A genetic predisposition is a genetic characteristic which influences the possible phenotypic development of an individual organism within a species or population under the influence of environmental conditions. In medicine, genetic susceptibility to a disease refers to a genetic predisposition to a health problem, which may eventually be triggered by particular environmental or lifestyle factors, such as tobacco smoking or diet. Genetic testing is able to identify individuals who are genetically predisposed to certain diseases.

The signs and symptoms of "activated PI3K Delta Syndrome" are consistent with the following:

- Immunodeficiency

- Lymphadenopathy

- Sinopulmonary infections

- Bronchiectasis

Activated PI3K delta syndrome is a primary immunodeficiency disease caused by activating gain of function mutations in the PIK3CD gene. Which encodes the p110δ catalytic subunit of PI3Kδ, APDS-2 (PASLI-R1) is caused by exon-skipping mutations in PIK3R1 which encodes for the regulatory subunit p85α. APDS and APDS-2 affected individuals present with similar symptoms, which include increased susceptibility to airway infections, bronchiectasis and lymphoproliferation.

WHIM Syndrome (or Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis syndrome) is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.

Nuclear factor-kappa B Essential Modulator (NEMO) deficiency syndrome is a rare type of primary immunodeficiency disease that has a highly variable set of symptoms and prognoses. It mainly affects the skin and immune system but has the potential to affect all parts of the body, including the lungs, urinary tract and gastrointestinal tract. It is a monogenetic disease caused by mutation in the IKBKG gene (IKKγ, also known as the NF-κB essential modulator, or NEMO). NEMO is the modulator protein in the IKK inhibitor complex that, when activated, phosphorylates the inhibitor of the NF-κB transcription factors allowing for the translocation of transcription factors into the nucleus.

The link between IKBKG mutations and NEMO deficiency was identified in 1999. IKBKG is located on the X chromosome and is X-linked therefore this disease predominantly affects males, However females may be genetic carriers of certain types of mutations. Other forms of the syndrome involving NEMO-related pathways can be passed on from parent to child in an autosomal dominant manner – this means that a child only has to inherit the faulty gene from one parent to develop the condition. This autosomal dominant type of NEMO deficiency syndrome can affect both boys and girls.

Signs of Seaver Cassidy syndrome include several facial disorders, including hypertelorism and telecanthus, epicanthal folds, downslanting palpebral fissures, ptosis, a broad nasal bridge, malar hypoplasia, a thin upper lip, a smooth philtrum, and low-set, prominent ears. Males with Seaver Cassidy syndrome may also experience an underdeveloped shawl scrotum and cryptorchidism. Skeletal anomalies, such genu valgum, hyperextended joints, or cubitus valgus, may also be present.

Patients exhibit increased susceptibility to bacterial and viral infections, especially from common serotype human papilloma virus, resulting in warts on the hands and feet starting in childhood. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). In addition, lymphocytes and IgG antibody levels (gammaglobulins) are often deficient.

Blau Syndrome is an autosomal dominant genetic inflammatory disorder which affects the skin, eyes, and joints. It is caused by a mutation in the NOD2 (CARD15) gene. Symptoms usually begin before the age of 4, and the disease manifests as early onset cutaneous sarcoidosis, granulomatous arthritis, and uveitis.

Cartilage–hair hypoplasia (CHH), also known as McKusick type metaphyseal chondrodysplasia, is a rare genetic disorder. It is a highly pleiotropic disorder that clinically manifests by form of short-limbed dwarfism due to skeletal dysplasia, variable level of immunodeficiency and predisposition to malignancies in some cases. It was first reported in 1965 by McKusick et al. Actor Verne Troyer is affected with this form of dwarfism, as was actor Billy Barty, who was renowned for saying "The name of my condition is Cartilage Hair Syndrome Hypoplasia, but you can just call me Billy."

This syndrome is characterized by an increased susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. There is profound monocytopenia, B lymphocytopenia and NK lymphocytopenia. Patients have an increased chance of developing malignancies, including: myelodysplasia/leukemia vulvar carcinoma, metastatic melanoma, cervical carcinoma, Bowen disease of the vulva, and multiple Epstein-Barr virus(+) leiomyosarcoma. Patients may also develop pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti-granulocyte-macrophage colony-stimulating factor autoantibodies. Last, patients may develop autoimmune phenomena, including lupus like syndromes, primary biliary cirrhosis or aggressive multiple sclerosis.

