BASICS
DESCRIPTION
- Kallmann syndrome (KS) refers to the clinical finding of hypogonadotropic hypogonadism in a patient with concurrent anosmia (lack of smell).
- Both familial and sporadic forms, with a range of genetic defects reflected in various modes of inheritance that display some phenotypic variability
- It is distinct from other forms of idiopathic hypogonadotropic hypogonadism, which have a different pathogenesis and do not present with anosmia.
EPIDEMIOLOGY
Incidence
- Prevalent sex: male > female (4:1)
- Overall incidence varies from 1:10,000 to 1:86,000.
- Men: 10/100,000/year; Women: 2/100,000/year
ETIOLOGY AND PATHOPHYSIOLOGY
In the developing embryo, the olfactory placodes represent ectodermal tissue that will develop to produce certain distinct types of neuronal tissue, including both olfactory neurons and gonadotropin-releasing hormone (GnRH) " “secreting neurons. During the 6th embryonic week of development, certain accessory neurons from the olfactory placode will migrate to the forebrain, induce the development of olfactory bulbs, and help guide the GnRH-secreting neurons to the medial hypothalamus. KS results from a disruption of this process, leading to a poorly developed olfactory system, an absence of GnRH-secreting neurons in the hypothalamus, and loss of FSH and LH production. ‚
Genetics
- Most cases due to sporadic mutations
- Genes involved: KAL1, FGFR1, CHD7, FGF8,PROKR2, and PROK2 (1)
- 25 " “30% of cases due to known forms of familial inheritance are as follows:
- X-linked recessive form: 14% of inherited cases
- Mutation in KAL1 gene (Xp 22.3) that codes for anosmin-1, an extracellular matrix protein that functions like an adhesion molecule
- Unique phenotypic findings: synkinesia (up to 80% of patients), renal agenesis (up to 30% of patients)
- Female carriers are phenotypically normal.
- Sensorineural hearing loss
- Autosomal dominant form: ~10% of inherited cases
- Mutation in FGFR1 gene (short arm chromosome 8) that codes for receptor protein
- Unique phenotypic findings: cleft palate or high-arched palate (up to 30% of patients)
RISK FACTORS
- Family history is a significant risk factor.
- No identified risk factors for the sporadic form of this syndrome.
COMMONLY ASSOCIATED CONDITIONS
Genetic overlap between KS and other midline defects include, but are not limited to, septo-optic dysplasia and holoprosencephaly (2). ‚
DIAGNOSIS
HISTORY
- Both genders will display delayed sexual maturation, but the classic presentations differ depending on gender.
- Female patients: primary amenorrhea and history of multiple fractures
- Male patients: present early in life with micropenis or cryptorchidism or delayed maturation at puberty; patients may or may not be aware of anosmia/hyposmia.
- Screen for a family history of GnRH deficiency, anosmia, or the presence of the various congenital abnormalities associated with the different variants of KS.
PHYSICAL EXAM
- Objective smell test, the University of Pennsylvania Smell Identification Test (UPSIT) must be performed to distinguish KS from idiopathic hypogonadotrophic hypogonadism. This test evaluates an individual 's ability to identify various odorants correctly and can be easily administered in the clinical setting. Identification of hyposmia, normosmia, or anosmia is based on the individual 's age at testing, gender, and score. Individuals scoring at the ≤5th percentile receive the diagnosis of KS.
- Synkinesia of the digits is present in ~80% of males with KAL1 gene mutations. This can be demonstrated clinically by asking the individual to extend both arms and hands fully and then move the fingers of one hand in isolation. The inability of the individual to move the fingers of one hand without exhibiting mirror movements of the digits of the other hand is considered a positive test.
- Due to delayed epiphyseal closure, patients may demonstrate eunuchoid proportions, with arm span longer than height by ≥5 cm. Note, however, that patients are often of appropriate stature due to normal adrenal function.
- Assessment of sexual maturation by Tanner stage
- Male patients
- Micropenis or small testes
- Testicular volume usually prepubertal (<4 mL)
- Stretched penile length <1.9 cm
- Delayed sexual maturation
- Voices fail to deepen
- Little facial or axillary hair. Pubic hair may develop due to normal adrenarche; however, it may take female distribution.
- Decreased muscle mass
- Other anomalies such as hyperlaxity of joints, ear/hearing defects, coloboma, pectus excavatum, and pes planus
- Female patients
- Delayed sexual maturation
- Poor breast development
- Little or no axillary hair
DIFFERENTIAL DIAGNOSIS
- CHARGE syndrome: This syndrome is characterized by the presence of coloboma, heart anomalies, choanal atresia, and developmental anomalies of the ear and genitals. Many patients will have olfactory bulb aplasia/hypoplasia and hypogonadotropic hypogonadism (1).
