cerebral ataxia, may also be present.[6] Color blindness and ocular window defects have also been observed.[3][6][8]

Kallman syndrome results from a defect in the differentiation or migration of embryonic GnRH neurons to the hypothalamus from the early developing olfactory placode during embryonic development.[9] Normally, the embryonic GnRH neurons and the olfactory nerves pass through the cribriform plate into the rostral forebrain and then migrate to the early hypothalamus.[9][10] Defects in the development or migration of the olfactory nerve also impact the GnRH neurons, leading to the anosmia and hypogonadotropic hypogonadism characteristic of Kallmann syndrome.[9][10] If there are no developmental migratory deficits, patients have isolated GnRH deficiency and hypogonadotropic hypogonadism without any loss of smell. This condition is known as normosmic, isolated, or idiopathic hypogonadotropic hypogonadism.[7][11] The cause of Kallmann syndrome is genetic but can result from many different mutations. Approximately 40 genes have been associated with hypogonadotropic hypogonadism, including Kallmann syndrome, often with slight variations in secondary characteristics.[12] The most common known genetic defects associated with Kallmann syndrome are in the genes KAL1 (ANOS1) and FGFR1, but approximately 35% to 45% of cases are not explained by the currently identified genetic abnormalities.[6][13][14][15] Other genetic mutations known to cause Kallmann syndrome include CCDC141, CHD7, DUSP6, FEZF1, FGF8, FGF17, HS6ST1, IL17RD, KISS1, NSMF(NELF), PROK2, PROKR2, SEMA3A, SEMA3E, SOX10, SPRY4, TAC3, and WDR11.[6][16][17] In cases of familial inheritance of Kallmann syndrome, approximately 64% display an autosomal dominant pattern, 25% exhibit autosomal recessive inheritance, and 11% follow an X-linked pattern. However, most cases of Kallmann syndrome are due to sporadic mutations. Clinical genetic testing can be used to determine the specific genes involved in an individual patient.[6] X-linked recessive inheritance of Kallmann syndrome is due to mutations in the KAL1 (ANOS1) gene, located on the X chromosome, found in 8% of all patients with Kallmann syndrome.[4][6][18][19] Mutations in the KAL1 (ANOS1) gene are associated with anosmia, cryptorchidism, decreased libido, erectile dysfunction, infertility, micropenis, one-sided renal agenesis, and synkinesia.[6][15][20][21][22]

X-linked recessive inheritance of Kallmann syndrome is due to mutations in the KAL1 (ANOS1) gene, located on the X chromosome, found in 8% of all patients with Kallmann syndrome.[4][6][18][19] Mutations in the KAL1 (ANOS1) gene are associated with anosmia, cryptorchidism, decreased libido, erectile dysfunction, infertility, micropenis, one-sided renal agenesis, and synkinesia.[6][15][20][21][22] Mutations involving Prokineticin-2 (PROK2), which affects the morphogenesis of the olfactory bulb and normal GnRH production, are found in about 10% of patients with Kallmann syndrome.[6][23][24][25][26][27][28][29] The KISS1 gene, encoding the kisspeptin signaling molecule, is of particular interest. Kisspeptin is a potent initiator of the production of GnRH in the hypothalamus, and its production is known to be impacted by environmental factors.[30] The KISS1/Kiss1 gene, which encodes for the kisspeptin hormone, is a well-known regulator of reproductive hormones, specifically acting upstream of GnRH.[31][32] Studies indicate that in some cases of hypogonadotropic hypogonadism, patients present with deletions and point mutations in the KISS1R.[33][34] The kisspeptin neuronal network resides within the hypothalamus preoptic and infundibular nuclei.[33][34][35] This elegant neuronal circuit regulates puberty and human reproductive functions by signaling GnRH secretion, which subsequentially controls FSH and LH.[36] Cranial nerve zero (0) has been described as an innocuous neuroanatomical structure associated with GnRH and potentially involved in regulating human reproductive functions and behaviors. Evidence suggests that CN0 GnRH axons play a role in the development and differentiation of the hypothalamic-pituitary-gonadal axis and may also trigger conceptually exhilarating endocrinologic responses independently or together with the kisspeptin neural circuit.[37][38][39] Please see StatPearls' companion references, "Neuroanatomy, Cranial Nerve 0 (Terminal Nerve)" and "Neuroanatomy, Cranial Nerve," for more information.