Of the 26, now 28, patients probably afflicted by this syndrome, 48% died of causes ranging from cancer to myelodysplasia with a mean age at death of 34.7 years and median age of 36.5 years.

Seaver Cassidy syndrome is a very rare disorder characterized by certain facial, genital, and skeletal deformities, as well as an unusual susceptibility to bleeding. Seaver Cassidy syndrome was first described in 1991 by Laurie Seaver and Suzanne Cassidy.

MonoMAC is a rare autosomal dominant syndrome associated with monocytopenia, B and NK cell lymphopenia and mycobacterial, fungal and viral infections. It was first described by Vihn and colleagues in 2010 and is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis and myeloid leukemias. Multiple mutations in the GATA2 are considered to be responsible for this syndrome.

In pregnancy, there is an increased susceptibility and/or severity of several infectious diseases.

CD25 deficiency or interleukin 2 receptor alpha deficiency is an immunodeficiency disorder associated with mutations in the interleukin 2 receptor alpha (CD25) (IL2RA) gene. The mutations cause expression of a defective α chain or complete absence thereof, an essential part of high-affinity interleukin-2 (IL-2) receptors. The result is a syndrome described as IPEX-like or a SCID.

In one patient, deficiency of CD25 on CD4+ lymphocytes caused significantly impaired sensitivity to IL-2. This was demonstrated by a lack of measurable response in anti-inflammatory interleukin-10 (IL-10) secretion to low-dose IL-2 incubation. Greatly reduced IL-10 secretion compared to healthy humans results in a syndrome comparable to IPEX syndrome, a type of autoimmunity which is caused by FoxP3 transcription factor dysfunction. In addition to IPEX-like symptoms, CD25 deficiency increases susceptibility to viral infections and possibly fungal and bacterial infections.

As IL-2 is an important inducer of lymphocyte proliferation, the absence of highly sensitive IL-2 receptors may also significantly hinder activation and clonal expansion of CD8+ and CD4+ lymphocytes and NK cells. One case also reported the absence of CD1, a MHC-like glycoprotein involved in the presentation of lipid antigens to T cells, in a CD25 deficient patient. Furthermore, chronic upregulation of anti-apoptotic Bcl-2 in thymocytes was also described possibly allowing autoreactive T cells to escape deletion.

Symptoms range widely in their onset and severity. The onset of the most severe form, type III, begins within the first months of life and includes a quick progression of intellectual disability, liver and spleen enlargement (splenomegaly), hearing loss, respiratory infections and skeletal abnormalities. Often the appearance of an affected individual includes the following facial features: protruding forehead, leveled nasal bridge, small nose and wide mouth. Muscular weakness or spinal abnormalities can occur due to the buildup of storage materials in the muscle. A milder form of alpha-mannosidosis involves mild to moderate intellectual disability which develops during childhood or adolescence.

OSLAM syndrome is a rare autosomal dominant hereditary disorder. Its name is an initialism of "osteosarcoma, limb anomalies, and erythroid macrocytosis with megaloblastic marrow syndrome". OSLAM syndrome was recognised and described by Mulvilhill "" as a syndrome that increases susceptibility to tumours and is characterised by an impaired regulation of bone and marrow development.

Individuals with OSLAM syndrome have an elevated risk of bone cancer, limb abnormalities, and enlarged red blood cells.

Theoretically, a mutation in any of the may cause disease, but below are some notable ones, with short description of symptoms:

- Adrenoleukodystrophy; leads to progressive brain damage, failure of the adrenal glands and eventually death.

- Alport syndrome; glomerulonephritis, endstage kidney disease, and hearing loss.

- Androgen insensitivity syndrome; variable degrees of undervirilization and/or infertility in XY persons of either gender

- Barth syndrome; metabolism distortion, delayed motor skills, stamina deficiency, hypotonia, chronic fatigue, delayed growth, cardiomyopathy, and compromised immune system.

- Blue cone monochromacy; low vision acuity, color blindness, photophobia, infantile nystagmus.

- Centronuclear myopathy; where cell nuclei are abnormally located in skeletal muscle cells. In CNM the nuclei are located at a position in the center of the cell, instead of their normal location at the periphery.