- Delayed puberty: It is difficult to distinguish any form of hypogonadotropic hypogonadism from delayed puberty in patients aged <18 years; however, certain clinical clues may aid in the attempt.
- Evidence of poorly formed or absent olfactory bulbs on imaging combined with the classic history and laboratory values is diagnostic.
- The presence of the congenital anomalies associated with KS in the patient is helpful in diagnosis.
- The presence of pubic hair suggests normal adrenarche and points toward hypogonadotropic hypogonadism as opposed to delayed puberty, in which adrenarche is delayed.
- Any family history of GnRH deficiency, anosmia, or any of the congenital anomalies associated with the different heritable forms of KS increases the likelihood of KS.
- Hypopituitarism: Hypogonadotropic hypogonadism may result from pituitary dysfunction. If this occurs prior to normal pubertal development in the young patient, the patient may fail to develop secondary sexual characteristics. The most common cause of hypopituitarism is a pituitary adenoma; other causes include infectious and ischemic causes. Imaging techniques are useful in ruling out this entity. Primary hypogonadism: This entity is produced when testicular or ovarian failure leads to insufficient sex hormone levels. Possible causes include Klinefelter syndrome (XXY) or Turner syndrome (XO).
- LH and FSH levels tend to be elevated as the hypothalamic " “pituitary axis attempts to correct for low estrogen or testosterone levels.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Serum LH and FSH: low (<4 to 5 IU/L)
- In female patients, estradiol levels are low (<50 pg/mL); in male patients, testosterone levels are low (<100 ng/dL).
- In male patients, a semen analysis may provide a decent indication of the function of seminiferous tubules.
- Serum prolactin, thyroid-stimulating hormone (TSH), growth hormone: Rule out other endocrine disorders that may be in differential diagnosis.
- MRI may identify the olfactory anomalies: present as absent or poorly formed olfactory bulbs or sulci
- Can rule out hypothalamic or pituitary lesions as cause of hypopituitarism in any patient presenting with delayed puberty
- Bone scan may be performed to determine bone mineral density.
- Studies have found that hormone replacement may increase bone mineral density in patients with hypogonadotropic hypogonadism, particularly in patients in whom epiphyseal closure has not yet occurred.
Follow-Up Tests & Special Considerations
- Because of local release of GnRH into hypothalamic " “pituitary portal system, systemic levels of GnRH are generally not used for the diagnosis.
- MRI is a useful diagnostic tool in the case of male patients presenting in infancy, as limited hypothalamic-pituitary-gonadal function makes hormonal screening poorly sensitive, and olfactory testing is not feasible in this population.
TREATMENT
- There are multiple management approaches and individual patient considerations must be taken into account in determining an appropriate course.
- In chronic GnRH deficiency, patients may demonstrate pituitary hypoplasia or deficient GnRH receptors, either of which may cause them to be poorly responsive to exogenous GnRH. To determine this, patients may undergo a GnRH test.
- 100 ˇ ¼g GnRH is administered IV, and LH and FSH levels are measured every 20 to 30 minutes for the next 2 hours.
- Appropriate levels suggest normal pituitary response to GnRH and thus predict a better outcome with GnRH therapy.
MEDICATION
First Line
- Treatment of female patients (3,4)[A]
- Hormone replacement should occur for several months before attempting conception, as this will allow for full development of reproductive system. The transdermal therapy appears to cause faster bone accrual and uterine growth versus oral therapy.
- Exogenous estrogens are used to induce and maintain secondary sexual development. Multiple factors determine when to start therapy (patient 's bone age, height percentiles and predicted/desired adult height, psychosexual needs). Early or overaggressive estrogen therapy may cause premature epiphyseal closure and halt growth.
- Estrogens should be initiated based on body weight per day. Route of administration will affect dose required. Doses are generally increased following 6 to 18 months of therapy, depending on level of breast development.
- Allow for proper breast development before initiating progestin therapy (usually 6 months). Early initiation of progestin therapy may prevent proper breast development and full endometrial proliferation. Progestin maintenance therapy is usually given for 12 to 14 days each month. This will induce a secretory endometrium and protect against endometrial cancer.
- Medroxyprogesterone (Provera) 5 to 10 mg daily or micronized progesterone (Prometrium) 200 mg daily for 5 days
- Another strategy, instead of scheduled estrogen and progestin therapy during maintenance phase, is to substitute with an oral contraceptive.
- Gonadotropin therapy to enable fertility: currently the most poorly responsive method for attempting conception
- Start FSH at 150 IU/day until one mature follicle is present (defined by presence of follicle diameter of 18 mm and/or serum estradiol concentration of 200 pg/mL/dominant follicle), then dose 250- ˇ ¼g recombinant human chorionic gonadotropin (hCG) (or 5,000 to 10,000 U urinary hCG) to induce ovulation.