Kallmann syndrome is a genetic condition, often X-linked, leading to a significantly higher prevalence in males of roughly 4 or 5:1. This rare heritable disorder is typically diagnosed during adolescence due to delayed puberty and is estimated to affect 1 in 48,000 individuals overall (1:30,000 in males, 1:125,000 in females).[40][41] However, other estimates suggest a higher prevalence, with Kallmann syndrome affecting 1 in 8,000 to 10,000 males and 1 in 50,000 females.[6][42][43][44][45]

Decreased gonadal function in Kallmann syndrome is due to deficient GnRH production, caused by the failure in the differentiation or migration of GnRH-producing neurons that arise embryologically in the olfactory mucosa to reach the hypothalamus.[1] This process is associated with abnormal olfactory nerve development, which is why Kallmann syndrome causes both anosmia and hypogonadotropic hypogonadism.[1][5][6] Deficient hypothalamic GnRH secretion results in the abnormal production of gonadotropins, such as FSH and LH, which in turn results in hypogonadism, infertility, pubertal delay, and the other clinical symptoms associated with Kallmann syndrome.[1][5][6]

A detailed medical and family history, a thorough physical examination, and genetic testing often reveal many of the primary reproductive features of hypogonadotropic hypogonadism described above, along with nonreproductive signs. The congenital absence of olfactory function (anosmia), characteristic of Kallmann syndrome, aids in distinguishing it from other forms of hypogonadotropic hypogonadism. A family history of delayed puberty presents in approximately 12% of Kallmann syndrome cases, compared to less than 1% in the general population.[46] The diagnosis of Kallmann syndrome typically becomes evident when symptoms of delayed puberty arise. Consequently, other causes must generally be excluded, further delaying the diagnosis. In male neonates, the most common associated clinical signs are micropenis (<1.9 cm when stretched) and cryptorchidism.[6] Cleft lip or small testes may also be observed.[6] There are minimal obvious clinical signs in female neonates with Kallmann syndrome. In addition to delayed puberty and lack of smell, associated anomalies found in Kallmann syndrome may include the following: Abnormal hearing Amenorrhea Bilateral male breast development Cardiac anomalies Cerebral ataxia Cleft palate Color blindness Congenital absence of a kidney Cryptorchidism Dental agenesis Eye movement disorders Family history of delayed puberty Fatty liver High-arched palate Hypogonadism Infertility Lack of pubic hair Loss of libido Micropenis Minimal virilization Neurological defects such as nystagmus and synkinesis Ocular hypertelorism Scarce pubic hair Scoliosis Seizures (epilepsy) Sensorineural hearing loss Short digits Small testes (testicular volume <4 mL before puberty) Solitary kidney Testicular microlithiasis Undeveloped breasts in females [5][6][47][48][49]

