TaoMedAI/RareMedData huggingface dataset:
Combined deficiency of factor V and factor VIII (ORPHA:35909)
A rare inherited bleeding disorder due to the reduction in activity and antigen levels of both factor V (FV) and factor VIII (FVIII) and characterized by mild-to-moderate bleeding symptoms.
Epidemiology
Prevalence is estimated between 1/100,000 and 1/1,000,000. The condition is more prevalent in the Mediterranean area and in areas where consanguineous marriages are common.
Clinical description
Combined FV and FVIII deficiency can manifest at any age. Epistaxis, easy bruising, post-surgical or post partum bleeding and menorrhagia are the most common symptoms. Hemarthrosis and muscular hematomas may occur. The symptoms are usually mild.
Etiology
Combined deficiency of factor V and factor VIII is caused by mutations either in the LMAN1 gene (chromosome 18; 18q21) or in the MCFD2 gene (chromosome 2; 2p21). LMAN1 encodes ERGIC-53, a transmembrane lectin, while MCFD2 is an EF-hand-containing protein. The ERGIC-53/MCFD2 protein complex functions as a cargo receptor that facilitates the transport of coagulation factors V and VIII from the endoplasmic reticulum to the Golgi apparatus. Mutations in LMAN1 account for approximately 70% of cases and include only null mutations. Mutations in MCFD2 account for approximately 30% of cases and include both null and missense mutations.
Diagnostic methods
Diagnosis is based on the measurement of factor V and factor VIII levels and on the detection of prolonged activated partial thromboplastin and prothrombin times. Levels of factor V and factor VIII range from as low as 1% to as high as 46%, but generally fall between 5% and 30%.
Differential diagnosis
Differential diagnosis includes co-inheritance of both FV deficiency (chromosome 1) and FVIII deficiency (chromosome X).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management aims at controlling the bleeding and includes treatments with fresh frozen plasma, FVIII concentrates and desmopressin administration.
Prognosis
The prognosis is favorable for moderate forms of the disease. Management of patients with more severe forms should be carried out at a specialized center.