- Charcot–Marie–Tooth disease (CMTX2-3); disorder of nerves (neuropathy) that is characterized by loss of muscle tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in the advanced stages of disease.

- Coffin–Lowry syndrome; severe mental retardation sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis as well as auditory and visual abnormalities.

- Fabry disease; A lysosomal storage disease causing anhidrosis, fatigue, angiokeratomas, burning extremity pain and ocular involvement.

- Hunter's Syndrome; potentially causing hearing loss, thickening of the heart valves leading to a decline in cardiac function, obstructive airway disease, sleep apnea, and enlargement of the liver and spleen.

- Hypohidrotic ectodermal dysplasia, presenting with hypohidrosis, hypotrichosis, hypodontia

- Kabuki syndrome; multiple congenital anomalies and mental retardation.

- Spinal and bulbar muscular atrophy; muscle cramps and progressive weakness

- Lesch-Nyhan syndrome; neurologic dysfunction, cognitive and behavioral disturbances including self-mutilation, and uric acid overproduction (hyperuricemia)

- Lowe Syndrome; hydrophthalmia, cataracts, intellectual disabilities, aminoaciduria, reduced renal ammonia production and vitamin D-resistant rickets

- Menkes disease; sparse and coarse hair, growth failure, and deterioration of the nervous system

- Nasodigitoacoustic syndrome; mishaped nose, brachydactyly of the distal phalanges, sensorineural deafness

- Nonsyndromic deafness; hearing loss

- Norrie disease; cataracts, leukocoria along with other developmental issues in the eye

- Occipital horn syndrome; deformations in the skeleton

- Ocular albinism; lack of pigmentation in the eye

- Ornithine transcarbamylase deficiency; developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen

- Siderius X-linked mental retardation syndrome; cleft lip and palate with mental retardation and facial dysmorphism, caused by mutations in the histone demethylase PHF8

- Simpson-Golabi-Behmel syndrome; coarse faces with protruding jaw and tongue, widened nasal bridge, and upturned nasal tip

- Spinal muscular atrophy caused by UBE1 gene mutation; weakness due to loss of the motor neurons of the spinal cord and brainstem

- Wiskott-Aldrich syndrome; eczema, thrombocytopenia, immune deficiency, and bloody diarrhea

- X-linked Severe Combined Immunodeficiency (SCID); infections, usually causing death in the first years of life

- X-linked sideroblastic anemia; skin paleness, fatigue, dizziness and enlarged spleen and liver.

Diagnosis

Originally NEMO deficiency syndrome was thought to be a combination of Ectodermal Dysplasia (ED) and a lack of immune function, but is now understood to be more complex disease. NEMO Deficiency Syndrome may manifest itself in the form of several different diseases dependent upon mutations of the IKBKG gene such as Incontinentia pigmenti or Ectodermal dysplasia.

The clinical presentation of NEMO deficiency is determined by three main symptoms:

1. Susceptibility to pyogenic infections in the form of severe local inflammation

2. Susceptibility to mycobacterial infection

3. Symptoms of Ectodermal Dysplasia

To determine whether or not patient has NEMO deficiency, an immunologic screen to test immune system response to antigen may be used although a genetic test is the only way to be certain as many individuals respond differently to the immunological tests.

Commonly Associated Diseases

NEMO deficiency syndrome may present itself as Incontinentia pigmenti or Ectodermal dysplasia depending on the type of genetic mutation present, such as if the mutation results in the complete loss of gene function or a point mutation.

Amorphic genetic mutations in the IKBKG gene, which result in the loss of gene function, typically present themselves as Incontinetia Pigmenti (IP). Because loss of NEMO function is lethal, only heterozygous females or males with XXY karyotype or mosaicism for this gene survive and exhibit symptoms of Incontinetia Pigmenti, such as skin lesions and abnormalities in hair, teeth, and nails. There are a variety of mutations that may cause the symptoms of IP, however, they all involve the deletion of exons on the IKBKG gene.