The diagnosis typically occurs in conjunction with an initial complaint of delayed puberty during adolescence. The most common clinical sign of Kallmann syndrome in patients with delayed puberty is anosmia. There is a higher association of cryptorchidism, cleft lip or palate, micropenis, and a family history of delayed puberty or Kallmann syndrome compared to the general population or other causes of delayed puberty.[6] The presence of anosmia or olfactory bulb deficits, as determined by magnetic resonance imaging (MRI), with delayed puberty, congenital hypogonadotropic hypogonadism, and otherwise normal pituitary function and anatomy, strongly suggests a diagnosis of Kallmann syndrome.[5][6][48][50] Such findings are often associated with cryptorchidism, micropenis, cleft lip or palate, and a family history of Kallmann syndrome or delayed puberty.[6] Genetic testing may be helpful in some cases. Constitutional delay of growth and puberty is the most common cause of delayed puberty and must be differentiated from Kallmann syndrome. This condition is associated with prepubertal body proportions beyond the age of expected puberty and is considered a normal variant that corrects itself. Various genetic and environmental factors contribute to this condition. Although there is also a family history of delayed puberty, it is not associated with anosmia or any of the other clinical signs of Kallmann syndrome. Please see StatPearls' companion references, "Constitutional Growth Delay" and "Delayed Puberty," for more information. Laboratory Testing for Suspected Kallmann Syndrome Laboratory testing for suspected Kallmann syndrome should be conducted to exclude unrelated hormonal deficiencies, pituitary tumors, and other systemic syndromes and to diagnose Kallmann syndrome. The testing includes LH, FSH, testosterone or estradiol, prolactin, free T4, thyroid stimulating hormone (TSH), and cortisol.[5] More specialized tests may also be performed, including serum adrenocorticotropic hormone (ACTH), ferritin, inhibin B, anti-Mullerian hormone, insulin-like 3, GnRH, inhibin B, insulin-like growth factor 1, and the human chorionic gonadotropin (hCG) stimulation test.[5] In cases of hypogonadism, testosterone levels in males are typically <100 ng/dL, and estradiol levels in females are <50 pg/mL, along with low FSH and LH levels.[6] Other findings may include the following:

Laboratory testing for suspected Kallmann syndrome should be conducted to exclude unrelated hormonal deficiencies, pituitary tumors, and other systemic syndromes and to diagnose Kallmann syndrome. The testing includes LH, FSH, testosterone or estradiol, prolactin, free T4, thyroid stimulating hormone (TSH), and cortisol.[5] More specialized tests may also be performed, including serum adrenocorticotropic hormone (ACTH), ferritin, inhibin B, anti-Mullerian hormone, insulin-like 3, GnRH, inhibin B, insulin-like growth factor 1, and the human chorionic gonadotropin (hCG) stimulation test.[5] In cases of hypogonadism, testosterone levels in males are typically <100 ng/dL, and estradiol levels in females are <50 pg/mL, along with low FSH and LH levels.[6] Other findings may include the following: Low levels of inhibin B (<35 pg/mL) suggest GnRH deficiency rather than CDGP and rule out primary testicular failure.[51][52][53][53] Insulin-like growth factor 1 can be used to assess growth hormone levels. If it is normal, a growth hormone deficiency is unlikely. The hCG stimulation test may help differentiate Kallmann syndrome from constitutional delay of growth and puberty. Cortisol, prolactin, thyroid hormones, ACTH, insulin-like growth factor, and growth hormones are generally normal in GnRH deficiency and Kallmann syndrome. Additional tests may include a semen analysis, bone density testing, renal ultrasonography, and a brain MRI.[5][6] Kisspeptin stimulation testing may also help differentiate patients with isolated GnRH deficiency and constitutional delay of growth and puberty. Kisspeptin activates LH secretion at puberty. An increase in LH of 0.8 mIU/mL or more after kisspeptin administration can reasonably predict natural puberty by age 18.[52][54] Laboratory Findings in Kallmann Syndrome Laboratory findings in Kallmann syndrome typically include low testosterone (<100 ng/dL in males) or estradiol (<50 pg/mL in females), with low FSH, LH, GnRH, and inhibin (in males) together with otherwise normal pituitary functions, such as ACTH, growth hormone, TSH, and prolactin.[6][48] Pituitary anatomy is also typically normal.[6][48]

