All people with ALPS have signs of lymphoproliferation, which makes it the most common clinical manifestation of the disease. The increased proliferation of lymphoid cells can cause the size of lymphoid organs such as the lymph nodes and spleen to increase (lymphadenopathy and splenomegaly, present in respectively over 90% and over 80% of patients). The liver is enlarged (hepatomegaly in 30 - 40% of patients).

Autoimmune disease is the second most common clinical manifestation and one that most often requires treatment. Autoimmune cytopenias: Most common. Can be mild to very severe. Can be intermittent or chronic. These include: Autoimmune hemolytic anemia, Autoimmune neutropenia, Autoimmune thrombocytopenia.

Other signs can affect organ systems similar to systemic lupus erythematosus (least common, affecting <5% of patients) Symptoms of the nervous system include: Autoimmune cerebellar ataxia; Guillain–Barré syndrome; transverse myelitis. Gastrointestinal signs like Autoimmune esophagitis, gastritis, colitis, hepatitis, pancreatitis can be found or (Dermatologic) Urticaria, (Pulmonary) bronchiolitis obliterans, (Renal) Autoimmune glomerulonephritis, nephrotic syndrome.

Another sign are cancers such as Hodgkin and non-Hodgkin lymphomas which appear to be increased, possibly due to Epstein–Barr virus-encoded RNA-positivity. Some carcinomas may occur. Unaffected family members with genetic mutations are also at an increased risk of developing cancer.

Clinically, RALD is characterized by splenomegaly, a relatively mild degree of peripheral lymphadenopathy, and autoimmunity. The autoimmune phenotype can present in childhood or adulthood and primarily includes autoimmune hemolytic anemia, ITP, and neutropenia. Some patients have a history of recurrent respiratory tract infections. It is unclear if increased risk for malignancy is part of RALD.

Importantly, however, the clinical and laboratory phenotype resembles juvenile myelomonocytic leukemia. The high fatality rate of this childhood blood cancer puts it in sharp contrast when compared to the relatively benign and chronic course of RALD. Approximately 15-30% of patients diagnosed with JMML have somatic, activating RAS mutations. However, due to the difficulty in distinguishing JMML from RALD, it is possible a subset of patients treated for JMML actually have RALD and could therefore avoid the aggressive JMML treatment. This distinction is under investigation.

RAS-associated autoimmune leukoproliferative disorder (RALD) is a rare genetic disorder of the immune system. RALD is characterized by lymphadenopathy, splenomegaly, autoimmunity, and elevation in granulocytes and monocytes. It shares many features with autoimmune lymphoproliferative syndrome and is caused by somatic mutations in NRAS or KRAS. This was first described by investigators João Oliveira and Michael Lenardo from the National Institutes of Health.

Lymphoproliferative disorders (LPDs) refer to several conditions in which lymphocytes are produced in excessive quantities. They typically occur in people who have a compromised immune system. They are sometimes equated with "immunoproliferative disorders", but technically lymphoproliferative disorders are a subset of immunoproliferative disorders, along with hypergammaglobulinemia and paraproteinemias.

Lymphoproliferative disorders are a set of disorders characterized by the abnormal proliferation of lymphocytes into a monoclonal lymphocytosis. The two major types of lymphocytes are B cells and T cells, which are derived from pluripotent hematopoetic stem cells in the bone marrow. Individuals who have some sort of dysfunction with their immune system are susceptible to develop a lymphoproliferative disorder because when any of the numerous control points of the immune system become dysfunctional, immunodeficiency or deregulation of lymphocytes is more likely to occur. There are several inherited gene mutations that have been identified to cause lymphoproliferative disorders; however, there are also acquired and iatrogenic causes.

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

X-linked lymphoproliferative disease (also known as "Duncan's disease" or "Purtilo syndrome") is a lymphoproliferative disorder.

The disease is believed to be induced by a combination of Epstein Barr virus infection and immunosuppression through; immunosuppressive drugs (with case reports of methotrexate and azathioprine), infections such as HIV or chronic viral hepatitis or endogenous T-cell defects.

