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Immunodeficiency Main Page
Editor-In-Chief: C. Michael Gibson, M.S., M.D.  Shyam Patel ; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.; Anum Gull M.B.B.S.; Farman Khan, MD, MRCP ; Sadaf Sharfaei M.D.
Please see Common variable immunodeficiency. There are a variety of syndromic conditions related to immunodeficiency. Some syndromic conditions are inherited.
|Combined Immunodeficiency Diseases with associated or syndromic features|
|Congenital thromocytopenia||DNA Repair Defects||Immuno-osseous dysplasias||Thymic Defects with additional congenital anomalies||Hyper-IgE syndromes(HIES)||Dyskeratosis congenita (DKC)||Defects of Vitamin B12 and Folate metabolism||Anhidrotic Ectodermodysplasia with ID||Others|
|Wiskott Aldrich Syndrome||Ataxia telangiectasia||Cartilage Hair Hypoplasia||DiDeorge Syndrome||Job Syndrome||Dyskeratosis congenita||Transcobalmin 2 deficiency||NEMO deficiency||Purine nucleoside phosphorylase deficiency|
|XL thrombocytopenia||Nijmegen breakage Syndrome||Schimke Syndrome||TBX1 deficiency||Comel Netherton Syndrome||COATS plus syndrome||Deficiency causing hereditary folate malabsorption||EDA-ID due to IKBA GOF mutation||ID with multiple intestinal atresias|
|WIP deficiency||Bloom syndrome||MYSM1 deficiency||Chromosome 10p13-p14 deletion Syndrome||PGM3 deficiency||SAMD9||Methylene-tetrahydrofolate-dehydrogenase 1 deficiency||Hepatic veno-occlusive disease with immunodeficiency|
|ARPC1B deficiency||PMS2 deficiency||MOPD1 deficiency||CHARGE Syndrome||SAMD9L||Vici Syndrome|
|Immunodeficiency with centromeric instability and facial anomalies(ICF1, ICF2, ICF3, ICF4)||EXTL3 deficiency||HOIL1 deficiency, HOIP1 deficiency|
|MCM4 deficiency||Calcium Channel Defects(ORAI-1 deficiency, STIM1 deficiency)|
|RNF168 deficiency||Hennekam-lymphangiectasia-lymphedema syndrome|
|POLE1 deficiency||STAT5b deficiency|
|POLE2 deficiency||Kabuki Syndrome|
|Ligase 1 deficiency|
- Wiskott Aldrich syndrome (WAS) is X-Linked recessive primary immunodeficiency disorder.
- The classic triad of Wiskott-Aldrich syndrome include followings:
- Recurrent infections
- WAS gene which helps in actin polymerization, signal transduction and cytoskeletal rearrangement.
- The only curative treatment for Wiskott-Aldrich syndrome is stem cell transplant.
X-linked thrombocytopenia (XLT)
- X-Liked thrombocytopenia is a less severe variant of wiskot aldrich syndrome.
- X-Liked thrombocytopenia presents as a benign disease with good long-term survival compared with classic WAS.
- There is a relationship between XLT and WAS as both are caused by mutations of the same gene.
- WAS gene is mutated in X linked thrombocytopenia .
- X linked thrombocytopenia is inherited as a X- linked-recessive pattern.
- X linked thrombocytopenia is characterized by:
- Mild-to-moderate eczema
- Mild infrequent infections
- Small-sized platelets
- Treatment for patients with XLT is still not determined.
- WIPF1 gene which is located on chromosome 2q31.1
- Mutation of WIPF1 gene leads to WIP deficiency.
- WASP is totally complexed with the WASP-interacting protein (WIP).
- Deficiency of WIP leads to autosomal recessive form of Wiskott Aldrich syndrome.
- A main function of WIP is to stabilize WASP and prevents its degradation.
- WASP protein levels are greatly reduced in T lymphocytes.
- The presentation is similar to Wiskott-Aldrich syndrome which includes followings:
- Immunologic analysis shows decreased numbers of B cells and T cells, especialy CD8+ T cells.
- Hematopoietic stem cell transplantation is the treatment of choice.
- ARPC1B is inherited as an autosomal recessive disorder.
- ARPC1B also known as actin-related protein 2/3 complex, subunit 1B which is located on 7q22.1.
- The human complex consists of 7 subunits, including the actin-related proteins ARP2 and ARP3.
- ARPC1B complex is involved in the control of actin polymerization in cells.
- Deficiency of ARPC1B complex leads to platelet abnormalities with eosinophilia and immune-mediated inflammatory disease.
- Severe manisfestations of ARPC1B deficiency include followings: 
- Less severe manisfestations include mild vasculitis and normal numbers of small platelets without severe infections.
- Laboratory studies show platelets with an abnormal shape and decreased dense granules.