Hypomorphic genetic mutations in the IKBKG gene, resulting in a partial loss of gene function, cause the onset of Anhidrotic ectodermal dysplasia with Immunodeficiency (EDA-IP). The lack of NEMO results in a decreased levels of NF-κB transcription factor translocation and gene transcription, which in turn leads to a low level of immunoglobulin production. Because NF-κB translocation is unable to occur without proper NEMO function, the cell signaling response to immune mediators such as IL-1β, IL-18, and LPS are ineffective thus leading to a compromised immune response to various forms of bacterial infections.

Treatment

The aim of treatment is to prevent infections so children will usually be started on immunoglobulin treatment. Immunoglobulin is also known as IgG or antibody. It is a blood product and is given as replacement for people who are unable to make their own antibodies. It is the mainstay of treatment for patients affected by primary antibody deficiency. In addition to immunoglobulin treatment, children may need to take antibiotics or antifungal medicines to prevent infections or treat them promptly when they occur. Regular monitoring and check-ups will help to catch infections early. If an autoimmune response occurs, this can be treated with steroid and/or biologic medicines to damp down the immune system so relieving the symptoms.

In some severely affected patients, NEMO deficiency syndrome is treated using a bone marrow or blood stem cell transplant. The aim is to replace the faulty immune system with an immune system from a healthy donor.

Patients with CHH usually suffer from cellular immunodeficiency. In the study of 108 Finnish patients with CHH there was detected mild to moderate form of lymphopenia, decreased delayed type of hypersensitivity and impaired responses to phytohaemagglutinin. This leads to susceptibility to and, in some more severe cases, mortality from infections early in childhood. There has also been detected combined immunodeficiency in some patients

Patients with CHH often have increased predispositions to malignancies.

Acquired hypocomplementemia may occur in the setting of bone infections (osteomyelitis), infection of the lining of the heart (endocarditis), and cryoglobulinemia. Systemic lupus erythematosus is associated with low C3 and C4 Membranoproliferative glomerulonephritis usually has low C3.

There are several potential risk factors or causes to this increased risk:

- An increased immune tolerance in pregnancy to prevent an immune reaction against the fetus

- Maternal physiological changes including a decrease in respiratory volumes and urinary stasis due to an enlarging uterus.

- The presence of a placenta for pathogens to use as a habitat, such as by "L. monocytogenes" and "P. falciparum".

Symptoms of enolase deficiency include exercise-induced myalgia and generalized muscle weakness and fatigability, both with onset in adulthood. Symptoms also include muscle pain without cramps, and decreased ability to sustain long term exercise.

Malignant hyperthermia (MH) is a type of severe reaction that occurs to particular medications used during general anesthesia, among those who are susceptible. Symptoms include muscle rigidity, high fever, and a fast heart rate. Complications can include rhabdomyolysis and high blood potassium. Most people who are susceptible are generally otherwise normal when not exposed.

The cause of MH is the use of certain volatile anesthetic agents or succinylcholine in those who are susceptible. Susceptibility can occur due to at least six genetic mutations, with the most common one being of the RYR1 gene. Susceptibility is often inherited from a person's parents in an autosomal dominant manner. The condition may also occur as a new mutation or be associated with a number of inherited muscle diseases, such as central core disease.

In susceptible individuals, the medications induce the release of stored calcium ions within muscle cells. The resulting increase in calcium concentrations within the cells cause the muscle fibers to contract. This generates excessive heat and results in metabolic acidosis. Diagnosis is based on symptoms in the appropriate situation. Family members may be tested to see if they are susceptible by muscle biopsy or genetic testing.

Treatment is with dantrolene and rapid cooling along with other supportive measures. The avoidance of potential triggers is recommended in susceptible people. The condition affects one in 5,000 to 50,000 cases where people are given anesthetic gases. Males are more often affected than females. The risk of death with proper treatment is about 5% while without it is around 75%. While cases that appear similar to MH have been documented since the early 20th century, the condition was only formally recognized in 1960.

An opportunistic infection is an infection caused by pathogens (bacteria, viruses, fungi, or protozoa) that take advantage of an opportunity not normally available, such as a host with a weakened immune system, an altered microbiota (such as a disrupted gut flora), or breached integumentary barriers. Many of these pathogens do not cause disease in a healthy host that has a normal immune system. However, a compromised immune system, a penetrating injury, or a lack of competition from normal commensals presents an opportunity for the pathogen to infect.

The following symptoms (signs) are consistent with complement deficiency in general: