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Kallmann syndrome

Kallmann syndrome is an example of hypogonadism (decreased functioning of the sex hormone-producing glands) caused by a deficiency of gonadotropin-releasing hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also known as hypothalamic hypogonadism, familial hypogonadism with anosmia, or gonadotropic hypogonadism, reflecting its disease mechanism. more...

Kallmann syndrome
Kallmann syndrome
Kallmann syndrome
Kallmann syndrome
Kaposi sarcoma
Karsch Neugebauer syndrome
Kartagener syndrome
Kawasaki syndrome
Kearns-Sayre syndrome
Kennedy disease
Keratoconjunctivitis sicca
Keratosis pilaris
Kikuchi disease
Klinefelter's Syndrome
Klippel Trenaunay Weber...
Klippel-Feil syndrome
Klumpke paralysis
Kluver-Bucy syndrome
Kniest dysplasia
Kohler disease
Korsakoff's syndrome
Kostmann syndrome
Seborrheic keratosis

Kallman syndrome was described in 1944 by Franz Josef Kallmann, a German geneticist. However, others had noticed a correlation between anosmia and hypogonadism before this such as the Spanish doctor Aureliano Maestre de San Juan 80 years previously.


Kallmann syndrome is characterized by:

  • Hypogonadotropic hypogonadism (a lack of the pituitary hormones LH and FSH)
  • Congenital (present from birth) anosmia (complete inability to smell) or hyposmia (decreased ability to smell).

It can also be associated with optic problems, such as color blindness or optic atrophy, nerve deafness, cleft palate, cryptorchidism, renal agenesis, and mirror movement disorder. However, it is not clear at this time how or if these other problems have the same cause as the hypogonadism and anosmia and these other problems are more often present in those without Kallmann syndrome.

Males present with delayed puberty and may have micropenis (although congenital micropenis is not present in the majority of male KS cases).

Females present with delayed puberty i.e.primary amenorrhea and lack of secondary sex characteristicd, such as breast development.


The diagnosis is often one of exclusion found during the workup of delayed puberty. The presence of anosmia together with micropenis in boys should suggest Kallmann syndrome (although micropenis alone may have other causes).


Under normal conditions, GnRH travels to the pituitary gland via the tuberoinfundibular pathway, where it triggers production of gonadotropins (LH and FSH). When GnRH is low, the pituitary does not create the normal amount of gonadotropins. The gonadotropins in turn affect the production of hormones in the gonads, so when they are low, the hormones will be low as well.

In Kallmann syndrome, the GnRH neurons do not migrate properly from the olfactory placode to the hypothalamus during development. The olfactory bulbs also fail to form or have hypoplasia, leading to anosmia or hyposmia.

Kallman syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL gene, which maps to chromosome Xp22.3. KAL encodes a neural cell adhesion molecule, anosmin-1. Anosmin-1 is normally expressed in the brain, facial mesenchyme, mesonephros and metanephros. It is required to promote migration of GnRH neurons from the hypothalamus to the pituitary gland. It also allows migration of olfactory neurons from the olfactory bulbs to the hypothalamus.


Treatment is directed at restoring the deficient hormones -- known as hormone replacement therapy (HRT). Males are administered human chorionic gonadotropin (hCG) or testosterone. Females are treated with oestrogen and progestins.


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Is imaging necessary in the evaluation of the patient with an isolated complaint of anosmia? - Original Article
From Ear, Nose & Throat Journal, 12/1/01 by Nicolas Y. Busaba


Imaging studies are often obtained during the evaluation of the patient with an olfactory deficit. The purpose of this article is to describe an investigation that was conducted to assess the effectiveness of imaging studies in determining the etiology of olfactory loss in the patient with an isolated complaint of anosmia and no relevant findings on physical examination, including nasal endoscopy. The author conducted a retrospective review of the records of 20 women and eight men, aged 22 to 71 years (mean: 45), whose duration of anosmia had ranged from 1 month to 2 years (median: 3 mo). Twenty of these patients had undergone contrast-enhanced magnetic resonance imaging of the paranasal sinuses and brain, and the other eight had undergone enhanced computed tomography. The author found that these imaging studies did not add to the information obtained by the clinical history and endascopic nasal examination and were thus not useful in determining the cause of anosmnia. Based on these findings, the author does not recommend that imaging studies be included as part of the evaluation of these patients.