Post-transplant lymphoproliferative disorder (PTLD) is the name given to a B-cell proliferation due to therapeutic immunosuppression after organ transplantation. These patients may develop infectious mononucleosis-like lesions or polyclonal polymorphic B-cell hyperplasia. Some of these B-cells may undergo mutations which will render them malignant, giving rise to a lymphoma.

In some patients, the malignant cell clone can become the dominant proliferating cell type, leading to frank lymphoma, a group of B cell lymphomas occurring in immunosuppressed patients following organ transplant.

Strangely, in boys with X-linked lymphoproliferative disorder, there is an inability to mount an immune response to the Epstein-Barr virus (EBV), which often leads to death from bone marrow failure, irreversible hepatitis, and malignant lymphoma. However, the connection between EBV and X-linked lymphoproliferative disorder is yet to be determined.

Patients produce insufficient numbers of CD27 memory B cells.

Lymphomatoid granulomatosis (LYG or LG) is a very rare lymphoproliferative disorder first characterized in 1972 with lymphomatoid meaning lymphoma-like and granulomatosis denoting one of its microscopic characteristics, polymorphic lymphoid infiltrates and focal necrosis within it. While most commonly found in middle age patients, it has been observed in young people with a study identifying 47 cases of patients aged 0–18 years in the literature. Males are found to be affected twice as often as females.

The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections or developmental delay as a result of infection. Particular organ problems (e.g. diseases involving the skin, heart, facial development and skeletal system) may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body's own tissues, or tumours (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.

The onset of HLH occurs under the age of 1 year in ~70% of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Each full sibling of a child with familial HLH has a 25% chance of developing the disease, a 50% chance of carrying the defective gene (which is very rarely associated with any risk of disease) and a 25% chance of not being affected and not carrying the gene defect.

Patients with HLH, especially when untreated, may need intensive therapy. Therefore, HLH should be included in the differential diagnosis of ICU (Intensive Care Unit) patients with cytopenia and hyperferritinemia.

HLH clinically manifests with fever, enlargement of the liver and spleen, enlarged lymph nodes, yellow discoloration of the skin and eyes, and a rash.

The differential diagnosis of HLH includes secondary HLH and macrophage-activation syndrome or other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as X-linked lymphoproliferative disease.

Other conditions that may be confused with this condition include autoimmune lymphoproliferative syndrome. As a syndrome of intense inflammation it needs to be differentiated from sepsis, what may be extremely challenging.

The diagnosis of acquired, or secondary, HLH is usually made in association with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased NK cell activity.

This disease is known for an indolent clinical course and incidental discovery. The most common physical finding is moderate splenomegaly. B symptoms are seen in a third of cases, and recurrent infections due to the associated neutropenia are seen in almost half of cases.

Rheumatoid arthritis is commonly observed in people with T-LGLL, leading to a clinical presentation similar to Felty's syndrome. Signs and symptoms of anemia are commonly found, due to the association between T-LGLL and erythroid hypoplasia.

Immunoproliferative disorders, also known as immunoproliferative diseases or immunoproliferative neoplasms, are disorders of the immune system that are characterized by the abnormal proliferation of the primary cells of the immune system, which includes B cells, T cells and natural killer (NK) cells, or by the excessive production of immunoglobulins (also known as antibodies).

These disorders are subdivided into three main classes, which are lymphoproliferative disorders, hypergammaglobulinemia, and paraproteinemia. The first is cellular, and the other two are humoral (however, humoral excess can be secondary to cellular excess.)

- "Lymphoproliferative disorders" (LPDs) refer to several conditions in which lymphocytes are produced in excessive quantities. They typically occur in patients who have compromised immune systems. This subset is sometimes incorrectly equated with "immunoproliferative disorders".

- Humoral

- "Hypergammaglobulinemia" is characterized by increased levels of immunoglobulins in the blood serum. Five different hypergammaglobulinemias are caused by an excess of immunoglobulin M (IgM), and some types are caused by a deficiency in the other major types of immunoglobulins.

- "Paraproteinemia" or "monoclonal gammopathy" is the presence of excessive amounts of a single monoclonal gammaglobulin (called a "paraprotein") in the blood.

The leukemic cells of T-LGLL can be found in peripheral blood, bone marrow, spleen, and liver. Nodal involvement is rare.