Laboratory findings in Kallmann syndrome typically include low testosterone (<100 ng/dL in males) or estradiol (<50 pg/mL in females), with low FSH, LH, GnRH, and inhibin (in males) together with otherwise normal pituitary functions, such as ACTH, growth hormone, TSH, and prolactin.[6][48] Pituitary anatomy is also typically normal.[6][48] The early diagnosis of Kallmann syndrome before 6 months of age is possible as they lack the normal neonatal surge in gonadotropins and testosterone or estrogen (mini-puberty), especially in boys.[5][55][56][57] They may also present with cryptorchidism, cleft lip or palate, small testes, micropenis, hearing deficits, cleft lip, or renal agenesis. Some patients may have seizures (epilepsy) or various cardiac anomalies. Young girls may not show any suggestive abnormal outward characteristics similar to cryptorchidism and micropenis in boys. A common presentation of Kallmann syndrome in females is primary amenorrhea with significantly reduced or even agent breast development.[6] Anosmia further suggests the diagnosis. Kallmann syndrome is particularly challenging to diagnose during adolescence, especially differentiating it from constitutional delay of growth and puberty or late blooming.[50] A GnRH stimulation test may help distinguish these 2 disorders, but the results may overlap, so the test is not always definitive (Please refer to the Differential Diagnosis section for more information).[58] Although the hormonal profiles of the 2 disorders are similar, inhibin levels can be used to help distinguish isolated hypogonadotropic hypogonadism found in Kallmann syndrome from constitutional delay of growth and puberty.[6][18][51][52][59][60][61] Please see StatPearls' companion reference, "Constitutional Growth Delay," for more information. Other findings in Kallmann syndrome may include the following: In children, bone age testing is typically performed using a left hand and wrist X-ray. Bone age is delayed in children with Kallmann syndrome. A growth hormone stimulation test may be required in some children with short stature to rule out growth hormone deficiency. Thyroxine, TSH, IGF-1, and gonadotropin levels (LH and FSH) may be appropriate for skeletal age in constitutionally delayed growth conditions. However, these levels may fall outside the normal range in patients with a genetic disorder. Ultrasound can identify solitary kidneys.

A growth hormone stimulation test may be required in some children with short stature to rule out growth hormone deficiency. Thyroxine, TSH, IGF-1, and gonadotropin levels (LH and FSH) may be appropriate for skeletal age in constitutionally delayed growth conditions. However, these levels may fall outside the normal range in patients with a genetic disorder. Ultrasound can identify solitary kidneys. MRI often shows abnormalities such as olfactory bulb defects, aplasia, or hypoplasia but do not necessarily correlate with the patient's sense of smell. Early-morning screening for adrenocortical insufficiency and elevated ACTH may indicate a subset of hypogonadotropic hypogonadism, potentially including Kallmann syndrome. Urinalysis and routine blood work could also screen these patients to identify inflammatory or autoimmune disorders. Patients who manage chronic pain with opioids have an increased association with induced hypogonadism later in life. Serum ferritin overload may be useful for screening adult-acquired hypogonadotropic hypogonadism due to hemochromatosis, whereas diabetes may also be present in such cases.[5][6][62][63][64] Please see StatPearls' companion reference, "Constitutional Growth Delay," for more information. Genetic Testing Genetic testing and establishing an inheritance pattern can help confirm the diagnosis and facilitate genetic counseling.[5][6][65][66][67] In genetic testing for Kallmann syndrome, gene sequence analysis is conducted first, followed by gene-targeted deletion or duplication analysis if needed.[6][68][69] X-linked inheritance, transmitted in males only from the maternal side, is typical for KAL1 (ANOS1) mutations associated with some cases of Kallmann syndrome.[70] Other mutations may involve characteristics of autosomal inheritance, such as dominant and recessive, or oligogenic, involving multiple genes. Of these, autosomal dominant and oligogenic are the most common.[71] Patients who demonstrate autosomal dominant inheritance should receive genetic counseling regarding the 50% risk of transmitting the condition to their offspring. Performing hormonal profiling in neonatal offspring of these patients during mini-puberty is strongly suggested in these cases.[5] Men with X-linked Kallmann syndrome transmit the mutation to their biological daughters, who become obligate carriers. After puberty, these females require genetic counseling.