- Levels of eosinophils, B-lymphocytes, IgA and IgE are increased due to immune dysregulations.
- Ataxia-telangiectasia (AT) is an autosomal recessive disorder caused by defective ATM gene.
- The ATM gene is located on chromosome 11q22.3.
- ATM gene is involved in cell responses to DNA damage and cell cycle control.
- Common manifestations of AT include followings:
- Neurologic abnormalities
- Progressive cerebellar ataxia
- Abnormal eye movements
- Oculomotor apraxia
- Mild to moderate cognitive impairment
- Dermatologic manifestations
- Telangiectasias on exposed areas including pinnae, nose, face, and neck
- Hypopigmented macules
- Melanocytic nevi
- Facial papulosquamous rash
- Oculocutaneous Telangiectasia
- Pulmonary disease
- Recurrent sinopulmonary infections
- Interstitial lung disease
- Pulmonary fibrosis
- Neuromuscular abnormalities
- Respiratory muscle weakness
- Neurologic abnormalities
- Diagnostic criteria for ataxia-telangiectasia includes followings:
- Definitive diagnosis
- Increased radiation-induced chromosomal breakage in cultured cells
- Progressive cerebellar ataxia and who has disabling mutations on both alleles of ATM
- Probable diagnosis
- Ocular or facial telangiectasia
- Serum IgA at least 2 SD below normal for age
- Alpha fetoprotein at least 2 SD above normal for age
- Increased radiation-induced chromosomal breakage in cultured cells
- Definitive diagnosis
- Diagnosis can also be made by rapid immunoblotting assay for ATM protein because its levels are greatly reduced.
- It leads to increased risk of development of lymphoid malignancies and immunodeficiency.
- Cerebellar atrophy will be seen on MRI or CT scan.
Nijmegen breakage Syndrome
- It is also known as Ataxia-telangiectasia variant-1.
- Nijmegen breakage syndrome (NBS) is caused by mutation in the NBS1 gene which is located on chromosome 8q21.
- It is inherited as an autosomal recessive disorder.
- Common manifestations include followings:
- Dysmorphic facial features
- Mild growth retardation
- Mild-to-moderate intellectual disability
- Café-au-lait spots and depigmented skin lesions
- Ovarian dysgenesis and premature ovarian failure in females
- Hypergonadotropic hypogonadism and infertility in males
- Recurrent sinopulmonary infections
- A strong predisposed to development of malignancies of lymphoid origin
- The patients are also hypersensitive to double stand DNA breaking-inducing agents e.g ionizing radiations.
- There is no specific treatment for NBS.
- Bloom syndrome is also called as Bloom-Torre-Machacek syndrome or congenital telangiectatic erythema.
- Bloom syndrome is caused by the mutation in the BLM gene which is located on chromosome 15q26.
- BLM gene encodes DNA helicase RecQ protein-like-3 (RECQL3).
- Bloom Syndrome is inherited as an autosomal recessive inherited disorder.
- Most common manifestations of Bloom syndrome include followings:
- Growth deficiency of prenatal onset
- Café-au-lait spots or hypopigmented skin lesions
- Excessive photosensitivity with facial lupus-like skin lesions
- Type 2 diabetes mellitus
- Predisposition to the development of all types of cancers
- Bloom syndrome is diagnosed by detecting mutations in BLM gene.
- There is no specific treatment for bloom syndrome.
- PMS2 also known as Post-Meiotic Segregation 2.
- PMS2 gene is located on chromosome 7p22.1
- PMS2 gene encodes for DNA repair proteins which are involved in DNA mismatch repair.
- PMS2 Deficiency is inherited as autosomal recessive pattern.
- Deficiency of PMS2 increases the risk of colorectal cancer and hereditary nonpolyposis.
Immunodeficiency with Centromeric instability and Facial anomalies(ICF1, ICF2, ICF3, ICF4)
- ICF2 is caused by mutation in the ZBTB24 gene on chromosome 6q21.
- ICF3 is caused by mutation in the CDCA7 gene on chromosome 2q31.
- ICF4 is caused by mutation in the HELLS gene on chromosome 10q23.
- It is an autosomal recessive disease.
- Common manifestations of ICF include followings:
- The presenting symptom is recurrent infections usually in early childhood.
- At least two immunoglobulin classes are affected in each patient and agammaglobulinemia can occur.
- T cell number and response to mitogen may be decreased.
- The centromeric instability most frequently involves chromosomes 1 and 16, often 9, and rarely 2 and 10.
- The differential diagnosis include Bloom syndrome, ataxia-telangiectasia, and Nijmegen breakage syndrome.
- Immunoglobulin should be given in the early phase.
- Severe cases can be treated with allogeneic hematopoietic cell transplantation.
- MCM stands for minichromosome maintenance complex component 4. MCM4 is one part of a MCM2-7 complex which functions as the replicative helicase which is essential for normal DNA replication and genome stability.