The true incidence of anosmia is difficult to determine, although the National Institutes of Health have estimated that more than 2 million persons in the United States have a smell dysfunction. (1) The etiology of olfactory loss is varied. Based on the site of the pathology, clinical olfactory deficits are classified as one of three types: transport, sensory, or neural. (2) Transport olfactory losses are caused by lesions that block the airflow to the olfactory region of the nose. Sensory disorders are the result of a direct injury or damage to the olfactory neuroepithelium. Neural deficits are attributable to disease processes that affect the olfactory bulb, olfactory tract, or the central olfactory pathway, including the prefrontal lobe, septal nuclei, amygdala, and temporal lobe.

The most common cause of olfactory dysfunction is sinonasal disease. (3) Other reported contributing factors include postviral upper respiratory tract infection (URI), head trauma, aging, congenital anomalies, exposure to toxic substances, medication side effects, neurologic disorders, sinonasal tumors, and intracranial tumors. In some patients, the etiology remains unknown despite extensive evaluation. (4)

A detailed clinical history and physical examination, including nasal endoscopy, is essential to a proper evaluation. In many cases, imaging studies of the brain and paranasal sinuses are obtained in an effort to determine the site and nature of the underlying pathology. The most common of these studies are high-resolution magnetic resonance imaging (MRI) and computed tomography (CT).

The purpose of the investigation described in this article was to determine the yield of imaging studies in helping to identify the etiology of the olfactory disorder in patients who had an isolated complaint of anosmia and in whom the endoscopic nasal examination was unremarkable.

Patients and methods

The author conducted a retrospective review of all patients who had come to his office with a chief complaint of anosmia during a 5-year period. Inclusion criteria for this study included an isolated complaint of acquired anosmia and an unremarkable nasal examination (anterior rhinoscopy and nasal endoscopy). The diagnosis of anosmia was based solely on each patient's complaint and was not verified or investigated further by specific olfactory function testing. Patients who had a history of rhinosinusitis, sinonasal or skull base surgery, epistaxis, visual or ocular complaints, headache, or a known neurologic disorder were excluded from this study. Also excluded were patients who were noted on physical examination and nasal endoscopy to have had intranasal polyps, a tumor, or any findings consistent with rhinosinusitis.

Twenty-eight patients--20 women and eight men, aged 22 to 71 years (mean: 45)--met the clinical criteria for inclusion. Their medical records were reviewed for demographic data as well as for information on the duration of symptoms, any history of antecedent URI, findings on physical examination, and the nature and duration of medical treatment.

All patients in this series had undergone an imaging evaluation by either MRI or CT. The results of the imaging studies reported in this article are based on the interpretations of the radiologists who read them.


The duration of anosmia symptoms among the 28 patients ranged from 1 month to 2 years (median: 3 mo) (table 1). Twenty-two patients said that the onset of their symptoms had been sudden, while the other six reported a gradual loss of smell over a period of 2 to 4 weeks. No patient had complained of nasal obstruction or drainage. Twenty-one patients reported that they had experienced a URI prior to the onset of their anosmia. Three patients had a history of environmental allergy that was adequately controlled with oral antihistamines.

Nasal examination (anterior rhinoscopy and nasal endoscopy) had revealed a deviation of the nasal septum in five patients and inferior turbinate hypertrophy in four. Physical examination showed that the nasal airway in these nine patients had been narrowed by less than 25% in three patients, between 25 and 50% in five, and more than 50% in one. In no case was the narrowing judged to be severe enough to block airflow to the olfactory region. Among the remaining 19 patients, findings on nasal examination were unremarkable.

All patients had been started on a tapering short course of an oral corticosteroid (usually methylprednisolone) and a I-month course of a steroid nasal spray. Those who experienced either a partial or complete recovery of smell function were continued on the nasal spray for 2 additional months.

Twenty patients had undergone contrast-enhanced MRI of the brain and paranasal sinuses as part of their evaluation. A maxillary retention cyst was detected in three of these patients, mild mucosal thickening in the maxillary and ethmoid sinuses in two, a nasopalatine cyst in one, and a deep-lobe parotid tumor in one (table 2). Findings on the remaining 13 MRI studies were normal.

Enhanced CT had been performed on eight patients. CT detected a maxillary sinus retention cyst in one patient and mild mucosal thickening involving the maxillary sinuses in another (table 2). Findings on the remaining six CT scans were normal.