Patients who demonstrate autosomal dominant inheritance should receive genetic counseling regarding the 50% risk of transmitting the condition to their offspring. Performing hormonal profiling in neonatal offspring of these patients during mini-puberty is strongly suggested in these cases.[5] Men with X-linked Kallmann syndrome transmit the mutation to their biological daughters, who become obligate carriers. After puberty, these females require genetic counseling. If both male and female partners demonstrate autosomal recessive heritability, the risk of newborn inheritance is very low (unless the parents are blood relatives) due to the extremely low incidence of heterozygous healthy carriers of identical Kallmann syndrome-producing mutations. Genetic counseling can be challenging when several different mutations are involved in the disorder, as transmission risk is variable and may be unpredictable even with genetic testing.[5][6][65][66] Summary Delayed puberty is the most common initial clinical presentation of Kallmann syndrome. The presence of anosmia or olfactory bulb defects on MRI and hypogonadotropic hypogonadism is characteristic of the condition.[5][6][48][50] Other than gonadotropins, normal pituitary anatomy and hormonal activity further suggest the diagnosis.[6][48][50] Kallmann syndrome is often associated with cryptorchidism, micropenis, cleft lip or palate, and a family history of Kallmann syndrome or delayed puberty.[5][6][48][50] Genetic testing may be helpful in some cases.[5][6]

The goal of treatment is to promote the development of normal secondary sexual characteristics, achieve and maintain bone mineral density, prevent loss of muscle mass, and establish fertility.[6] Kallmann syndrome is typically treated pharmacologically with hormone replacement therapy, such as testosterone or estrogen-progestin supplementation as appropriate, to allow the maturation of secondary sexual features. Life-long hormone androgen replacement therapy is required.[6] Treatment for male infants with Kallmann syndrome may include early surgery to correct associated undescended testicles or other anomalies.[5] Restoration of fertility requires regular injections of the missing gonadotropins, such as FSH and LH, or pulsatile synthetic GnRH.[6] Later in life, patients with Kallmann syndrome have an increased risk of developing osteoporosis due to decreased sex hormone production and often require calcium and Vitamin D supplementation with bisphosphonates or similar treatment to prevent bone loss.[72] The failure of normal puberty frequently causes significant negative emotional, psychological, psychosexual, and social effects.[6][73][74] Such psychosocial disorders should be expected in adolescent patients with Kallmann syndrome with delayed puberty, and appropriate mental health counseling and treatment should be provided.[6] Fertility and Virilization Fertility and virilization in individuals with Kallmann syndrome can be normalized through gonadotropin-based pharmacologic therapies.[6][75] In children with congenital hypogonadotropic hypogonadism, puberty should be induced at the median age rather than delaying until the upper age limit of normal puberty.[5][6][50][76] Sex hormone administration alone, such as testosterone in males, does not produce or restore spermatogenesis, which requires FSH or pulsatile GnRH.[5][6] Male: Virilization in young males diagnosed with Kallmann syndrome begins at 12 years with low-dose testosterone supplementation. The dose is gradually increased over 18 to 24 months to simulate natural puberty and allow for psychosexual development.[5][77] Patients who present in late adolescence or as adults are generally treated with full testosterone supplementation. However, such supplementation does not restore fertility or increase testicular size to normal.[5][6][53]

Virilization in young males diagnosed with Kallmann syndrome begins at 12 years with low-dose testosterone supplementation. The dose is gradually increased over 18 to 24 months to simulate natural puberty and allow for psychosexual development.[5][77] Patients who present in late adolescence or as adults are generally treated with full testosterone supplementation. However, such supplementation does not restore fertility or increase testicular size to normal.[5][6][53] For men with Kallmann syndrome, maximizing their fertility requires long-term pulsatile GnRH therapy.[6][77][78][79][80] Pulsatile GnRH treatment for males with Kallmann syndrome is generally administered at 25 ng/kg subcutaneously every 2 hours as required to maintain testosterone levels.[6][77][80] Alternatively, combined hormonal therapy involves FSH injections of 75 to 150 IU and hCG injections of 1000 to 1500 IU 2 to 3 times a week.[5][6][75][77][78][80][81][82][83] This approach is typically selected in patients with testicular volume <4 mL.[6][80] hCG monotherapy can be used in adult patients without cryptorchidism. FSH can be added if an adult male patient continues to be azoospermic after 3 to 6 months of hCG monotherapy.[6] These therapies both induce spermatogenesis and testosterone production, but pulsatile GnRH appears to provide earlier spermatogenesis, greater testicular volume, and a higher pregnancy rate.[77][80][84][85][86] Gonadotropin and pulsatile GnRH therapies can produce spermatogenesis in 75% to 80% of men with Kallmann syndrome, although their semen analyses may not always meet the minimal normal World Health Organization criteria.[77][87] Female: Young girls with Kallmann syndrome are typically treated with low-dose estradiol, typically as a transdermal formulation, starting at age 12. The dose is slowly increased over the next 12 to 24 months to mimic normal puberty. Estrogen is then added after the first menstrual bleed to maximize breast development.[6] In adulthood, estrogen and progesterone supplementation are used to promote sexual development and menstrual bleeding. However, achieving fertility requires the administration of gonadotropins or pulsatile GnRH to induce ovulation.[5][6][17][88]

