The diagnosis of immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is consistent with the following criteria:

- Clinical examination

- Family history

- Laboratory findings

- Genetic testing

In the heart, there are two forms of the hypereosinophilic syndrome, endomyocardial fibrosis and Loeffler's endocarditis.

- Endomyocardial fibrosis (also known as Davies disease) is seen in tropical areas.

- Loeffler's endocarditis does not have any geographic predisposition.

The old diagnostic criteria for the illness included: Chronic non-malignant lymphoproliferation, elevated peripheral blood DNTs and defective in vitro Fas mediated apoptosis.

The new criteria require chronic non-malignant lymphoproliferation (over six months lymphadenopathy and/or splenomegaly), elevated peripheral blood DNTs. A primary accessory in diagnosis is defective in vitro Fas mediated apoptosis and somatic or germline mutation in ALPS causative gene (FAS, FASL, CASP10).

The secondary accessory in diagnosis are elevated biomarkers (plasma sFASL over 200 pg/ml, plasma IL-10 >20 pg/ml, plasma or serum vitamin B12 >1500 ng/L, Plasma IL-18 >500pg/ml) and immunohistochemical findings on biopsy consistent with ALPS as determined by an experienced hematopathologist. Another sign is autoimmune cytopenias and polyclonal hypergammaglobulinemia and a family history of ALPS or non-malignant lymphoproliferation.

A definitive diagnosis is chronic non-malignant lymphoproliferation and/or elevated peripheral blood DNTs plus one primary accessory criterion. A probable diagnosis is the same but with one secondary accessory criterion.

Numerous techniques are used to diagnose hypereosinophilic syndrome, of which the most important is blood testing. In HES, the eosinophil count is greater than 1.5 × 10/L. On some smears the eosinophils may appear normal in appearance, but morphologic abnormalities, such as a lowering of granule numbers and size, can be observed. Roughly 50% of patients with HES also have anaemia.

Secondly, various imaging and diagnostic technological methods are utilised to detect defects to the heart and other organs, such as valvular dysfunction and arrhythmias by usage of echocardiography. Chest radiographs may indicate pleural effusions and/or fibrosis, and neurological tests such as CT scans can show strokes and increased cerebrospinal fluid pressure.

A proportion of patients have a mutation involving the "PDGFRA" and "FIP1L1" genes on the fourth chromosome, leading to a tyrosine kinase fusion protein. Testing for this mutation is now routine practice, as its presence indicates response to imatinib, a tyrosine kinase inhibitor.

2003 nomenclature

- IA - Fas

- IB - Fas ligand

- IIA - Caspase 10

- IIB - Caspase 8

- III - unknown

- IV - Neuroblastoma RAS viral oncogene homolog

Revised nomenclature (2010)

- ALPS-FAS: Fas. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described.

- ALPS-sFAS: Fas. Somatic FAS mutations in DNT compartment. 10% of patients

- ALPS-FASL: Fas ligand. Germline FASL mutations. 3 reported cases

- ALPS-CASP10: Caspase 10. Germline CASP10 mutation. 2% of patients

- ALPS-U: Undefined. 20% of patients

- CEDS: Caspase 8 deficiency state. No longer considered a subtype of ALPS but distinct disorder

- RALD: NRAS, KRAS. Somatic mutations in NRAS and KRAS in lympocyte compartment. No longer considered a subtype of ALPS but distinct disesase

Once a diagnosis is made, the treatment is based on an individual’s clinical condition. Based on the apparent activation of the mTOR pathway, Lucas and colleagues treated patients with rapamycin, an mTOR inhibitor. This effectively reduced hepatosplenomegaly and lymphadenopathy, most likely by restoring the normal balance of naïve, effector, and memory cells in the patients’ immune system. More research is needed to determine the most effective timing and dosage of this medication and to investigate other treatment options. Investigators at the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health currently have clinical protocols to study new approaches to the diagnosis and treatment of this disorder.

In terms of treatment the following are done to manage the IPEX syndrome in those affected individuals(corticosteroids are the first treatment that is used):

- TPN(nutritional purpose)

- Cyclosporin A and FK506

- Sirolimus(should FK506 prove non-effective)