- MCM4 deficiency is caused by mutation in the MCM4 gene located on 8q11.21. 
- MCM4 deficiency is characterized by:
- Short stature
- Adrenal insufficiency
- NK cell deficiency which leads to recurrent viral illnesses
- MCM4 deficiency is a variant of familial glucocorticoid deficiency (FGD), an autosomal recessive form of adrenal failure.
- MCM4 deficiency shares biochemical features of familial glucocorticoid deficiency, with isolated glucocorticoid deficiency, increased ACTH, and normal aldosterone and renin levels.
- Individuals with adrenal insufficiency should be given corticosteroid replacement therapy.
- RNF168 stands for Ring finger protein 168(RNF168).
- RNF168 gene is located on chromosome 3q29.
- RNF168 gene encodes E3 ubiquitin ligase which is involved in repair of double strand DNA breaks.
- Mutation of RNF168 gene leads to RIDDLE syndrome which is inherited as an autosomal recessive pattern.
- RIDDLE syndrome is characterized by:
- Dysmorphic features
- Learning difficulties
- Short stature
- Motor control problems
- It is pathologically similar to the ataxia-telangiectasia syndrome.
- POLE1 stands for DNA polymerase, epsilon subunit 1.
- The POLE1 gene is located on chromosome 12q24.33.
- POLE1 gene encodes the catalytic subunit of DNA polymerase epsilon.
- POLE1 deficiency is inherited as an autosomal recessive pattern.
- Mutation in the POLE1 leads to FILS syndrome.
- The age of onset of FILS syndrome is less than 40 years.
- It is characterized by:
- Facial dysmorphism
- Livedo on the skin since birth
- Short stature
- If the mutation in POLE1 gene is inherited as an autosomal dominant pattern, it leads to colorectal cancer-12 which is characterized by a high predisposition of colorectal adenomas and carcinomas.
- POLE2 stands for DNA polymerase epsilon subunit 2.
- POLE2 gene is located on choromosome 14q21.
- POLE2 is involved in both DNA replication and DNA repair.
- POLE2 deficiency is inherited as an autosomal recessive pattern.
- POLE2 deficiency is characterized by the followings:
- NSMCE3 stands for non structural maintenance of chromosomes element 3.
- NSMCE3 gene is located on chromosome 15q13.1.
- NSMCE3 gene encodes a component of the SMC5/SMC6complex.
- SMC5/SMC6 complex is important for responses to DNA damage and chromosome segregation during cell division.
- LICS syndrome is inherited as an autosomal recessive pattern.
- Mutation in the NSMCE3 gene leads to LICS syndrome.
- LICS stands for:
- Lung disease
- Chromosome breakage syndrome
- Other features include:
- Defective T cells and B cell
- Acute respiratory distress syndrome in early childhood
ERCC6L2 (Hebo deficiency)
- ERCC6L2 gene is located on chromosome 9q22.32.
- ERCC6L2 gene belongs to a family of helicases.
- ERCC6L2 gene is involved in chromatin unwinding, transcription regulation, DNA recombination, and repair.
- Mutation of ERCC6L2 gene leads to bone marrow failure syndrome 2 which is inherited as an autosomal recessive pattern.
- Bone marrow failure syndrome 2 is characterized by the followings:
Ligase 1 Deficiency
- LIG1 gene is located on chromosome 19q13.33.
- LIG1 gene encodes DNA ligase.
- DNA ligase function at the replication fork is to join okazaki fragments during replication of lagging strand DNA.
- Mutation of LIIG1 gene leads to reclassified-variant of unknown significance formerly called as DNA ligase 1 deficiency.
- Ligase 1 deficiency is characterized by:
- Cellular hypersensitivity to DNA-damaging agents
- GINS1 gene is located on chromosome 20p11.2.
- GINS1 gene encodes GINS complex.
- GINS1 deficiency is inherited as an autosomal recessive pattern.
- GINS1 deficiency is characterized by followings:
- Natural killer cell deficiency
- Chronic neutropenia
- Intrauterine growth retardation
- Mild facial dysmorphism
- Eczematous skin
- Recurrent infections
Cartilage hair hypoplasia
- Cartilage hair hypoplasia is also known as metaphyseal chondroplasia.
- Cartilage hair hypoplasia is caused by mutation in the RMRP gene.
- RMRP gene is located on chromosome 9p13.
- RMRP gene encodes mitochondrial RNA-processing endoribonuclease which is involved in cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of pre-rRNA.
- Cartilage hair hypoplasia is inherited as an autosomal recessive pattern.
- Cartilage hair hypoplasia is characterized by the followings:
- Short limbs
- Short stature
- Fine and sparse hair
- Ligamentous laxity
- Defective immunity
- Hypoplastic anemia
- Neuronal dysplasia of the intestine
- Clinical diagnosis is made by observing fine and sometimes sparse hair in an individual with short stature and disproportionally short limbs.