Estrogen is then added after the first menstrual bleed to maximize breast development.[6] In adulthood, estrogen and progesterone supplementation are used to promote sexual development and menstrual bleeding. However, achieving fertility requires the administration of gonadotropins or pulsatile GnRH to induce ovulation.[5][6][17][88] Optimal pulsatile GnRH dosing in women with Kallmann syndrome is 5, 10, or 20 μg/bolus every 60 to 90 minutes, with intravenous administration giving better results compared to the subcutaneous route.[80][89] After ovulation, hCG or progesterone injections are required until endogenous hCG production is sufficient to manage the remainder of the pregnancy.[5][6] In women, fertility outcomes with gonadotropin therapy are equivalent to normal females.[87] Although most patients seeking fertility assistance have a good response to hormonal therapy, some may not tolerate the treatment or may remain infertile despite aggressive therapy. In such cases, assisted reproduction techniques can be successfully used. Preimplantation genetic testing can be used to eliminate the disorder from any progeny, especially as next-generation gene sequencing technology advances to allow for easier and earlier diagnosis of the syndrome.[6][67] Please see StatPearls' companion references, "Female Infertility," "Male Infertility," "Male Hypogonadism," "Androgen Replacement," and "Hormone Replacement Therapy," for more information.

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 a distinct form of hypogonadotropic hypogonadism, characterized by the presence of hyposmia or anosmia. Normosmic idiopathic or isolated hypogonadotropic hypogonadism is a similar disorder characterized by delayed puberty but without an abnormal sense of smell. Together, these 2 disorders—Kallmann syndrome (60%) and normosmic idiopathic hypogonadotropic hypogonadism (40%)—constitute isolated GnRH deficiency with otherwise normal pituitary anatomy and function.[6][7] Normosmic idiopathic hypogonadotropic hypogonadism is also called idiopathic or isolated hypogonadotropic hypogonadism. CHARGE syndrome is a rare genetic condition associated with congenital hypogonadism. The acronym CHARGE came into use for newborn children with the congenital features of coloboma of the eye, heart defects, atresia of the nasal choanae, restricted growth or development, genital or urinary abnormalities, and ear abnormalities and deafness. This condition affects various organ systems, including facial abnormalities and the genitals, and is caused by a mutation in the CHD7 gene.[90] Patients may also have abnormal olfactory function.[90] CHARGE syndrome can be differentiated from Kallmann syndrome by the associated clinical abnormalities and genetic testing. Please see StatPearls' companion reference, "CHARGE syndrome," for more information. Bardet-Biedl syndrome is an autosomal-recessive genetic disorder of the cilia that may cause anosmia and hypogonadotropic hypogonadism.[91][92] Other associated anomalies include obesity, polydactyly, and renal abnormalities.[91][92]