- Pulsatile GnRH therapy to enable fertility: benefit is that LH and FSH levels generally remain within normal limits, so ovarian hyperstimulation and multiple pregnancies are rare. Less convenient than other methods. Not currently available in the United States
- IV dosing: 2.5 to 10 ˇ ¼g q60 " “90 min. Begin at lower dose and increase to minimum dose required for ovulation.
- Treatment of male patients (4,5)[A]
- Testosterone is indicated in order to develop secondary sexual characteristics; however, this therapy alone is unlikely to result in normal spermatogenesis. Most commonly treated transdermally
- Patch: provides 2 to 4 mg per 24 hours of testosterone
- Gels: differently dosed preparations; applied once daily, men usually achieve normal ranges of testosterone within a month.
- IM injections: Usual starting doses are 25 to 50 mg of long-acting testosterone ester. Doses gradually increased by 25 to 50 mg every 2 to 3 months until full virilization is achieved. Once adult doses (~200 mg every 2 weeks) are reached, further adjustments are based on testosterone concentration. Therapy continued indefinitely
- Gonadotropin therapy to induce spermatogenesis results in more stable androgen levels than direct testosterone replacement. Spermatogenesis is achieved in 80% of patients on long-term treatment (5,6)[A].
- Begin hCG therapy, 1,000 to 2,000 IU IM 2 to 3 times a week (if patient has not reached full adult bone development, use dose once weekly), checking testosterone levels at 2-week intervals until level is within normal range, then lower dose to maintain proper testosterone level. Measure sperm count every 2 to 4 weeks to monitor response.
- If patient does not achieve adequate sperm counts with hCG therapy alone or if testicular volume is 1 to 5 mL, FSH (75 to 150 IU every other day, 3 times per week) may be administered to further increase spermatogenesis. Begin serial measurements of sperm count when testicular volume is 8 mL.
- GnRH therapy may be administered through portable infusion pump (100 to 400 ng/kg every 2 hours for up to 4 months). Equally effective as gonadotropin therapy in inducing spermatogenesis
- LH, FSH, and testosterone levels must be checked every 2 weeks until they normalize, afterwards they may be monitored every 2 months.
ONGOING CARE
DIET
In addition to weight-bearing exercise, patients should have adequate calcium intake in order to achieve optimal bone density. ‚
PATIENT EDUCATION
- Patients with autosomal dominant form of KS may be counseled regarding in vitro fertilization with preimplantation diagnosis in order to prevent passing the mutation to their progeny.
- All daughters of male patients with X-linked recessive form of KS will be carriers of the defective gene.
- Advancements in assisted reproductive technology (ART) allows men with severely impaired sperm counts to conceive.
REFERENCES
11 Dode ‚ C, Hardelin ‚ JP. Kallmann syndrome. Eur J Hum Genet. 2009;17(2):139 " “146.22 Vaaralahti ‚ K, Raivio ‚ T, Koivu ‚ R, et al. Genetic overlap between holoprosencephaly and Kallmann syndrome. Mol Syndromol. 2012;3(1):1 " “5.33 Meczekalski ‚ B, Podfigurna-Stopa ‚ A, Smolarczyk ‚ R, et al. Kallmann syndrome in women: from genes to diagnosis and treatment. Gynecol Endocrinol. 2013;29(4):296 " “300.44 Dunkel ‚ L, Quinton ‚ R. Transition in endocrinology: induction of puberty. Eur J Endocrinol. 2014;170(6): R229 " “R239.55 Han ‚ TS, Bouloux ‚ PM. What is the optimal therapy for young males with hypogonadotropic hypogonadism? Clin Endocrinol (Oxf). 2010;72(6):731 " “737.66 Dwyer ‚ AA, Raivio ‚ T, Pitteloud ‚ N. Gonadotropin replacement for induction of fertility in hypogonadal men. Best Pract Res Clin Endocrinol Metab. 2015;29(1):91 " “103.
CODES
ICD10
E23.0 Hypopituitarism ‚
ICD9
253.4 Other anterior pituitary disorders ‚
SNOMED
- hypogonadism with anosmia (disorder)
- Hypogonadotropic hypogonadism (disorder)
- Idiopathic hypogonadotropic hypogonadism (disorder)
- Female Kallmans syndrome (disorder)
CLINICAL PEARLS
- KS represents a specific variant of hypogonadotropic hypogonadism resulting from failed migration of hypothalamic neurons from the olfactory placode during embryologic development.
- KS should be considered in the differential diagnosis of any patient presenting with delayed sexual maturation.
- With proper hormone therapy, patients may undergo secondary sexual development and achieve fertility.