                            Last update: 
                            October 2020


                            - Expert reviewer(s): 
                            Pr Jenny GOUDEMAND
Combined hamartoma of the retina and retinal pigment epithelium (ORPHA:440727)
A rare benign eye tumor characterized by the presence of glial cells, vascular tissue, and sheets of pigment epithelial cells lacking the distribution and organization of the normal retina and retinal pigment epithelium. The lesion is most commonly found unilaterally as a slightly elevated mass in a peripapillary location but can also occur in the macula or the retinal periphery. It is sometimes associated with neurofibromatosis type 1 or 2, nevoid basal cell carcinoma syndrome, or branchio-oculo-facial syndrome. Patients may be asymptomatic or present with progressive loss of vision.
Combined hepatocellular carcinoma and cholangiocarcinoma (ORPHA:529852)
A rare hepatic tumor characterized by the presence of both hepatocytic and cholangiocytic differentiation within a primary liver carcinoma. The lesion commonly arises in the context of chronic liver disease (such as hepatitis B or C, or steatohepatitis) or exposure to a variety of exogenous agents. Patients may present with signs and symptoms related to the tumor, as well as to the underlying condition. Typical manifestations include right upper quadrant abdominal pain, weight loss, hepatosplenomegaly, jaundice, and ascites. The entity has been associated with a worse prognosis than hepatocellular carcinoma after resection.
Combined hyperactive dysfunction syndrome of the cranial nerves (ORPHA:221078)
A rare, acquired peripheral neuropathy characterized by symptoms arising from combined overactivity in cranial nerves, without any explanatory structural lesion. The symptoms may be unilateral or bilateral, may occur synchronously or metachronously, and include trigeminal neuralgia, hemifacial spasm and glossopharyngeal neuralgia.
Combined immunodeficiency due to CARD11 deficiency (ORPHA:357237)
Severe combined immunodeficiency due to CARD11 deficiency is a rare combined T and B cell immunodeficiency characterized by normal numbers of T and B lymphocytes, increased numbers of transitional B cells and hypo- to agammaglobulinemia, decreased numbers of regulatory T cells and defects in T-cell functions. It presents with severe susceptibility to infections, including opportunistic infections.
Combined immunodeficiency due to CARMIL2 deficiency (ORPHA:542301)
A rare immune dysregulation disease with immunodeficiency characterized by infantile or childhood onset of a variable phenotype including recurrent/persistent bacterial, fungal, and viral infections with involvement of the skin, lower respiratory tract, and gastrointestinal tract, eczema, allergies, and inflammatory bowel disease, among others. EBV-related smooth muscle tumors have also been reported. Immunophenotyping shows decreased Treg counts, as well as a deficient CD3/CD28 co-stimulation response in CD4+ and CD8+ T-cells.
Combined immunodeficiency due to CD27 deficiency (ORPHA:238505)
A rare autosomal recessive primary immunodeficiency characterized by Epstein-Barr virus (EBV)-triggered lymphoprolipherative disorders such as malignant B-cell proliferation, Hodgkin lymphoma, B-cell lymphoma and EBV-driven hemophagocytic lymphohistiocytosis (HLH). Aplastic anemia and inflammatory disorders such as uveitis and oral ulcers are also observed.
Combined immunodeficiency due to CD3gamma deficiency (ORPHA:169082)
A rare autosomal recessive primary immunodeficiency characterized by partial T lymphopenia (in particular cytotoxic CD8+ cells) and decreased expression of the T cell receptor (TCR)/CD3 complex with impaired proliferative response to TCR-dependent stimuli, while the mature memory T cell pool is comparatively well preserved, and B cells, natural killer cells, and immunoglobulins are typically normal. The clinical phenotype is highly heterogeneous, ranging from asymptomatic to infancy-onset of severe recurrent infections, as well as occurrence of autoimmune disease or enteropathy.
Combined immunodeficiency due to CD70 deficiency (ORPHA:538958)
A rare autosomal recessive primary immunodeficiency characterized by susceptibility to Epstein-Barr virus (EBV)-related disorders (B-cell lymphoproliferative disorders including Hodgkin lymphoma) as well as dysgammaglobulinemia and recurrent infections. Patients can present with recurrent fever, lymphadenopathy, hepatosplenomegaly, Behçet-like stomatitis, pharyngitis, tonsillitis, adenitis, and viral encephalitis.
Combined immunodeficiency due to CRAC channel dysfunction (ORPHA:169090)
Combined immunodeficiency (CID) due to Ca2+ release activated Ca2+(CRAC) channel dysfunction is a form of CID characterized by recurrent infections, autoimmunity, congenital myopathy and ectodermal dysplasia. It comprises two sub-types that are due to mutations in the ORAI1 and STIM1 genes: CID due to ORAI1 deficiency and CID due to STIM1 deficiency.
Epidemiology
CID due to CRAC channel dysfunction has been reported in 10 patients from 5 families, 6 patients in 3 families with ORAI1 mutations and 4 patients in two families with STIM1 mutations.
Clinical description
CID due to CRAC channel dysfunction is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy, which is characterized by non-progressive generalized muscular dysplasia. For cases with ORAI1 mutations this presents as poor head control after birth, delayed ambulation and a positive Gower's sign, while patients with STIM1 mutations present with global muscular hypotonia and partial iris hypoplasia. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients with ORAI1 mutations also have anhydrosis, which is characterized by inability to sweat and recurrent fever episodes associated with impaired thermoregulation. Patients with STIM1 mutations also show signs of lymphoproliferative and autoimmune disease including lymphadenopathy, hepatosplenomegaly, autoimmune thrombocytopenia and autoimmune hemolytic anemia.
Etiology
CID due to CRAC channel dysfunction is caused by mutations in the ORAI1 and STIM1 genes (12q24 and 11p15.5).
Diagnostic methods
Diagnosis is based on clinical features and testing the function and proliferation of T cells. Patients have normal lymphocyte counts and serum immunoglobulin levels but severely compromised T cell activation.
Differential diagnosis
Differential diagnoses include combined immunodeficiency (CID) due to ZAP70 deficiency, CID due to CD3gamma deficiency, immunodeficiency due to CD25 deficiency, hypohidrotic ectodermal dysplasia with immunodeficiency and anhidrotic ectodermal dysplasia - immunodeficiency - osteopetrosis - lymphedema syndrome.
Antenatal diagnosis
Prenatal diagnosis can be performed where there is a family history and where the genetic mutation has been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment with hematopoietic stem cell transplantation (HSCT) has been successful in some cases.
Prognosis
Without treatment, patients fail to thrive and die in their first year of life.