- Suspected cases of skeletal dysplasia may be evaluated on radiography.
- X-ray findings shows metaphyseal ends to be abnormal and appear as scalloped, irregular surfaces that may contain cystic areas.
- Definitive diagnosis is made by genetic analysis of the RMRP gene.
Schimke Immuno-osseous dysplasia (SIOD)
- SMARCAL1 gene is located on chromosome 2q25.
- SMARCAL1 gene encodes matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1.
- Homozygous or compound heterozygous mutation of SMARCAL1 gene causes Schimke immuno-osseous dysplasia (SIOD).
- Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder.
- It is characterized by:
- Short stature (often with prenatal growth deficiency)
- Spondyloepiphyseal dysplasia
- Defective cellular immunity
- Progressive renal failure
- The diagnosis should be considered in patients with short stature and immunodeficiency.
- Renal function should be assessed if the diagnosis is suspected.
- Radiographs for the characteristic bony anomalies should be performed.
- Bone marrow transplantation markedly improved the marrow function.
- MYSM1 gene is located on chromosome 1p32.1.
- MYSM1 gene encodes a deubiquitinase which is involved in regulation of trancription and mediates histone deubiquitination.
- MYSM1 deficiency leads to bone marrow failure syndrome 4.
- MYSM1 deficiency is inherited as an autosomal recessive pattern.
- MYSM1 deficiency is associated with:
- Developmental aberrations
- Progressive bone marrow failure with myelodysplastic features
- Increased susceptibility to genotoxic stress
- Hematopoietic stem cell transplant is a curative therapy.
- MOPD1 stands for microcephalic osteodysplastic primordial dwarfism type 1.
- MOPD1 deficiency, also known as Taybi-Linder syndrome, caused by mutations of RNU4ATAC gene.
- RNU4ATAC gene encodes a small nuclear RNA (snRNA) component of the U12-dependent spliceosome on chromosome 2q14.
- MOPD1 deficiency is inherited as an autosomal recessive pattern.
- Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is characterized by:
- Intrauterine growth retardation
- Post-natal growth retardation with the following features:
- Distinctive facial features
- Brain anomalies
- Diagnosis is made on the basis of the clinical and radiological phenotype.
- Common radiological features include:
- There are no specific treatments for MOPD1 deficiency. There is only supportive therapy.
- The prognosis is poor, as most affected individuals die within the first year of life.
- EXTL3 stands for exostosin-like-glycosyltransferase 3.
- EXTL3 gene located on chromosome 8p21.1
- EXTL3 regulates the synthesis of heparan sulfate which is important for both skeletal development and hematopoiesis.
- Mutation of EXTL3 gene leads to a syndrome called immunoskeletal dysplasia with neurodevelopmental abnormalities.
- DiGeorge syndrome is caused by a hemizygous deletion of chromosome 22q11.2 which encodes TBX1 gene.
- T-box genes are transcription factors involved in the regulation of developmental processes.
- Chromosome 22q11.2 deletion syndrome includes DiGeorge syndrome and other similar syndromes such as velocardiofacial syndrome.
- DiGeorge syndrome is inherited as an autosomal dominant pattern.
- 22q11.2 deletion leads to defective development of the 3rd and 4th pharyngeal pouch system.
- DiGeorge syndrome presents with the following:
- Conotruncal cardiac anomalies
- Hypoplastic thymus
- Palatal abnormalities
- Developmental delay
- T cell immunodeficiency presents with:
- Recurrent sinopulmonary infections
- Severe combined immunodeficiency
- Any neonate with a conotruncal heart lesion, hypocalcemia or cleft palate should be evaluated for DiGeorge syndrome.
- DiGeorge syndrome is diagnosed by decreased numbers of CD3+ T cells, combined with either characteristic clinical findings or deletion in chromosome 22q11.2.
- T cell receptor excision circles (TRECS), a biomarker of T cell development is also used to made by diagnosis during newborn screening.
- DiGeorge syndrome should be treated with supplementation of vitamin D or calcium and with parathyroid hormone.
- Hematopoietic stem cell transplantation is the definitive treatment.
- T-box transcription factor, TBX1 gene, also known as T-box protein 1 is located on chromosome 22q11.21.
- Genes in the T-box family play important roles in the formation of tissues and organs during embryonic development.
- Mutations in the TBX1 gene leads to conotruncal anamoly face syndrome and velocardiofacial syndrome.
Chromosome 10p13-p14 deletion Syndrome
- Chromosome 10p13-p14 deletion syndrome is a rare disease in which the end portion of the short arm (p) of chromosome 10 is missing.
- The severity of symptoms is variable, depending upon the exact size or location of the deletion on chromosome 10p.