An autoimmune disease is a condition arising from an abnormal immune response to a normal body part. There are at least 80 types of autoimmune diseases. Nearly any body part can be involved. Common symptoms include low grade fever and feeling tired. Often symptoms come and go.

People with monoclonal gammopathy generally do not experience signs or symptoms. Some people may experience a rash or nerve problems, such as numbness or tingling. Severe renal disease has also been found in a subset of those with monoclonal gammopathy. MGUS is usually detected by chance when the patient has a blood test for another condition or as part of standard screening.

The myeloproliferative neoplasms (MPNs), previously myeloproliferative diseases (MPDs), are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than these conditions. The concept of myeloproliferative disease was first proposed in 1951 by the hematologist William Dameshek. In the most recent World Health Organization classification of hematologic malignancies, this group of diseases was renamed from "myeloproliferative diseases" to "myeloproliferative neoplasms". This reflects the underlying clonal genetic changes that are a salient feature of this group of disease.

The increased numbers of blood cells may not cause any symptoms, but a number of medical problems or symptoms may occur. The risk of thrombosis is increased in some types of MPN.

The disease is an uncontrolled proliferation of B cell lymphocytes latently infected with Epstein-Barr virus. Production of an interleukin-10, an endogenous, pro-regulatory cytokine, has also been implicated.

In immunocompetent patients, Epstein-Barr virus can cause infectious mononucleosis in adolescents, which is otherwise asymptomatic in children during their childhood. However, in immunosuppressed transplant patients, the lack of T-cell immunosurveillance can lead to the proliferation of these EBV-infected of B-lymphocytes.

However, calcineurin inhibitors (tacrolimus and ciclosporin), used as immunosuppressants in organ transplantation inhibit T cell function, and can prevent the control of the B cell proliferation.

Depletion of T cells by use of anti-T cell antibodies in the prevention or treatment of transplant rejection further increases the risk of developing post-transplant lymphoproliferative disorder. Such antibodies include ATG, ALG and OKT3.

Polyclonal PTLD may form tumor masses and present with symptoms due to a mass effect, e.g. symptoms of bowel obstruction. Monoclonal forms of PTLD tend to form a disseminated malignant lymphoma.

Although not a malignant neoplasm like other cancers, MPNs are classified within the hematological neoplasms. There are four main myeloproliferative diseases, which can be further categorized by the presence of the Philadelphia chromosome:

In 2008, the World Health Organization listed these diagnoses as types of MPD:

- Chronic myelogenous leukemia (BCR-ABL1–positive)

- Chronic neutrophilic leukemia

- Polycythemia vera

- Primary myelofibrosis

- Essential thrombocythemia

- Chronic eosinophilic leukemia (not otherwise specified)

- Mastocytosis

Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a "primary" immunodeficiency, the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 100 recognized PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, autoinflammatory disorders, tumors, and disorders of various organs. There are currently no cures for these conditions; treatment is palliative and consists of managing infections and boosting the immune system.

Chronic recurrent multifocal osteomyelitis (CRMO) ("multifocal" because it can erupt in different sites, primarily bones; "osteomyelitis" because it is very similar to that disease but appears to be without any infection), also known as chronic recurring multifocal osteomyelitis, is a rare condition (1:1,000,000), in which the bones have lesions, inflammation, and pain. Its definition is evolving. Many doctors and articles described CRMO as an autoimmune disease that has symptoms similar to osteomyelitis, but without the infection. Some doctors thought CRMO was related to SAPHO syndrome. Research now classifies CRMO as an inherited autoinflammatory disease but have yet to isolate the exact gene responsible for it. Some specialists believe they have discovered a link between CRMO with a rare allele of marker D18S60, resulting in a haplotype relative risk (HRR) of 18. Other experts found that "mutations in LPIN2 cause a syndromic form of chronic recurrent multifocal osteomyelitis known as Majeed syndrome, while mutations in pstpip2 cause a murine form of the disorder. The roles played by LPIN2 and the human homolog of pstpip2, PSTPIP2, in the cause of chronic recurrent multifocal osteomyelitis are uncertain. The professional theories seem to be moving in the direction of an inherited gene.