Diagnosing a patient can be difficult as they are often frustrated from ineffective therapy and being told they have mental illnesses. Some patients actually have trouble deciding whether they have a taste or smell problem. In this case asking questions about food choices will help determine whether a patient has a smell or taste disorder. It is important to identify whether the distortion applies to an inhaled odorant or if an odor exists without the stimulus. The distortion of an odorant is presented in two types: the stimuli are different from what one remembers and in the second, everything has a similar smell. A clinical history can also help determine what kind of disorder one has because events such as respiratory infection and head trauma are usually indications of parosmia where as phantosmias usually have no history of such events and occur spontaneously. Unfortunately there are no accurate diagnostic tests or methods for dysosmia. Evaluation must be done through questionnaires and medical history.

The most challenging task for the examiner is to determine and obtain the correct symptoms and associate them with one of the olfactory disorders, as there are several of them and they are related to each other.

The first step the examiner usually takes is to investigate if the problem is olfactory or gustatory related. As it may be that the patient releases certain bodily odors that are causing them to have this perception.

If the examiner is able to confirm that the problem is olfactory related, the next step is to determine which olfactory disorder the patient suffers from. The following is a list of possible olfactory disorders:

- anosmia

- dysosmia

- hyperosmia

- hyposmia

- parosmia or troposmia

- phantosmia

The second step is very difficult for both the examiner and the patient as the patient has some difficulty describing their perception of the phantom odor. Furthermore, the patient is in a position of stress and anxiety thus it is crucial that the examiner be patient.

After determining the nature of the disorder, and confirming phantosmia, the examiner must then have the patient describe their perception of the phantom odor. In many cases, patients have described the odor to be that of something burning and rotten and have described it to be unpleasant and foul.

The third step for the examiner is to determine the health history of the patient to take note of head trauma, accidents, upper respiratory infections, allergic rhinitis or chronic rhinitis. Although these may be events that have resulted in the phantom odor, studies conducted by Zilstrof have found that the majority of phantosmia patients have no previous history of head trauma and upper respiratory infections.

Anosmia can be diagnosed by doctors by using acetylcysteine tests. Doctors will begin with a detailed elicitation of history. Then the doctor will ask for any related injuries in relation to anosmia which could include upper respiratory infections or head injury. Psychophysical Assessment of order and taste identification can be used to identify anosmia. A nervous system examination is performed to see if the cranial nerves are damaged. The diagnosis as well as the degree of impairment can now be tested much more efficiently and effectively than ever before thanks to "smell testing kits" that have been made available as well as screening tests which use materials that most clinics would readily have. Occasionally, after accidents, there is a change in a patient's sense of smell. Particular smells that were present before are no longer present. On occasion, after head traumas, there are patients who have unilateral anosmia. The sense of smell should be tested individually in each nostril.

Many cases of congenital anosmia remain unreported and undiagnosed. Since the disorder is present from birth the individual may have little or no understanding of the sense of smell, hence is unaware of the deficit. It may also lead to reduction of appetite.

Fortunately for patients afflicted with parosmia, symptoms usually decrease with time. Although there are instances of parosmia affecting patients for years at a time, this is certainly not the majority of cases. There have been experiments done to treat parosmia with L-Dopa, but besides that there are no current treatments other than inducing anosmia or hyposmia to the point where the odors are negligible.

The frequency of phantosmia is rare in comparison with the frequency of parosmia. Parosmia has been estimated to be in 10-60% of patients with olfactory dysfunction and from studies, it has been shown that it can last anywhere from 3 months to 22 years. Smell and taste problems result in over 200,000 visits to physicians annually in the US. Lately, it has been thought that phantosmia might co-occur with Parkinson's disease. However, its potential to be a premotor biomarker for Parkinson's is still up for debate as not all patients with Parkinson's disease have olfactory disorders

Due to the rareness of the disorder there is no well-defined treatment. Sometimes the patients are just told to live with the disorder or the patients end up performing "stereotypical methods" that might help in reducing the severity of the odor. This might include forced crying, bending over holding knees while holding breath, rinsing the nose with saline water and gagging. All these behaviours at the end fail to resolve the hallucination. Various treatments like prophylactic have been suggested but more research is needed for its confirmation. Also, due to being a poorly understood disorder, and having analogies to some psychiatric conditions, some patients are told that they have a mental illness. It is also usual for these patients to have suicidal thoughts as they are not provided with much support or hope from many physicians.