- Clinical features often include followings:
- Severe mental retardation
- Postnatal growth retardation resulting in short stature
- Distinctive malformations of the skull and craniofacial region
- A short neck
- Congenital heart defects
- Affected individuals have some features of DiGeorge syndrome.
- Chromosome 10p13-p14 deletion syndrome is diagnosed prenatally by tests such as amniocentesis or chorionic villus sampling.
- The treatment of affected individuals is symptomatic and supportive.
- CHARGE syndrome is caused by heterozygous mutation in the CHD7 gene located on chromosome 8q12.
- CHARGE Syndrome is inherited as an autosomal dominant pattern.
- CHD7 gene is essential for the formation of multipotent migratory neural crest cells. Neural crest cells are ectodermal in origin, but undergo a major transcriptional reprogramming event and acquire a differentiation potential and ability to migrate throughout the body.
- CHARGE syndrome stands for:
- Heart anamoly
- Choanal atresia
- Genital anamolies
- Ear anamolies
- STAT3 gene stands for signal transducer and activator of transcription 3.
- STAT3 gene is important in the JAK-STAT signaling pathway activated by cytokines such as IL-6 and IL-2.
- Defects in the JAK-STAT pathway also lead to impaired T helper cell type 17 (Th17) differentiation and function.
- Defect in Th17 cells function also results in decreased neutrophil proliferation and chemotaxis to the site of infection.
- Job syndrome, also known as Hyper-IgE syndrome, is caused by heterozygous mutation in the STAT3 gene on chromosome 17q21.
- Job syndrome is inherited as autosomal dominant pattern.
- Job syndrome is characterized by the following:
- Chronic eczema
- Recurrent staphylococcal infections resulthing in cold abcess
- Increased serum IgE
- Skeletal manifestation such as:
- Distinctive coarse facial appearance
- Abnormal dentition
- Hyperextensibility of the joints
- Bone fractures
- The diagnosis of job syndrome is based upon the presence of suggestive clinical and laboratory findings, and confirmed by molecular testing of STAT3 gene.
- Management of jobs syndrome is focused on skin care and antimicrobial prophylaxis.
Comel Netherton syndrome
- Comel Netherton syndrome is caused by mutations in the serine protease inhibitor of Kazal type 5 gene (SPINK5) on chromosome 5q32.
- SPINK5 gene encodes a multidomain serine protein kinase known as lymphoepithelial Kazal type inhibitor (LEKTI) expressed in epithelial and mucosal surfaces.
- Lymphoepithelial Kazal type inhibitor directly inhibits kallikreins, especially kallikrein 5 (KLK5).
- Kallikreins are critical epidermal proteases and essential for regulating skin desquamation.
- Comel Netherton syndrome is inherited as an autosomal recessive pattern.
- Comel Netherton syndrome is clinically characterized by the followings:
- Congenital ichthyosiform erythroderma
- Astrichorrhexis invaginata ("bamboo hair")
- Atopic diathesis
- Comel Netherton syndrome patients exhibit absent LEKTI staining in the epidermis.
- Genetic testing will identify a germline SPINK5 mutation and confirm the diagnosis in approximately 66 to 75 percent of cases.
- There is no specific therapy for Comel Netherton syndrome. It is mainly supportive.
- PGM 3 stands for phosphoglucomutase3.
- PGM3 gene is located on chromosome 6q14.
- Mutation of PGM3 gene leads to immunodeficiency-23 (IMD23).
- PGM3 deficiency is inherited as an autosomal recessive.
- PGM3 deficiency, also known as immunodeficiency-vasculitis-myoclonus syndrome, is characterized by the following:
- Recurrent respiratory and skin infections beginning in early childhood
- Developmental delay
- Cognitive impairment of varying severity
- Increased serum IgE
- Dyskeratosis congenita is caused by mutation in DKC1 gene on chromosome Xq28.
- DKC1 gene maintains telomere length in rapidly dividing cells.
- Mutations in DKC1 gene lead to premature cell death and senescence.
- Dyskeratosis congenita is inherited as an X-linked recessive disorder.
- Dyskeratosis congenita is characterized by the following:
- Abnormal skin pigmentation
- Nail dystrophy
- Leukoplakia of the oral mucosa
COATS plus syndrome
- COATS plus syndrome is also known as cerebroretinal microangiopathy with calcifications and cysts-1.
- COATS plus syndrome is caused by mutation in the CTC1 gene on chromosome 17p13.
- COATS plus syndrome is inherited as an autosomal recessive pattern.
- COATS plus syndrome is characterized by followings:
- SAMD9 gene stands for sterile alpha motif domain-containing protein 9.
- SAMD9 gene located on 7q21.2.
- SAMD9 gene is encodes a protein which is localized in cytoplasm and involved in regulating cell proliferation and apoptosis.