- Granulocyte colony stimulating factor

- Bone marrow transplant

- Rituximab

The MRI of patients with VWM shows a well defined leukodystrophy. These MRIs display reversal of signal intensity of the white matter in the brain. Recovery sequences and holes in the white matter are also visible. Over time, the MRI is excellent at showing rarefaction and cystic degeneration of the white matter as it is replaced by fluid. To show this change, displaying white matter as a high signal (T2-weighted), proton density, and Fluid attenuated inversion recovery (FLAIR) images are the best approach. T2-weighted images also displaying cerebrospinal fluid and rarefied/cystic white matter. To view the remaining tissue, and get perspective on the damage done (also helpful in determining the rate of deterioration) (T1-weighted), proton density, and FLAIR images are ideal as they show radiating stripe patterns in the degenerating white matter. A failure of MRI images is their ineffectiveness and difficulty in interpretation in infants since the brain has not fully developed yet. Though some patterns and signs may be visible, it is still difficult to conclusively diagnose. This often leads to misdiagnosis in infants particularly if the MRI results in equivocal patterns or because of the high water content in infants' brains. The easiest way to fix this problem is a follow-up MRI in the following weeks. A potentially similar appearance of MRI with white matter abnormalities and cystic changes may be seen in some patients with hypomelanosis of Ito, some forms of Lowe's (oculocerebrorenal) disease, or some of the mucopolysaccharidoses.

Franklin's disease (gamma heavy chain disease)

It is a very rare B-cell lymphoplasma cell proliferative disorder which may be associated with autoimmune diseases and infection is a common characteristic of the disease. It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. The most distinctive symptom is palatal edema, caused by nodal involvement of Waldeyer's ring.

Diagnosis is made by the demonstration of an anomalous serum M component that reacts with anti-IgG but not anti-light chain reagents. Bone marrow examination is usually nondiagnostic.

Patients usually have a rapid downhill course and die of infection if left untreated or misdiagnosed.

Patients with Franklin disease usually have a history of progressive weakness, fatigue, intermittent fever, night sweats and weight loss and may present with lymphadenopathy (62%), splenomegaly (52%) or hepatomegaly (37%). The fever is considered secondary to impaired cellular and humoral immunity, and thus recurrent infections are the common clinical presentation in Franklin disease. Weng et al. described the first case of Penicillium sp. infection in a patient with Franklin disease and emphasized the importance of proper preparation for biopsy, complete hematologic investigation, culture preparation and early antifungal coverage to improve the outcome.

The γHCD can be divided into three categories based on the various clinical and pathological features. These categories are disseminated lymphoproliferative disease, localized proliferative disease and no apparent proliferative disease.

- Disseminated lymphoproliferative disease is found in 57-66% of patients diagnosed with γHCD. Lymphadenopathy and constitutional symptoms are the usual features.

- Localized proliferative disease is found in approximately 25% of γHCD patients. This is characterized by a localization of the mutated heavy chains in extramedullary tissue, or solely in the bone marrow.

- No apparent proliferative disease is seen in 9-17% of patients with γHCD, and there is almost always an underlying autoimmune disorder.

Following observation of the symptoms, the patients need to get complete blood counts and a bone marrow examination. If the patient has leukemia, the morphology and immunophenotype check is needed to make sure the type of leukemia.

The morphology of the blast in BAL is not certain. The cells could display both myeloid lineage and lymphoid or undifferentiated morphology. Therefore, the diagnosis cannot based on the morphology result. The immunophenotype check is the most important basis of the diagnosis of BAL.

Before 2008, the diagnosis of BAL was based on a score system proposed by the European Group for the Immunological Classification of Leukemias (EGIL) which could differentiate from other kinds of acute leukemia. The table shows this method.

If the score of only one lineage is higher than 2, the acute leukemia could be acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). According to the original EGIL scoring system BAL is defined when scores are over two points for both myeloid and T- or B- lymphoid lineages.

In 2008, WHO established a new and strict criteria standard for diagnosis of BAL. The presence of specific T-lymphoid antigens, cytoplasmic CD3 (cCD3), MPO and CD 19 became the most important standard for recognizing the lineage. Other B-lineage markers (CD22, CD79a, CD 10) and monocytic markers are also needed. Table 2 shows the method.

Compared with the EGIL scoring system, the current 2008 WHO criteria applied less but more specific markers to define the lineage of the blasts, and incorporated the intensity of markers expression into the diagnostic algorithm.

The diagnosis of BAL is so difficult that sometimes is misdiagnosed with AML or ALL because the morphology thus the therapy would not have a good effect.

Diagnosis requires a neurological examination and neuroimaging can be helpful.

BVVL can be differentially diagnosed from similar conditions like Fazio-Londe syndrome and amyotrophic lateral sclerosis, in that those two conditions don't involve sensorineural hearing loss, while BVVL, Madras motor neuron disease, Nathalie syndrome, and Boltshauser syndrome do. Nathalie syndrome does not involve lower cranial nerve symptoms, so it can be excluded if those are present. If there is evidence of lower motor neuron involvement, Boltshauser syndrome can be excluded. Finally, if there is a family history of the condition, then BVVL is more likely than MMND, as MMND tends to be sporadic.

Genetic testing is able to identify genetic mutations underying BVVL.