One of the surgical treatments proposed has included olfactory bulb ablation through a bifrontal craniotomy approach. But a counter-argument by Leopold, Loehrl and Schwob (2002) has stated that this ablation process results in a bilateral permanent anosmia and includes risks associated with a craniotomy. According to them, the use of transnasal endoscopic exhibition of olfactory epithelium is a safe and effective treatment for patients with unremitting Phantosmia with the olfactory function being potentially spared.

It is also cautioned that the surgery is challenging one and is associated with major risks, and that it should be restricted to expertise centres.

On the other hand, many cases have also reported that the strength of their symptoms have decreased with time. (Duncan and Seidan, 1995)

A case involving long term phantosmia has been treated with the use of an anti depressive medication by the common name Venlafaxine. The brand name of the drug is Effexor. The relation between mood disorders and phantosmia is unknown, and is a widely researched area. In many cases, the symptoms of phantosmia have been reduced by the use of anti seizure and anti depressants that act on the central and peripheral neurons.

The most commonly used treatment method is the removal of the olfactory epithelium or the bulb by means of surgery to alleviate the patient from the symptoms.

Other traditional methods include the use of topical anesthetics (Zilstorff-Pederson, 1995) and use of sedatives.

One method used to establish parosmia is the University of Pennsylvania Smell Identification Test, or UPSIT. "Sniffin' Sticks" are another method that can be used to properly diagnose parosmia. These different techniques can also help deduce whether a specific case of parosmia can be attributed to just one stimulating odor or if there is a group of stimulating odors that will generate the displaced smell. One case study performed by Frasnelli "et al." offers a situation where certain smells, specifically coffees, cigarettes, onions, and perfumes, induced a "nauseating" odor for the patient, one which was artificial but unable to be aptly related to another known smell. In another case study cited in the same paper, one woman had parosmia in one nostril but not the other. Medical examinations and MRIs did not reveal any abnormalities; however the parosmia in this case was degenerative and only got worse with time. The authors do comment, however, that cases of parosmia can predict regeneration of olfactory senses.

Though anosmia caused by brain damage cannot be treated, anosmia caused by inflammatory changes in the mucosa may be treated with glucocorticoids. Reduction of inflammation through the use of oral glucocorticoids such as prednisone, followed by long term topical glucocorticoid nasal spray, would easily and safely treat the anosmia. A prednisone regimen is adjusted based on the degree of the thickness of mucosa, the discharge of oedema and the presence or absence of nasal polyps. However, the treatment is not permanent and may have to be repeated after a short while. Together with medication, pressure of the upper area of the nose must be mitigated through aeration and drainage.

Anosmia caused by a nasal polyp may be treated by steroidal treatment or removal of the polyp.

There have also been cases where the use of acupuncture have successfully treated anosmia.

Although very early in development, gene therapy has restored a sense of smell in mice with congenital anosmia when caused by ciliopathy. In this case a genetic condition had affected cilia in their bodies which normally enabled them to detect air-borne chemicals, and an adenovirus was used to implant a working version of the IFT88 gene into defective cells in the nose, which restored the cilia and allowed a sense of smell.

Hyposmia is a reduced ability to smell and to detect odors. A related condition is anosmia, in which no odors can be detected. Some of the causes of olfaction problems are allergies, nasal polyps, viral infections and head trauma. It is estimated that up to 4 million people in the United States have hyposmia or the related anosmia.