- Mutation of SAMD9 gene leads to MIRAGE syndrome.
- MIRAGE syndrome is inherited as an autosomal dominant pattern.
- MIRAGE syndrome is form of syndromic adrenal hypoplasia characterized by the following:
- Restriction of growth
- Adrenal hypoplasia
- Genital phenotypes
- MIRAGE syndrome is often fatal within the first decade of life as a result of invasive infection.
- If the mutation is SAMD9 gene is inherited as an autosomal recessive pattern, it leads to familial tumoral calcinosis
- Familial tumoral calcinosis is characterized by massive periarticular and visceral deposition of calcified tumors.
- SAMD9L stands for sterile alpha motif domain containing protein 9-like.
- SAMD9L gene is located on chromosome 7q21.2.
- Mutation of SAMD9L gene leads to ataxia-pancytopenia syndrome.
- Ataxia-pancytopenia syndrome is inherited as an autosomal dominant pattern.
- Ataxia-pancytopenia syndrome is characterized by the following:
- Cerebellar ataxia
- Variable hematologic cytopenias
- Bone marrow failure
- Myeloid leukemia
Transcobalmin 2 deficiency
- Transcobalmin 2 deficiency is caused by mutation in TCN2 gene.
- TCN2 gene is located on chromosome 22q12.2.
- The TCN2 gene encodes transcobalamin II which is a plasma globulin that acts as the primary transport protein for vitamin B12.
- Transcobalmin 2 is also called as vitamin B12 binding protein 2.
- Transcobalamin 2, as well as intrinsic factor, is required for transportation of cobalamin from the intestine to the blood.
- Transcobalmin 2 deficiency is inherited as an autosomal recessive pattern.
- Transcobalmin 2 deficiency is characterized by the following:
- Definitive treatment is cobalamin supplement.
Hereditary Folate Malabsorption
- Hereditary folate malabsorption is caused by mutation of SLC46A1 gene.
- SLC46A1 gene is located on chromosome 17q11.
- Hereditary folate malabsorption is an autosomal recessive disorder.
- Hereditary folate malabsorption leads to impaired intestinal folate absorption and impaired transport of folate into the central nervous system.
- Hereditary folate malabsorption presents in infancy and characterized by signs and symptoms of folate deficiency.
- Hereditary folate malabsorption presents by the following features:
- Low blood and cerebrospinal fluid folate levels
- Megaloblastic anemia
- Neurologic deficits
- Definitive treatment is folate supplementation.
- The MTHFD1 gene encodes a trifunctional protein comprising 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase.
- These 3 sequential enzymes are involved in the interconversion of 1-carbon derivatives of tetrahydrofolate (THF) which are substrates for methionine, thymidylate, and de novo purine synthesis.
- Mutation of MTHFD1 gene leads to combined immunodeficiency and megaloblastic anemia with or without increased homocysteinemia.
- The MTHFD1 deficiency is inherited as an autosomal recessive disorder.
- The deficiency is characterized by the following:
- Hemolytic uremic syndrome
- Hearing loss
- Mild mental retardation
- Low T-cell receptor excision circle
- MTHFD1 deficiency is treated by folinic acid and hydroxycobalamin supplementation.
- NEMO stands for NF-kappa-B essential modifier.
- NEMO is encoded by a IKBKG gene on the X chromosome.
- NEMO also known as IKBKG gene (inhibitor of kappa polypeptide gene enhancer kinase gamma).
- IKBKG belongs to a family of NEMO-like kinases that function in numerous cell signaling pathways.
- NEMO-like kinases specifically phosphorylate serine or threonine residues that are followed by a proline residue.
- Ectodermal dysplasia and immune deficiency-1 (EDAID1) is caused by mutation in the IKK-gamma gene (IKBKG or NEMO )on Xq28.
- NEMO deficiency is inherited as an X-linked recessive disorder.
- NEMO deficiency is characterized by ectodermal dysplasia with combined immunodeficiencies.
EDA-ID due to IKBA GOF mutation
- Mutations in the NFKBIA gene result in functional impairment of NFKB , a master transcription factor required for normal activation of immune responses.
- Interruption of NFKB signaling results in decreased production of proinflammatory cytokines and certain interferons, rendering patients susceptible to infection.
- Ectodermal dysplasia and immune deficiency-2 (EDAID2) is caused by heterozygous mutation in the NFKBIA gene on chromosome 14q13.
- It is inherited as an autosomal dominant pattern
- EDAID2 is characterized by variable features of ectodermal dysplasia e.g.hypo/anhidrosis, sparse hair, tooth anomalies) and various immunologic and infectious phenotypes of differing severity.
Purine nucleoside phosphorylase deficiency
- Purine nucleoside phosphorylase deficiency is caused by mutation in the PNP gene.
- Purine nucleoside phosphorylase is one of the enzymes of purine salvage pathway.