                            Last update: 
                            July 2012


                            - Expert reviewer(s): 
                            Pr Andrew GENNERY
Combined immunodeficiency due to DOCK2 deficiency (ORPHA:447737)
A rare, primary combined T and B cell immunodeficiency characterized by early-onset of recurrent, invasive viral and bacterial infections associated with T and B cell lymphopenia, functional defects in T and B cells, poor antibody response and thrombocytopenia. Depending on the type of infectious agent, variable clinical manifestations commonly include recurrent pneumonia, bronchiolitis, otitis media, meningoencephalitis, colitis, and diarrhea, leading to fatal multiorgan failure in severe cases.
Combined immunodeficiency due to DOCK8 deficiency (ORPHA:217390)
Combined immunodeficiency due to dedicator of cytokinesis 8 protein (DOCK8) deficiency is a form of T and B cell immunodeficiency characterized by recurrent cutaneous viral infections, susceptibility to cancer and elevated serum levels of immunoglobulin E (IgE).
Epidemiology
Prevalence is unknown. To date, 11 patients in eight families have been reported.
Clinical description
Patients present in childhood with symptoms including atopic dermatitis, severe food and environmental allergies, asthma, recurrent upper and lower respiratory tract infections including otitis media, recurrent sinusitis, bronchitis and pneumonia, and extensive cutaneous viral and bacterial infections including superficial, often ulcerating herpes simplex virus infections, flat and verrucous warts, molluscom contagiosum infections, S. aureus skin infections or abscesses, mucosal or nail candidiasis and otitis externa. Patients with long-term herpes simplex virus infections, human papillomavirus infections or molluscom contagiosum have developed vulvar, facial and anal squamous cell dysplasia and carcinoma. The neurologic, vasculitic and autoimmune symptoms associated with autosomal dominant hyper IgE syndrome due to mutations in STAT3 (see this term), are not observed.
Etiology
CID due to DOCK8 deficiency is caused by homozygous or compound heterozygous deletions and point mutations in the DOCK8 gene (9p24), which leads to an absence of DOCK8 protein in lymphocytes, resulting in low absolute T and B lymphocyte counts, mild-to-moderate eosinophilia and very high levels of serum IgE.
Genetic counseling
Transmission is autosomal recessive.