Hyposmia might be a very early sign of Parkinson's disease. Hyposmia is also an early and almost universal finding in Alzheimer's disease and dementia with Lewy bodies. Lifelong hyposmia could be caused by Kallmann syndrome.

The presence of the disease can be confirmed with a genetic test. In a study of 10 infants with clinical indications of NSML prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient with the suspected mutation was subsequently found to have NF1, following evaluation of the mother.

There are 5 identified allelic variants responsible for NSML. Y279C, T468M, A461T, G464A, and Q510P which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion.

The olfactory system is the system related to the sense of smell (olfaction). Many fish activities are dependent on olfaction, such as: mating, discriminating kin, avoiding predators, locating food, contaminant avoidance, imprinting and homing. These activities are referred to as “olfactory-mediated.” Impairment of the olfactory system threatens survival and has been used as an ecologically relevant sub-lethal toxicological endpoint for fish within studies. Olfactory information is received by sensory neurons, like the olfactory nerve, that are in a covered cavity separated from the aquatic environment by mucus. Since they are in almost direct contact with the surrounding environment, these neurons are vulnerable to environmental changes. Fish can detect natural chemical cues in aquatic environments at concentrations as low as parts per billion (ppb) or parts per trillion (ppt).

Studies have shown that exposures to metals, pesticides, or surfactants can disrupt fish olfaction, which can impact their survival and reproductive success. Many studies have indicated copper as a source of olfactory toxicity in fishes, among other common substances. Olfactory toxicity can occur by multiple, complex Modes of Toxic Action.

The diagnosis is often one of exclusion found during the workup of delayed puberty.

A paper published in 2012 by Prof. Jacques Young highlights a typical example of the diagnostic work up involved in a suspected case of KS/CHH.

One of the biggest problems in the diagnosis of KS and other forms of CHH is the ability to distinguish between a normal constitutional delay of puberty and KS or CHH.

The main biochemical parameters in men are low serum testosterone and low levels of the gonadotropins LH and FSH, and in women low serum oestrogen and low levels of LH and FSH.

For both males and females with constitutional delay of puberty, endogenous puberty will eventually commence without treatment. However a delay in treatment in a case of KS/HH will delay the physical development of the patient and can cause severe psychological damage. The "wait and see" approach applied to "late bloomers" is probably counterproductive to the needs of the patient whereas a step-by-step approach with hormone replacement therapy used with slowly increasing doses can be used as a diagnostic tool.

Post natal diagnosis of KS / CHH before the age of 6 months is sometimes possible. The normal post natal hormonal surge of gonadotropins along with testosterone or oestrogen is absent in babies with KS / CHH. This lack of detectable hormones in the blood can be used as a diagnostic indicator, especially in male infants.

Normally testicular enlargement is the key sign for the onset of puberty in boys however the use of nighttime LH sampling can help predict the onset of puberty.

In females diagnosis is sometimes further delayed as other causes of amenorrhoea normally have to be investigated first before a case of KS/CHH is considered. KS/CHH can still occur in females in cases when menstruation has begun but stopped after one or two menstrual bleeds. A study of GnRH deficient women in 2011 showed that 10% had experienced one or two bleeds before the onset of amenorrhoea.

In males, treatment with age-appropriate levels of testosterone can be used to distinguish between a case of KS/CHH from a case of delayed puberty. If just delayed the testosterone can "kick-start" endogenous puberty, as demonstrated by testicular enlargement, whereas in the case of KS/CHH there will be no testicular enlargement while on testosterone therapy alone. If no puberty is apparent, especially no testicular development, then a review by a reproductive endocrinologist may be appropriate. Dr Richard Quinton, a leading UK expert on KS/CHH, suggests that if puberty is not apparent by the age of 16 then the patient should be referred for endocrinological review.