- Defects in purine nucleoside phosphorylase enzyme lead to intracellular accumulation of metabolites that incldes deoxyguanosine triphosphate (dGTP).
- Deoxyguanosine triphosphate is particularly toxic to T cells.
- Purine nucleoside phosphorylase deficiency is autosomal recessive disorder.
- Purine nucleoside phosphorylase deficiency is characterized mainly by decreased T-cell function.
- Patients typically present in infancy to early childhood with frequent bacterial, viral, and opportunistic infections.
- Purine nucleoside phosphorylase deficiency also presents with progressive neurologic symptoms which includes ataxia, developmental delay and spasticity
- Low serum uric acid associated with T cell deficiency is highly suggestive of PNP deficiency.
- Diagnosis of purine nucleoside phosphorylase deficiency is confirmed by measurement of PNP enzyme activity.
- The only curative procedure for PNP deficiency is a hematopoietic stem cell transplantation.
ID with multiple intestinal atresias
- Also known as familial intestinal polyaterisa syndrome.
- Mutation in the TTC7A gene leads to gastrointestinal defects and immunodeficiency syndrome.
- TTC7A gene is located on chromosome 2p21.
- TT7CA stands for tetratricopeptide repeat domain 7A.
- TTC7A protein involves in proper development andfunction of both thymic and GI epithelium.
- Gastrointestinal defects and immunodeficiency syndrome is inherited as an autosomal recessive inheritance.
- Gastrointestinal defects and immunodeficiency syndrome is characterized by followings
- Multiple intestinal atresia, in which atresia throughout intestines.
- Combined immunodeficiency
- Surgical outcomes are poor, and the condition is usually fatal within the first month of life.
Hepatic veno-occlusive disease with immunodeficiency
- Hepatic venoocclusive disease with immunodeficiency is caused by mutation in the SP110 gene.
- SP110 gene is located on chromosome 2q37.
- SP10 gene encodes a protein called SP110 nuclear body protein which is involved in immuni reguation.
- Hepatic venoocclusive disease with immunodeficiency is an autosomal recessive disorder.
- Hepatic venoocclusive disease is associated with hepatic vascular occlusion and fibrosis.
- The immunodeficiency in hepatic venoocclusive disease is characterized by followings:
- Severe hypogammaglobulinemia
- Combined T and B cell immunodeficiency
- Absent lymph node germinal centers
- Absent plasma cells
- Hepatic veno-occlusive disease should be treat with intravenous immunoglobulin and pneumocystis jerovici prophylaxis.
- Vici syndrome is caused by mutation in the EPG5 gene.
- EPG5 gene is located on chromosome 18q.
- EPG5 encodes a gene called EPG5 which stands for ectopic P-granules autophagy protein 5.
- Ectopic P-granules autophagy protein 5 a key regulator in autophagy and forms autolysosomesrome.
- Vici syndrome is inherited as an autosomal recessive pattern.
- Vici syndrome is characterized by followings:
- Agenesis of the corpus callosum
- Pigmentary defects
- Progressive cardiomyopathy
- Variable immunodeficiency
- Profound psychomotor retardation
- Hypotonia due to a myopathy
- HOIL1 stands for heme -oxidized IRP2 ubiquitin ligase 1.
- HOIL1 also RBCK1 gene.
- RBCK1 gene encodes 1 of the components of the linear ubiquitin chain assembly complex(LUBAC)
- RBCK1 gene is located on chromosome 20p13
- Mutation in the RBCK1 leads to polyglucosan body myopathy.
- Polyglucosan body myopathy is inherited as autosomal recessive disorder.
- Polyglucosan body myopathy-1 is characterized by progressive proximal muscle weakness in early childhood.
- Most patients with polyglucosan body myopathy-1 also develop progressive dilated cardiomyopathy.
- Some patients with polyglucosan body myopathy also presents with severe immunodeficiency.
- HOIP stands for Hoil 1-Interacting Protein.
- HOIP1 deficiency is caused by the mutation in RNF31 gene.
- RNF31 gene is located chromosome 14q11.2.
- HOIP deficincy is characterized by followings:
- Multiorgan autoinflammation
- Combined immunodeficiency
- Subclinical amylopectinosis
- Systemic lymphangiectasia
Calcium Channel Defects (ORAI-1 deficiency)
- ORAI1 is also known as calcium release-activated calcium modulator1 (CRAMC1).
- ORAI1 gene is located on chromosome 12q24.
- ORAI1 (CRAMC1) gene encodes a plasma membrane protein essential for pore-forming subunit of the Ca2+ release-activated calcium channels.
- Mutation in the ORAI1 gene leads to primary immunodeficiency-9.
- Primary immunodeficiency-9 in inherited as an autosomal recessive disorder.