PASLI disease is a rare genetic disorder of the immune system. PASLI stands for “p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency.” The immunodeficiency manifests as recurrent infections usually starting in childhood. These include bacterial infections of the respiratory system and chronic viremia due to Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV). Individuals with PASLI disease also have an increased risk of EBV-associated lymphoma. Investigators Carrie Lucas, Michael Lenardo, and Gulbu Uzel at the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health and Sergey Nejentsev at the University of Cambridge, UK simultaneously described a mutation causing this condition which they called Activated PI3K Delta Syndrome (APDS).

Niemann–Pick Type B involves an enlarged liver and spleen hepatosplenomegaly, growth retardation, and problems with lung function including frequent lung infections. Other signs include blood abnormalities such as abnormal cholesterol and lipid levels, and low numbers of blood cells involved in clotting (platelets). The brain is not affected in Type B and the disease often presents in the pre-teen years.

Flow cytometry is a diagnostic tool in order to count/visualize the amount of lymphatic cells in the body. T cells, B cells and NK cells are nearly impossible to distinguish under a microscope, therefore one must use a flow cytometer to distinguish them.

In the classic presentation of the disease death usually occurs within 3 years, however there are rarely both fast and slower progressions. Faster deterioration in cases of acute fulminant SSPE leads to death within 3 months of diagnosis.

If the diagnosis is made during stage 1 of the SSPE infection then it may be possible to treat the disease with oral isoprinosine (Inosiplex) and intraventricular interferon alfa, but the response to these drugs varies from patient to patient. However, once SSPE progresses to stage 2 then it is universally fatal in all occurrences. The standard rate of decline spans anywhere between 1–3 years after the onset of the infection. The progression of each stage is unique to the sufferer and cannot be predicted although the pattern or symptoms/signs can be.

Although the prognosis is bleak for SSPE past stage 1, there is a 5% spontaneous remission rate—this may be either a full remission that may last many years or an improvement in condition giving a longer progression period or at least a longer period with the less severe symptoms.

Traditionally, mycosis fungoides has been divided into three stages: premycotic, mycotic and tumorous. The premycotic stage clinically presents as an erythematous (red), itchy, scaly lesion. Microscopic appearance is non-diagnostic and represented by chronic nonspecific dermatosis associated with psoriasiform changes in epidermis.

In the mycotic stage, infiltrative plaques appear and biopsy shows a polymorphous inflammatory infiltrate in the dermis that contains small numbers of frankly atypical lymphoid cells. These cells may line up individually along the epidermal basal layer. The latter finding if unaccompanied by spongiosis is highly suggestive of mycosis fungoides. In the tumorous stage a dense infiltrate of medium-sized lymphocytes with cerebroid nuclei expands the dermis.

Niemann–Pick Type A, the most common type, occurs in infants and is characterized by jaundice, an enlarged liver, failure to thrive, progressive deterioration of the nervous system and profound brain damage. Children affected by Niemann Pick Type A rarely live beyond 18 months. Niemann–Pick Type A occurs more frequently among individuals of Ashkenazi (eastern and central European) Jewish descent than in other ethnicities. The incidence within the Ashkenazi population is approximately 1 in 40,000 people. The incidence for other populations is 1 in 250,000 people.

The IgM type of heavy chain disease, μHCD, is often misdiagnosed as chronic lymphoid leukemia (CLL) because the two diseases are often associated with each other and show similar symptoms.

A diagnosis is made by measuring the enzymatic activity of alpha--mannosidase in white blood cells. If there is a decreased level of the enzyme in comparison to standard levels, a diagnosis can be made. It is thought that this disorder might be under-diagnosed for a few different reasons—the diagnosis is often made late in the disease's progression, symptoms are often mild, or the biochemical diagnosis does not yield conclusive results.

The individual was examined at age 32, but he stated that he started noting differences 5 years before. He noticed sexual impotency, social isolation, unexplained aggression and sadness, loss of motivation, inert laughs, auditory hallucinations, thought insertion, delusions, and imperative commenting. He showed very minimal physical impairments, commonly seen in child-onsets. However, his MRI showed characteristic signs of VWM disease.

A neurological examination would show evidence of muscle rigidity; weakness; and abnormal postures, movements, and tremors. If other family members are also affected, this may help determine the diagnosis. Genetic tests can confirm an abnormal gene causing the disease. However, this test is not yet widely available. Other movement disorders and diseases must be ruled out. Individuals exhibiting any of the above listed symptoms are often tested using MRI (Magnetic Resonance Imaging) for a number of neuro-related disorders. As PKAN is a disease prominently evident in the brain, MRIs are very useful in making a sound diagnosis. An MRI usually shows iron deposits in the basal ganglia. Development of diagnostic criteria continues in the hope of further separating PKAN from other forms of neurodegenerative diseases featuring NBIA.

The life expectancy in alpha-mannosidosis is highly variable. Individuals with early onset severe disease often do not survive beyond childhood, whereas those with milder disorders may survive well into adult life.

