Phenocopies of primary immunodeficiency

# Overview
These disorders behave and present like primary PIDs, but they are acquired secondary to the occurrence of autoantibodies or somatic mutations.These conditions are not caused by inherited genetic mutations, but instead are acquired during life.

# Classification

# Autoimmune Lymphoproliferative Syndrome due to Somatic FAS Mutations (ALPS-SFAS)
- ALPS-SFAS is a heritable disorder of apoptosis, resulting in the accumulation of autoreactive lymphocytes.
- Manifests in early childhood as nonmalignant lymphadenopathy with hepatosplenomegaly and autoimmune cytopenias.
- Patients with mutations have developed B and T-cell lymphomas.
- Peripheral blood analysis in patients has demonstrated hypergammaglobulinemia along with increased numbers of B and T lymphocytes.
- Some studies have demonstrated that ALPS is compatible with long-term survival.

# RAS-Associated Autoimmune Leukoproliferative Disease (RALD)
- RALD is a leukoproliferative disorder characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia.
- Some patients have recurrent infections with increased risk of hematologic malignancy.
- Mutated genes involved include NRAS and KRAS.

# Cryopyrinopathy (Muckle-Wells Syndrome)
- Cryopyrinopathy is caused by heterozygous mutation in the gene encoding cryopyrin (NLRP3) and the locus identified at chromosome 1q44.
- Characterized by episodic skin rash, arthralgias, and fever associated with late-onset sensorineural deafness and renal amyloidosis.
- Limb pains emphasized on as a feature.

# Hypereosinophilic Syndrome due to Somatic Mutations in STAT5b
- Hypereosinophilic syndrome due to somatic mutations in STAT5b is characterized by atopic dermatitis, urticarial rash, diarrhea and eosinophilia

# Chronic Mucocutaneous Candidiasis
- Chronic mucocutaneous candidiasis includes a group of rare disorders with altered immune responses, selective against Candida.
- Characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused mainly by Candida albicans.
- Can also be associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome which is driven by mutations in AIRE (autoimmune regulator).
- High titers of neutralizing autoantibodies against IL-17 and/or IL-22 are also detected.

# Adult-Onset Immunodeficiency with Susceptibility to Mycobacteria
- Adult-onset immunodeficiency with susceptibility to mycobacteria is a disorder predominantly found in Southeast Asians.
- Associated with severe or disseminated infections caused by non-tuberculous mycobacteria and other opportunistic pathogens such as non-typhoidal salmonella, cytomegalovirus, varicella zoster virus, and some fungi.
- An infection may act as an initial trigger for the production of autoantibodies with repeated infections leading to increased activity.

# Recurrent Skin Infections
- Patients with recurrent staphylococcal cellulitis and subcutaneous abscesses have shown high titers of IgG1 autoantibodies against IL-6, a pleiotropic cytokine released by several important cellular lineages of the skin.
- The autoantibodies against IL-6 prevent the increase in C-reactive protein (CRP) concentration during infection and the impaired IL-6 mediated immunity contributes to the disease development.
- Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) can also lead to cutaneous infections typically caused by Staphylococcus aureus.

# Pulmonary Alveolar Proteinosis
- Pulmonary alveolar proteinosis is characterized by intra-alveolar surfactant accumulation.
- A severe autoimmune disease caused by autoantibodies against granulocytemacrophage colony-stimulating factor (GM-CSF) resulting in impaired function of alveolar macrophages.
- Lung biopsy shows preserved lung architecture with alveoli filled with granular, eosinophilic PAS-positive material with degenerating macrophages.
- Hereditary pulmonary alveolar proteinosis may be caused by compound heterozygous abnormalities affecting the CSF2RA gene and CSF2 signaling, critical for surfactant homeostasis in humans.
- Patients with pulmonary alveolar proteinosis can also present with cryptococcal meningitis in the setting of anti-GM-CSF autoantibodies as GM-CSF regulates the function of phagocytes and pulmonary alveolar macrophages, critical elements in cryptococcal control.
For more information on pulmonary alveolar proteinosis, click here.

# Acquired Angioedema
- Acquired angioedema is rare disorder that causes recurrent episodes of swelling (edema) of the face or body.
- The edema can involve the lining of the digestive tract causing abdominal pain and may require unnecessary laparotomy. It can also involve the upper airway, which can be life-threatening.
- It can occur due to the deficiency of C1 inhibitor in the setting of autoantibodies against it.
- It has been associated with benign or malignant B-cell lymphoproliferative disorders such as chronic lymphocytic leukemia, multiple myeloma, or essential cryoglobulinemia.

# Atypical Hemolytic Uremic Syndrome (aHUS)
- Atypical hemolytic uremic syndrome is a rare form of thrombotic microangiopathy that associates, in 70% of cases, with genetic or acquired disorders leading to dysregulation of the alternative complement pathway.
- It can present with anemia, thrombocytopenia, hypertension, and acute renal failure. Renal biopsy shows a thrombotic microangiopathy and deposition of complement component C3 in vessel walls.
- Autoantibodies against factor H causes at least 6% to 10% of aHUS cases.
- aHUS in the setting of antibodies against factor H primarily affects children between 9 and 13 years old but it also affects adults.

# Thymoma with Hypogammaglobulinemia (Good Syndrome)
- Good syndrome is a rare acquired combined T- and B-cell immunodeficiency associated with thymoma.
- It can present with intractable opportunistic infections, lichen planus and therapy resistant secretory diarrhea.
- Laboratory examination results indicate hypogammaglobulinemia and complete absence or decrease in the proportion of cells bearing B cells markers.