CHARGE syndrome is a rare genetic condition associated with congenital hypogonadism. The acronym CHARGE came into use for newborn children with the congenital features of coloboma of the eye, heart defects, atresia of the nasal choanae, restricted growth or development, genital or urinary abnormalities, and ear abnormalities and deafness. This condition affects various organ systems, including facial abnormalities and the genitals, and is caused by a mutation in the CHD7 gene.[90] Patients may also have abnormal olfactory function.[90] CHARGE syndrome can be differentiated from Kallmann syndrome by the associated clinical abnormalities and genetic testing. Please see StatPearls' companion reference, "CHARGE syndrome," for more information. Bardet-Biedl syndrome is an autosomal-recessive genetic disorder of the cilia that may cause anosmia and hypogonadotropic hypogonadism.[91][92] Other associated anomalies include obesity, polydactyly, and renal abnormalities.[91][92] Constitutional delay of growth and puberty (CDGP) is the most common developmental condition causing delayed puberty in children. Sometimes called late bloomers, the condition affects about 15% of the pediatric population. This condition tends to be familial and inherited in an autosomal dominant manner. CDGP is typically associated with short stature, delayed skeletal maturity, and reduced growth velocity compared to peers. This condition lacks signs of abnormal sexual development, is self-limiting, and is not associated with color blindness, cryptorchidism, renal agenesis, or anosmia. Please see StatPearls' companion reference, "Constitutional Growth Delay," for more information. The child's growth rate is typically constant after 4 years until the expected onset of puberty—13 years for girls and 14 years for boys—when growth deviates from the predicted curve with the late onset of puberty and delayed bone age. Bone age in children with CDGP typically shows a 20% delay from the expected norm for age. There is a significant growth spurt after puberty, and patients typically enjoy normal development afterward. Height, secondary sex characteristics, reproductive hormones, and fertility potential also become normal as adults. A family history of delayed puberty is present in 50% to 75% of patients.

Bone age in children with CDGP typically shows a 20% delay from the expected norm for age. There is a significant growth spurt after puberty, and patients typically enjoy normal development afterward. Height, secondary sex characteristics, reproductive hormones, and fertility potential also become normal as adults. A family history of delayed puberty is present in 50% to 75% of patients. A baseline or GnRH-stimulated gonadotropin levels can be helpful but may not be adequate to differentiate constitutional delay of growth and puberty in adolescents, which is self-limiting, from the more permanent forms of hypogonadotropic hypogonadism, such as Kallmann syndrome. Although hormonal levels are alike, Kallmann syndrome is characterized by low inhibin B levels (<35 pg/mL), a feature not observed in constitutional delay of growth and puberty.[6][18][59][60][61] An HCG stimulation test or low inhibin levels may also help differentiate the 2 disorders.[51][52][93][94] GnRH agonist testing may provide better diagnostic differentiation than the standard GnRH test due to its higher potency.[58][95][96][97][98][99][100][101][102] Please see StatPearls' companion reference, "Constitutional Growth Delay," for more information. Functional hypogonadotropic hypogonadism can be caused by a temporary delay in maturation of the hypothalamic-pituitary-gonadal axis due to several disorders, such as anorexia nervosa, celiac disease, hypothyroidism, inflammatory bowel disease, and renal insufficiency.[50] Various pituitary and hypothalamic neoplasms can cause hypogonadotropic hypogonadism, including adenomas, craniopharyngiomas, microadenomas, and prolactinomas.[17] Panhypopituitarism may also mimic Kallmann syndrome and hypogonadotropic hypogonadism but may demonstrate additional abnormal pituitary function.

Kallmann syndrome alone is not associated with decreased life expectancy, but its possible association with heart conditions, osteoporosis, and reduced fertility may separately impact the patient's health and longevity. Cryptorchidism and cleft lip or palate are surgically correctable. Micropenis can be treated medically using low-dose testosterone or gonadotropin therapy in prepubertal males and surgically in adult men. Fertility and secondary sexual development can be effectively normalized with appropriate hormonal supplementation, but there are no known remedies for the olfactory deficit (anosmia), synkinesia, or solitary kidneys.[5][6][68] Please see StatPearls' companion reference, "Micropenis," for more information. Spontaneous recovery of hypotrophic hypogonadism associated with Kallmann syndrome has been reported in about 10% to 20% of patients who may experience a return to normal hormonal function.[5][103][104] This hormonal recovery occurs without warning and may even go unnoticed.[103] Unfortunately, such sporadic reversals may not be permanent.[104][105] The reasons for this unpredictable and sporadic return of normal hormonal function remain unexplained.