The nasopalatine cyst and the parotid gland tumor discovered by MRI were not associated with the olfactory deficit in these two patients. The detection of a maxillary sinus retention cyst in four patients was considered to be an incidental finding that did not contribute to the anosmia. Similarly, the mucosal thickening seen in the maxillary and ethmoid sinuses of three patients was mild; the ostiomeatal complex was patent in all three of these patients, and none exhibited any air-fluid level in the paranasal sinuses. These three patients did not report any sinonasal symptoms other than anosmia, and their nasal examination did not reveal mucosal inflammation or mucopurulent drainage. As a result, they were not diagnosed with sinusitis and they were not treated with antibiotics.

The attainment of imaging studies did not alter the medical treatment of any of the patients in this series. The etiology of the anosmia was determined to be postviral (post-URI) in 21 patients and idiopathic in seven. Five of the patients with postviral anosmia and one with idiopathic anosmia subsequently reported that they had experienced either a partial or full recovery of their sense of smell.


There is no site-of-lesion testing similar to auditory evoked potentials available to help assess olfactory disorders. Electrophysiologic tests such as olfactory evoked potentials and electro-olfactography are primarily confined to research efforts and are generally not available in the patient care setting. Consequently, efforts to determine the nature of the underlying pathology are based primarily on the clinical evaluation. This entails a detailed medical history, physical examination (including the neurologic system), and nasal endoscopy. Imaging studies are generally obtained when an anatomic deformity or obstruction is suspected, when there is a history of nasal or sinus disease, or when the diagnosis is not clear. The most frequently utilized imaging studies are MRI and CT. (5,6) Functional MRI has been used for precise localization of olfactory processing, and might allow for more accurate diagnoses of olfactory disorders in the future. (7)

Nasal inflammatory diseases such as rhinosinusitis, rhinitis, and nasal polyposis are the most common and most treatable types of olfactory dysfunction. (8) Sinonasal disease causes olfactory loss mainly by limiting the airflow to the olfactory region. (9) Such patients typically complain of nasal congestion or obstruction. Anterior rhinoscopy and nasal endoscopy can assess the degree of obstruction of the nasal airway. A recent study by Kern identified inflammatory changes in the olfactory mucosa of patients with rhino sinusitis that can be responsible, at least in part, for an olfactory deficit. (8) However, the author is not aware of any report in the English-language literature in which anosmia was the only symptom of rhinosinusitis.

Intranasal masses such as polyps or neoplasms can cause anosmia either by interfering with the patency of the nasal airway or by directly destroying the olfactory receptors. Soft-tissue masses of this size present with nasal obstruction or epistaxis, with anosmia being a late symptom. (10) Such masses are readily visualized with nasal endoscopy.

Numerous central nervous system disorders are associated with olfactory dysfunction. They include Alzheimer's disease, (11) Parkinson's disease, (12) Huntington's disease, Korsakoff's psychosis, schizophrenia, congenital anosmia (most commonly Kallmann's syndrome), head trauma, and brain tumor. (5) The multiplanar capability of MRI is especially advantageous in the evaluation of brain disorders.

Patients with Alzheimer's disease have been shown to have a significantly poorer average olfactory threshold sensitivity than do age-matched controls. (11) This phenomenon is believed to be neurologically mediated. On brain imaging, the anterior olfactory nuclei, olfactory bulbs, amygdala, and temporal lobes in Alzheimer's patients exhibit senile plaques, neurofibrillary tangles, granulo-vascular degeneration, and cell loss. (5)

Patients with Parkinson's disease experience a generalized impairment of olfactory identification that does not correlate with disease duration, motor function, tremor, or cognition. (12) The major feature of Parkinson's disease on MRI appears to be a trend toward a narrowing of the pars compacta of the substantia nigra. Positron-emission tomography and single-photon-emission tomography can reveal a moderate global decrease in cerebral metabolism, especially in the temporoparietal region. (5)

The prevalence of chemosensory changes caused by intracranial tumors has rarely been investigated. In a study of 750 consecutive patients with chemosensory disorders seen at the University of Pennsylvania's Smell and Taste Center, only two cases (0.3%) were induced by brain tumors. (13) In general, tumors that involve the olfactory bulb, olfactory tract, or prefrontal lobe can cause olfactory deficits, while temporal lobe tumors are associated with olfactory hallucination. However, patients with tumors usually have visual complaints or other telling central nervous system signs and symptoms. In a series of 36 patients with olfactory meningiomas, Bakay found that 83% had visual deficits. (14) In addition, 70% of these patients had mental changes such as dementia, disorientation, speech disorders, and urinary and fecal incontinence.

In the present series, the author excluded patients who had a known neurologic disorder and those who complained of visual changes or other neurologic symptoms. The brain imaging scans of those who were studied did not produce any findings that would elucidate the etiology of anosmia in any of the 28 patients. Furthermore, these imaging studies did not detect any sinonasal pathology relevant to anosmia that was missed by the medical history and nasal examination, including nasal endoscopy. Considering the cost and potential morbidity of medical imaging, the author believes that sinonasal and brain imaging is not indicated in the evaluation of patients who have an isolated complaint of anosmia without other neurologic signs and symptoms and in whom the nasal examination, including nasal endoscopy, is unremarkable. However, this recommendation cannot be extrapolated to encompass all patients with olfactory deficits, because the present series is small. Larger studies are needed to better address this issue.

The role of objective olfactory testing in the diagnosis and treatment of olfactory disorders is controversial. The diagnosis of anosmia in this study was based on the medical history, without objective olfactory function testing. However, the author believes that his findings and recommendations would not have been any different had the olfactory loss been only partial. In order for sinonasal disease or central nervous system disorders (including tumors) to cause a complete loss of olfaction, the pathology would have had to be more advanced than that which causes a partial loss. Instead of having anosmia alone, patients with these conditions are likely to exhibit signs or symptoms of their disease other than an olfactory complaint.

In conclusion, imaging studies in this investigation did not add any information to that available from the clinical history and endoscopic nasal examination with respect to determining the cause of anosmia. Therefore, the author does not recommend imaging studies as part of the evaluation of the patient who has an isolated complaint of anosmia and in whom the endoscopic nasal examination is unremarkable.


(1.) Mott AE, Leopold DA. Disorders in taste and smelt. Med Clin North Am 1991;75:1321-53.

(2.) Snow JB. Causes of olfactory and gustatory disorders. In: Getchell TV, Bartoshuk LM, Doty RL, Snow JB, eds. Smell and Taste in Health and Disease. New York: Raven Press, 1991:445-9.

(3.) Loury M, Kennedy DW. Chronic sinusitis and nasal polyposis. In: Getchell TV, Bartoshuk LM, Doty RL, Snow JB, eds. Smell and Taste in Health and Disease. New York: Raven Press, 1991:711-30.

(4.) Leopold DA. Olfactory function and disorders. In: Bailey BJ, ed. Head and Neck Surgery--Otolaryngology. Vol. 1. Philadelphia: J.B. Lippincott, 1993:250-61.

(5.) Li C, Yousem DM, Doty RL, Kennedy DW. Neuroimaging in patients with olfactory dysfunction. AJR Am J Roentgenol 1994;162:411-8.

(6.) Suzuki M, Takashima T, Kadoya M, et al. MR imaging of olfactory bulbs and tracts. AJNR Am J Neuroradiol 1989;10:955-7.

(7.) Koizuka I, Yano H, Nagahara M, et al. Functional imaging of the human olfactory cortex by magnetic resonance imaging. ORL J Otorhinolaryngol Relat Spec 1994;56:273-5.

(8.) Kern RC. Chronic Sinusitis and anosmia: Pathologic changes in the olfactory mucosa. Laryngoscope 2000;110:1071-7.

(9.) Doty RL, Frye R. Influence of nasal obstruction on smell function. Otolaryngol Clin North Am 1989;22:397-411.

(10.) Cantrell RW, Ghorayeb BY, Fitz-Hugh OS. Esthesioneuroblastoma: Diagnosis and treatment. Ann Otol Rhinol Laryngol 1977;86:760-5.

(11). Feldman JI, Murphy C, Davidson TM, et al. The rhinologic evaluation of Alzheimer's disease. Laryngoscope 1991;10l:1198-202.

(12.) Hawkes CH, Shephard BC. Selective anosmia in Parkinson's disease? Lancet 1993;341:435-6.

(13.) Deems DA, Doty RL, Settle RG, et al. Smell and taste disorders, a study of 750 patients from the University of Pennsylvania Smell and Taste Center. Arch Otolaryngol Head Neck Surg 1991;117:519-28.

(14.) Bakay L. Olfactory meningiomas: The missed diagnosis. JAMA 1984;251:53-5.

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COPYRIGHT 2002 Gale Group

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