- Common manifestations of calcium channel defects include followings:
- Recurrent infections due to defective T-cell activation
- Congenital myopathy
- Muscle weakness
- Ectodermal dysplasia including soft dental enamel
- If the mutation in the ORAI1 gene is inherited as an autosomal dominant pattern it leads to tubular aggregate myopathy-2.
- Tubular aggregate myopathy-2 is characterized by muscle pain, cramping, or weakness that begins in childhood and worsens over time.
- Tubular aggregate myopathy-2 involves build up of proteins abnormally in both type I and type II muscle fibers and forms clumps of tube-like structures called tubular aggregates
- STM1 stands for stromal interaction molecule 1.
- STIM1 gene is located on chromosome 11p15.
- STIM1 gene encode stromal interaction molecule 1
- Stromal interaction molecule1 senses release of Ca2+ from endoplasmic reticulum and activates CRAC channels in the plasma membrane.
- Mutation in the STIM1 gene leads to primary immunodeficiency-10.
- Immunodeficiency-10 is iherited as an autosomal recessive disorder.
- Immunodeficiency-10 is characterized by recurrent infections in childhood due to defective T- and NK-cell function.
- Immunodeficiency-10 also have followigs:
- Dental enamel hypoplasia consistent with amelogenesis imperfecta
Hennekam-lymphangiectasia-lymphedema syndrome 2
- Hennekam lymphangiectasia-lymphedema syndrome-2 is caused by mutation in the FAT4 gene on chromosome 4q28.
- Hennekam lymphangiectasia-lymphedema syndrome-2 is inherited as an autosomal recessive pattern.
- FAT4 gene encodes a protein which is a member of a large family of protocadherins.
- Hennekam-lymphangiectasia-lymphedema syndrome 2 is characterized by followigs:
- Generalized lymphatic dysplasia
- Facial dysmorphism
- Cognitive impairment.
- STAT5b deficiency also known as signal transducer and activator of transcription 5B.
- STAT5 proteins are components of the common growth hormone and interleukin-2 families of cytokines signaling pathway.
- STAT family members are phosphorylated by the receptor associated kinases in response to cytokines and growth factors.
- STAT proteins then form homo-or heterodimers that translocate to the cell nucleus where they act as transcription activators.
- Growth hormone insensitivity is caused by a mutation in the STAT5B gene which is required for normal signaling of the GH receptor.
- Growth hormone insensitivity includes the followings:
- Severe growth failure
- Elevated serum concentrations of GH
- Clinical phenotype that identical to congenital GH deficiency.
- Kabuki syndrome-1 (KABUK1) is caused by heterozygous mutation in the MLL2 gene (KMT2D).
- MLL2 gene (KMT2D) encodes histone methyltransferase which methylates the Lys-4 position of histone H3.
- It usually inherits as an autosomal dominant pattern.
- Common manifestations of Kabuki syndrome include:
- Congenital mental retardation syndrome
- Postnatal dwarfism
- long palpebral fissures with eversion of the lateral third of the lower eyelids (reminiscent of the make-up of actors of Kabuki, a Japanese traditional theatrical form)
- Broad and depressed nasal tip
- Large prominent earlobes
- Cleft or high-arched palate
- Short fifth finger
- Persistence of fingerpads
- Radiographic abnormalities of the vertebrae, hands, and hip joints
- Recurrent otitis media in infancy
- ↑ Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA (December 1994). "A multiinstitutional survey of the Wiskott-Aldrich syndrome". J. Pediatr. 125 (6 Pt 1): 876–85. PMID 7996359.
- ↑ Buchbinder D, Nugent DJ, Fillipovich AH (2014). "Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments". Appl Clin Genet. 7: 55–66. doi:10.2147/TACG.S58444. PMC 4012343. PMID 24817816.
- ↑ Buchbinder D, Nugent DJ, Fillipovich AH (2014). "Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments". Appl Clin Genet. 7: 55–66. doi:10.2147/TACG.S58444. PMC 4012343. PMID 24817816.
- ↑ Muñoz A, Olivé T, Martinez A, Bureo E, Maldonado MS, Diaz de Heredia C, Sastre A, Gonzalez-Vicent M (September 2007). "Allogeneic hemopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON)". Pediatr Hematol Oncol. 24 (6): 393–402. doi:10.1080/08880010701454404. PMID 17710656.
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- ↑ Medina SS, Siqueira LH, Colella MP, Yamaguti-Hayakawa GG, Duarte B, Dos Santos Vilela MM, Ozelo MC (June 2017). "Intermittent low platelet counts hampering diagnosis of X-linked thrombocytopenia in children: report of two unrelated cases and a novel mutation in the gene coding for the Wiskott-Aldrich syndrome protein". BMC Pediatr. 17 (1): 151. doi:10.1186/s12887-017-0897-6. PMC 5480256. PMID 28641574. Vancouver style error: initials (help)
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