                            Last update: 
                            July 2012


                            - Expert reviewer(s): 
                            Pr Andrew GENNERY
Combined immunodeficiency due to GINS1 deficiency (ORPHA:505227)
A rare syndrome with combined immunodeficiency characterized by intrauterine and postnatal growth retardation, chronic neutropenia, and natural killer (NK) cell deficiency due a defect in DNA replication leading to blockade of immune cell differentiation in the bone marrow, particularly affecting NK cells. Other clinical features include recurrent viral and bacterial infections and eczema, as well as mild facial dysmorphism.
Combined immunodeficiency due to IL21R deficiency (ORPHA:357329)
A rare, genetic, non-severe combined immunodeficiency disorder characterized by variable B- and T-cell defects (including defective B-cell differentiation and impaired T-cell proliferation to mitogens and bacterial antigens) and natural killer cell dysfunction (ranging from impaired cytotoxicity to lymphopenia) due to IL21R deficiency, manifesting with recurrent respiratory and/or gastrointestinal tract infections and, in some cases, with severe, chronic, progressive cholangitis and liver cirrhosis associated with cryptosporidial infection.
Combined immunodeficiency due to ITK deficiency (ORPHA:538963)
A rare autosomal recessive primary immunodeficiency characterized by susceptibility to Epstein-Barr virus (EBV)-associated lymphoproliferative disorders such as malignant B-cell proliferation, Hodgkin lymphoma, B-cell lymphoma, lymphoid granulomatosis, hemophagocytic lymphohistiocytosis, and smooth muscle tumor. Patients present persistent symptoms of infectious mononucleosis including recurrent febrile episodes, lymphadenopathies, and hepatosplenomegaly, accompanied by high EBV viral load in the blood. Additional manifestations are autoimmune diseases like hemolytic anemia or renal disease.
Combined immunodeficiency due to LRBA deficiency (ORPHA:445018)
A rare, genetic, primary immunodeficiency characterized by early onset of recurrent respiratory infections and variable combination of autoimmune disorders, including hemolytic anemia, thrombocytopenic purpura, lymphoproliferative disease, inflammatory bowel disease, colitis, diabetes, arthritis, and dermatitis. Failure to thrive, hepatosplenomegaly and endocrine abnormalities have also been associated. Variable immunologic findings include deficiency of CD4+ T regulatory cells, decreased B-cells, and hypogammaglobulinemia.
Combined immunodeficiency due to MALT1 deficiency (ORPHA:397964)
Combined immunodeficiency due to MALT1 deficiency is a rare, genetic form of primary immunodeficiency characterized by growth retardation, early recurrent pulmonary infections leading to bronchiectasis, inflammatory gastrointestinal disease, and other symptoms, such as rash, dermatitis, skin infections.
Combined immunodeficiency due to Moesin deficiency (ORPHA:504530)
A rare combined T and B cell immunodeficiency characterized by childhood onset of recurrent bacterial and varicella zoster virus infections. Eczema and recurrent molluscum have also been reported. Laboratory studies reveal profound and persistent lymphopenia, hypogammaglobulinemia, poor immune response to vaccine antigens, and fluctuating neutropenia.
Combined immunodeficiency due to ORAI1 deficiency (ORPHA:317428)
Combined immunodeficiency (CID) due to ORAI1 deficiency is a form of CID due to Calcium release activated Ca2+ (CRAC) channel dysfunction (see this term) characterized by recurrent infections, congenital myopathy, ectodermal dysplasia and anhydrosis.
Epidemiology
To date, it has been reported in 6 patients in 3 families.
Clinical description
The disease is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy (see this term), characterized by non-progressive generalized muscular dysplasia. This presents as poor head control after birth, delayed ambulation and a positive Gower's sign. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients also have anhydrosis, which is characterized by inability to sweat and recurrent fever episodes associated with impaired thermoregulation.
Etiology
The disease is caused by mutations in the ORAI1 gene (12q24.31) which codes for calcium release-activated calcium channel protein 1.
Genetic counseling
Transmission is autosomal recessive.

                            Last update: 
                            July 2012


                            - Expert reviewer(s): 
                            Pr Andrew GENNERY
Combined immunodeficiency due to OX40 deficiency (ORPHA:431149)
Combined immunodeficiency due to OX40 deficiency is a rare combined T and B cell immunodeficiency characterized by susceptibility to develop an aggressive, childhood-onset, disseminated, cutaneous and systemic Kaposi sarcoma.
Combined immunodeficiency due to partial RAG1 deficiency (ORPHA:231154)
Combined immunodeficiency due to partial RAG1 deficiency is a form of combined T and B cell immunodeficiency (CID; see this term) characterized by severe and persistent cytomegalovirus (CMV) infection and autoimmune cytopenia.
Epidemiology
Prevalence is unknown. To date, 9 cases have been reported.
Clinical description
Patients present before the age of one year with severe disseminated CMV infection, which can manifest with fever and splenomegaly, and recurrent and severe co-infections including sepsis and pneumonitis. Autoimmune cytopenia also occurs and can include autoimmune hemolytic anemia (see these terms) or neutropenia.
Etiology
SCID due to partial RAG1 deficiency is caused by hypomorphic mutation in the RAG1 gene (11p13). This results in oligoclonal expansion of T cell receptor (TCR) gamma-delta T cells and TCR alpha-beta T cell lymphopenia, although total lymphocyte counts are normal, in combination with CMV infection and autoimmunity.
Diagnostic methods
Diagnosis is based on clinical evaluation, immunological investigation, including lymphocyte subset phenotyping, lymphocyte proliferation to mitogen stimulation, immunoglobulin levels and antibody response to vaccine antigens, and genetic confirmation.
Differential diagnosis
Differential diagnoses include other combined immunodeficiencies.
Antenatal diagnosis
Prenatal diagnosis can be performed in families where there is a family history and in which the genetic mutation has been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment involves antiviral treatment and management of recurrent infections. Bone marrow transplant has been attempted but may result in graft versus host disease (GVHD; see this term) associated with reactivation of CMV disease. Patients should be treated in centers with experience of transplanting complex primary immunodeficiencies.
Prognosis
The majority of patients reported to date have died within the first few years of life.