A full endocrine workup will be required to measure the levels of the other pituitary hormones, especially prolactin, to check that the pituitary gland is working correctly. There can be other general health issues such as being overweight or having an underlying chronic or acute illness which could cause a delay of puberty. This makes it essential for a patient to get a full endocrine review to distinguish between a case of KS/CHH and another cause for the pubertal delay.

Bone age can be assessed using hand and wrist X-rays. If the bone age is significantly lower than the chronological age of the patient, this could suggest delayed puberty unless there is another underlying reason for the discrepancy.

A karyotype may be performed to rule out Klinefelter syndrome and Turner syndrome, although the hormones levels would also rule out both these relatively common reasons for hypogonadism.

A magnetic resonance imaging (MRI) scan can be used to determine whether the olfactory bulb is present and to check for any physical irregularities of the pituitary gland or hypothalamus.

A standard smell test can be used to check for anosmia, but it must be remembered that even in total anosmia various substances (such as menthol and alcohol) can still be detected by direct stimulation of the trigeminal nerve.

Genetic screening can be carried out, but in light of the unknown genes involved in the majority of KS and CHH cases, a negative result will not rule out a possible diagnosis.

A review paper published in 2014 highlighted the need for doctors to be aware of the possible diagnosis of KS / HH if pubertal delay is found alongside associated "red flag" symptoms. The symptoms listed in the paper were split into two categories; reproductive symptoms associated with the lack of mini puberty seen between birth and six months of age and non-reproductive symptoms which are associated with specific forms of HH. As with other review papers the authors also warned against the "wait and see" approach when puberty appears to be delayed.

It is suggested that, once diagnosed, individuals be routinely followed by a cardiologist, endocrinologist, dermatologist, and other appropriate specialties as symptoms present.

It is recommended that those with the syndrome who are capable of having children seek genetic counseling before deciding to have children. As the syndrome presents frequently as a "forme fruste" (incomplete, or unusual form) variant, an examination of all family members must be undertaken. As an autosomal dominant trait there is a fifty percent chance with each child that they will also be born with the syndrome. Although fully penetrant, since the syndrome has variable expressivity, one generation may have a mild expression of the syndrome, while the next may be profoundly affected.

Once a decision to have children is made, and the couple conceives, the fetus is monitored during the pregnancy for cardiac evaluation. If a gross cardiac malformation is found, parents receive counseling on continuing with the pregnancy.

Other management is routine care as symptoms present:

1. For those with endocrine issues (low levels of thyrotopin [a pituitary hormone responsible for regulating thyroid hormones], follicle stimulating hormone) drug therapy is recommended.

2. For those who are disturbed by the appearance of lentigines, cryosurgery may be beneficial. Due to the large number of lentigines this may prove time consuming. An alternative treatment with tretinoin or hydroquinone creams may help.

3. Drug therapies for those with cardiac abnormalities, as those abnormalities become severe enough to warrant the use of these therapies. ECG's are mandatory prior to any surgical interventions, due to possible arrythmia.

The third indicator is the presence of clues to specific disorders of the reproductive system.

- Malnutrition or anorexia nervosa severe enough to delay puberty will give other clues as well.

- Poor growth would suggest the possibility of coeliac disease, hypopituitarism or Turner syndrome.

- Reduced sense of smell (hyposmia) or no sense of smell (anosmia) suggests Kallmann syndrome.

The first is simply degree of lateness: although no recommended age of evaluation cleanly separates pathologic from physiologic delay, a delay of 2–3 years or more warrants evaluation.

- In girls, no breast development by 13 years, or no menarche by 3 years after breast development (or by 16).

- In boys, no testicular enlargement by 14 years, or delay in development for 5 years or more after onset of genitalia enlargement.

A delay of two standard deviations has been proposed as a standard.

Reversal of symptoms have been reported in between 15% to 22% of cases. The causes of this reversal are still under investigation but have been reported in both males and females.

Reversal appears to be associated with 14 of the known gene defects linked to KS/CHH. The study suggests no obvious gene defect showing a tendency to allow reversal. There is a suggestion that the TAC3 and TACR3 mutations might allow for a slightly higher chance of reversal, but the numbers involved are too low to confirm this. The ANOS1 mutations appear to be least likely to allow reversal with to date only one recorded instance in medical literature. Even male patients who previous had micro-phallus or cryptorchidism have been shown to undergo reversal of symptoms.

The reversal might not be permanent and remission can occur at any stage; the paper suggests that this could be linked to stress levels. The paper highlighted a reversal case that went into remission but subsequently achieved reversal again, strongly suggesting an environmental link.

Reversal cases have been seen in cases of both KS and normosmic CHH but appear to be less common in cases of KS (where the sense of smell is also affected). A paper published in 2016 agreed with the theory that there is a strong environmental or epigenetic link to the reversal cases. The precise mechanism of reversal is unclear and is an area of active research.

Reversal would be apparent if testicular development was seen in men while on testosterone therapy alone or in women who menstruate or achieved pregnancy while on no treatment. To date there have been no recorded cases of the reversal of anosmia found in Kallmann syndrome cases.

Early investigation by Hasler and Wisby (1951) examined how fish use olfactory imprinting to discriminate smells in order for fish to find their natal streams. This research provided the framework for testing synthetic chemicals used by hatcheries to examine homing and straying by hatchery fish. The investigation of the toxicity of mercury and copper to the olfactory systems in fish began in the early 1970s. Where they found that solutions of mercury chloride (HgCl) and copper sulfate (CuSO) depressed olfactory response during exposure to the two toxicants and found that toxicant concentration and olfactory response had an inverse relationship to each other.

Esthesioneuroblastoma can resemble small blue cell tumors like squamous cell carcinoma, sinonasal undifferentiated carcinoma, extranodal NK/T cell lymphoma, nasal type, rhabdomyosarcoma, Ewing/PNET, mucosal malignant melanoma and neuroendocrine carcinomas (NEC) that occur in the intranasal tract. Compared to other tumors in the region, esthesioneuroblastoma has the best prognosis, with an overall 5 year survival rate of 60-80%. Fewer than 700 cases have been documented in the United States alone. Esthesioneuroblastoma is characterized by neurofibrillary stroma and neurosecretary granules that are not seen concurrently by any other pathologies in the region. Histological tests such as keratin, CK5/6, S-100 protein or NSE can be run to further differentiate esthesioneuroblastoma from other tumors.

Esthesioneuroblastoma is a slow developing but malignant tumor with high reoccurrence rates because of its anatomical position. The tumor composition, location and metastatic characteristics as well as the treatment plan determine prognosis. Common clinical classification systems for esthesioneuroblastoma include the Kadish classification and the Dulguerov classfictation. Histopathological characteristics on top of Kadish classification can further determine cancer prognosis. In severe, Kadish class C tumors, Haym's grades of pathology are important for prognosis. Patients with low grade Kadish class C tumors have a 10-year survival rate of 86 percent compared to patients with high grade class C tumors who have a survival rate of 28 percent. Surgically treated patients with high grade tumors are more likely to experience leptomeningeal metastases or involvement of the cerebral spinal fluid unlike patients with low grade tumors who usually only see local recurrence. Survival rates for treated esthesioneuroblastoma are best for surgery with radiotherapy (65%), then for radiotherapy and chemotherapy (51%), just surgery (48%), surgery, radiotherapy and chemotherapy (47) and finally just radiotherapy (37%). From the literature, radiotherapy and surgery seem to boast the best outcome for patients. However, it is important to understand that to some degree, prognosis is related to tumor severity. More progressed, higher grade tumors would result in chemotherapy or radiotherapy as the only treatment. It is no surprise that the prognosis would be worse in these cases.