Diagnosing SS is complicated by the range of symptoms a patient may manifest, and the similarity between symptoms of SS and those of other conditions. Also, patients who have symptoms of SS approach different specialities regarding their symptoms which make the diagnosis difficult. Since the symptoms of this autoimmune disorder such as dry eyes and dry mouth are very common among people, and mostly observed from the age of 40 and above, it is often mistaken as age-related, thus ignored. However, some medications can also cause symptoms that are similar to those of SS. The combination of several tests, which can be done in a series, can eventually lead to the diagnosis of SS.

SS is usually classified as either 'primary' or 'secondary'. Primary Sjögren syndrome occurs by itself and secondary Sjögren syndrome occurs when another connective tissue disease is present.

Blood tests can be done to determine if a patient has high levels of antibodies that are indicative of the condition, such as antinuclear antibody (ANA) and rheumatoid factor (because SS frequently occurs secondary to rheumatoid arthritis), which are associated with autoimmune diseases. Typical SS ANA patterns are SSA/Ro and SSB/La, of which Anti-SSB/La is far more specific; Anti-SSA/Ro is associated with numerous other autoimmune conditions, but are often present in SS. However, Anti-SSA and Anti-SSB tests are frequently not positive in SS.

The rose bengal test uses a stain that measures state and function of the lacrimal glands. This test involves placing the non-toxic dye rose bengal on the eyes. The dye’s distinctive colour helps in determining the state and functioning of tear film and the rate of tear evaporation. Any distinctive colour change observed will be indicative of SS, but many related diagnostic tools will be used to confirm the condition of SS.

Schirmer's test measures the production of tears: a strip of filter paper is held inside the lower eyelid for five minutes, and its wetness is then measured with a ruler. Producing less than of liquid is usually indicative of SS. This measurement analysis varies among people depending on other eye-related conditions and medications in use when the test is taken. A slit-lamp examination can reveal dryness on the surface of the eye.

Symptoms of dry mouth and dryness in the oral cavity are caused by the reduced production of saliva from the salivary glands (parotid gland, submandibular gland, and sublingual gland). To check the status of salivary glands and the production of saliva, a salivary flow-rate test is performed, in which the person is asked to spit as much as they can into a cup, and the resulting saliva sample is collected and weighed. This test's results can determine whether the salivary glands are functioning adequately. Not enough saliva produced could mean the person has SS. An alternative test is non-stimulated whole saliva flow collection, in which the person spits into a test tube every minute for 15 minutes. A resultant collection of less than is considered a positive result.

A lip/salivary gland biopsy takes a tissue sample that can reveal lymphocytes clustered around salivary glands, and damage to these glands due to inflammation. This test involves removing a sample of tissue from a person’s inner lip/salivary gland and examining it under a microscope. In addition, a sialogram, a special X-ray test, is performed to see if any blockage is present in the salivary gland ducts (i.e. parotid duct) and the amount of saliva that flows into the mouth.

Also, a radiological procedure is available as a reliable and accurate test for SS. A contrast agent is injected into the parotid duct, which opens from the cheek into the vestibule of the mouth opposite the neck of the upper second molar tooth. Histopathology studies should show focal lymphocytic sialadenitis. Objective evidence of salivary gland involvement is tested through ultrasound examinations, the level of unstimulated whole salivary flow, a parotid sialography or salivary scintigraphy, and autoantibodies against Ro (SSA) and/or La (SSB) antigens.

SS can be excluded from people with past head and neck radiation therapy, acquired immunodeficiency syndrome (AIDS), pre-existing lymphoma, sarcoidosis, graft-versus-host disease, and use of anticholinergic drugs.

Diagnosis is sometimes difficult because the early phases of the disease often resemble eczema or even psoriasis. As with any serious disease,

it is advisable to pursue the opinion of a medical professional if a case is suspected. Diagnosis is generally accomplished through a skin biopsy. Several biopsies are recommended, to be more certain of the diagnosis. The diagnosis is made through a combination of the clinical picture and examination, and is confirmed by biopsy.

To stage the disease, various tests may be ordered, to assess nodes, blood and internal organs, but most patients present with disease apparently confined to the skin, as patches (flat spots) and plaques (slightly raised or 'wrinkled' spots).

Peripheral smear will often show buttock cells.

The prognosis for BAL patients is not good which is worse than ALL and AML. Medical Blood Institute reported cases of CR rate was 31.6%, with a median remission are less than 6 months

The median survival time is only 7.5 months. The life quality is also low because the immune function of patient is damaged seriously. They have to stay in hospital and need 24h care.

In another study, the results showed that young age, normal karyotype and ALL induction therapy will have a better prognosis than Ph+, adult patients. The study shows median survival of children is 139 months versus 11 months of adults, 139 months for normal karyotype patients versus 8 months for ph+ patients.