                            Last update: 
                            July 2012


                            - Expert reviewer(s): 
                            Pr Andrew GENNERY
Combined immunodeficiency due to RELA haploinsufficiency (ORPHA:596759)
A rare non-severe combined immunodeficiency characterized by TNF-dependent chronic mucocutaneous ulcerations and inflammatory bowel disease presenting during the first years of life. Ulcerations occur primarily in the oral, gastrointestinal, and vaginal mucosa.
Combined immunodeficiency due to STIM1 deficiency (ORPHA:317430)
Combined immunodeficiency (CID) due to STIM1 deficiency is a form of CID due to Calcium release activated Ca2+(CRAC) channel dysfunction (see this term) characterized by recurrent infections, autoimmunity, congenital myopathy and ectodermal dysplasia.
Epidemiology
To date, it has been reported in 4 patients from two families.
Clinical description
CID due to STIM1 deficiency is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy (see this term), characterized by non-progressive generalized muscular dysplasia. This presents as global muscular hypotonia and partial iris hypoplasia. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients also show signs of lymphoproliferative and autoimmune disease including lymphadenopathy, hepatosplenomegaly, autoimmune thrombocytopenia and autoimmune hemolytic anemia (see these terms).
Etiology
The disease is caused by mutations in the STIM1 gene (11p15.5) which codes for stromal interaction molecule 1.
Genetic counseling
Transmission is autosomal recessive.

                            Last update: 
                            July 2012


                            - Expert reviewer(s): 
                            Pr Andrew GENNERY
Combined immunodeficiency due to STK4 deficiency (ORPHA:314689)
A rare, genetic, combined T and B cell immunodeficiency characterized by T- and B-cell lymphopenia, hypergammaglobulinemia and intermittent neutropenia. It presents with recurrent opportunistic viral, bacterial and fungal infections involving skin (cutaneous papillomatosis, molluscum contagiosum, skin abscesses, mucocutaneous candidiasis), upper and lower respiratory tract or septicemia. Other clinical features include autoimmune manifestations (autoimmune hemolytic anemia) and congenital heart defects (atrial septal defects, patent foramen ovale, mitral, triscupid and pulmonary valve insufficiency).
Combined immunodeficiency due to TFRC deficiency (ORPHA:476113)
A rare genetic combined T and B cell immunodeficiency characterized by life-threatening infections due to disrupted transferrin receptor 1 endocytosis, resulting in defective cellular iron transport and impaired T and B cell function. Patients present with early-onset chronic diarrhea, severe recurrent infections, and failure to thrive. Laboratory studies reveal hypo- or agammaglobulinemia, normal lymphocyte counts but decreased numbers of memory B cells, intermittent neutropenia and thrombocytopenia, and mild anemia (resistant to iron supplementation) with low mean corpuscular volume.
Combined immunodeficiency due to ZAP70 deficiency (ORPHA:911)
A very rare, severe, genetic, combined immunodeficiency disorder characterized by lymphocytosis, decreased peripheral CD8+ T-cells, and presence of normal circulating CD4+ T-cells, leading to immune dysfunction.
Combined immunodeficiency with facio-oculo-skeletal anomalies (ORPHA:221139)
A rare combined immunodeficiency disorder characterized by primary immunodeficiency manifesting with repeated bacterial, viral and fungal infections, in association with neurological manifestations (hypotonia, cerebellar ataxia, myoclonic seizures), developmental delay, optic atrophy, facial dysmorphism (high forehead, hypoplastic supraorbital ridges, palpebral edema, hypertelorism, flat nasal bridge, broad nasal root and tip, anteverted nares, thin lower lip overlapped by upper lip, square chin) and skeletal anomalies (short metacarpals/metatarsals with cone-shaped epiphyses, osteopenia).
Combined immunodeficiency with granulomatosis (ORPHA:157949)
A rare, genetic, non-severe combined immunodeficiency disease characterized by immunodeficiency (manifested by recurrent and/or severe bacterial and viral infections), destructive noninfectious granulomas involving skin, mucosa and internal organs, and various autoimmune manifestations (including cytopenias, vitiligo, psoriasis, myasthenia gravis, enteropathy). Immunophenotypically, T-cell and B-cell lymphopenia, hypogammaglobulinemia, abnormal specific antibody production and impaired T-cell function are observed.