Although Kallmann syndrome cannot be cured, its complications and morbidity can be minimized by early diagnosis, dietary optimization, physical therapy, psychological support, and appropriate medical treatment.[6] Complications of the condition may include osteoporosis, cardiac anomalies, seizures, and psychological or neurological disorders. Patients should be evaluated for these conditions, and consultations with appropriate specialists should be considered if indicated. Dietary supplementation, physical therapy, and rehabilitation may be required to address specific complications. Psychological aspects secondary to lack of sexual maturation, a lengthy diagnostic journey, the rarity and chronicity of the genetic condition, and the prolonged pharmacological management are likely to be present, and referral to specialty care is important for improved quality of life.[73] A range of congenital heart disorders has been observed in a small subset of patients with Kallmann syndrome. These disorders include atrial and ventricular septal defects, atrioventricular blocks, Ebstein anomalies, right aortic arch, right bundle-branch block, transposition of the great vessels, and Wolff-Parkinson-White syndrome.[106][107] Young male children with X-linked isolated hypogonadotropic hypogonadism may also have congenital adrenal hypoplasia, which can lead to adrenal insufficiency. Without early diagnosis and appropriate treatment, this condition can be life-threatening. The development of congenital bone malformations, such as cleft palate, is also possible and can be identified at birth. Dry skin is also a potential complication of chronic hypogonadal conditions such as Kallmann syndrome. Patients may have had treatment for adrenocortical insufficiency in infancy or childhood. The transition from pediatric to adult care is particularly challenging. Gaps in therapy must be avoided to minimize complications. Close coordination between pediatric and adult healthcare providers can minimize this risk. If left untreated, Kallmann syndrome may cause sexual dysfunction, infertility, diabetes, obesity, and osteoporosis. Treatment involves early diagnosis; appropriate treatment with sex hormone therapies, such as androgens, gonadotropins, and GnRH; and dietary modifications, including vitamin D, calcium supplements, and bisphosphonates.[6]

If left untreated, Kallmann syndrome may cause sexual dysfunction, infertility, diabetes, obesity, and osteoporosis. Treatment involves early diagnosis; appropriate treatment with sex hormone therapies, such as androgens, gonadotropins, and GnRH; and dietary modifications, including vitamin D, calcium supplements, and bisphosphonates.[6] Patients may be infertile without treatment; however, their fertility can often be restored with appropriate hormonal supplementation.[5] Please see StatPearls' companion references, "Female Infertility" and "Male Infertility," for more information.

Although there are reports of spontaneous reversal of hypogonadotropic hypogonadism in individuals with Kallmann syndrome, the disorder is generally a life-long condition requiring permanent hormone replacement therapy.[108] Fertility can typically be restored with appropriate hormonal therapy. Life expectancy is not directly affected, but complications of Kallmann syndrome can affect longevity, particularly if not treated.

Kallmann syndrome can be reasonably diagnosed in patients with delayed puberty who have anosmia and olfactory bulb abnormalities on MRI imaging and hypogonadal hypogonadism with no other identifiable pituitary functional or anatomical abnormalities.[6][48][50] The presence of associated anatomical aberrations, such as cryptorchidism, micropenis, cleft lip, solitary kidney, or a family history of Kallmann syndrome, supports the diagnosis.[6] Patients with congenital GnRH deficiency generally do not have a significant concomitant growth hormone deficit and do not benefit from growth hormone supplementation. Low inhibin levels, anosmia, and abnormal olfactory bulbs on MRI can differentiate Kallmann syndrome from the more common constitutional delay of growth and puberty. Isolated hypogonadotropic hypogonadism can be differentiated by normal olfactory function and anatomy on MRI imaging.

A delay in starting puberty is often first noticed by a child's parents after consulting with a pediatrician or family practice clinician. Pediatric endocrinology typically makes the definitive diagnosis. In addition to the reproductive abnormalities and anosmia associated with Kallmann syndrome, if fertility is a concern or if one or more non-reproductive manifestations are present, a referral to a reproductive endocrinologist should be considered.[109] Nurses assist with patient evaluation and monitoring. Pharmacists review medications and assess potential drug interactions. Psychological care is essential for supporting overall wellness. Urology and pediatric urology may also need to be involved for genitourinary issues. Effective communication among the members of this interprofessional team is crucial to improving patient outcomes.