Combined immunodeficiency

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Immunodeficiency Main Page




Immunodeficiency Affecting Cellular and Humoral Immunity

Combined Immunodeficiency

Predominantly Antibody Deficiency

Diseases of Immune Dysregulation

Congenital Defects of Phagocytes

Defects in Intrinsic and Innate Immunity

Auto-inflammatory Disorders

Complement Deficiencies

Phenocopies of Primary Immunodeficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2], Anum Gull M.B.B.S.[3]



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
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
Methylene-tetrahydrofolate-dehydrogenase 1 deficiency
Hepatic veno-occlusive disease with immunodeficiency
ARPC1B deficiency
PMS2 deficiency
MOPD1 deficiency
CHARGE Syndrome
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
NSMCE3 deficiency
ERCC6L2(Hebo deficiency)
Ligase 1 deficiency
GINS1 deficiency

Wiskott-Aldrich Syndrome

  • Wiskott–Aldrich syndrome (WAS) is a rare X-linked Recessive primary immunodeficiency disorder characterized by the triad of eczema, microthrombocytopenia, and often recurrent infections caused by mutation of WASp gene.[1]

X-linked thrombocytopenia (XLT)

Presents with mild eczema and/or infections, it is suspected to be a variant of WAS.Patients with XLT shown to have mutations in the (WAS)Wiskott-Aldrich syndrome protein gene.

X-linked thrombocytopenia (XLT) should be suspected in a male with:

  • Congenital thrombocytopenia (5,000-50,000 platelets/mm3).
  • Small platelet size (platelet volume <7.5 fL).
  • Absence of other clinical findings of Wiskott-Aldrich syndrome.
  • Family history of one or more maternally related males with a WAS-related phenotype or disorder.
  • Decreased or absent WASP by flow cytometry or western blotting..
  • Some affected individuals have near-normal amounts of WAS.


NEED TO COMPLETE THIS (WIP)WISKOTT-ALDRICH-INTERACTING PROTEIN; gene :WIPF1 is located on 2q31.1 . lymphocytes, WASP is almost totally complexed with the WASP-interacting protein (WIP). A major function of WIP is to stabilize WASP and prevent its degradation. WASP protein levels, but not mRNA levels, are severely reduced in T cells [4]


  • ARPC1B gene (ACTIN-RELATED PROTEIN 2/3 COMPLEX, SUBUNIT 1B) is located on 7q22.1 and its deficieny leads to PLTEID(Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease)
  • The ARP2/3 protein complex is involved in the control of actin polymerization in cells. The human complex consists of 7 subunits, including the actin-related proteins ARP2 and ARP3 .[5]
  • PLTEID is an autosomal recessive immune-mediated inflammatory disease with highly variable manifestations. More severely affected individuals have recurrent infections, vasculitis, and thrombocytopenia, whereas other patients have mild vasculitis and normal numbers of small platelets without severe infections.
  • Laboratory studies show platelets with abnormal shape, decreased dense granules, and impaired spreading ability, as well as immune dysregulation with increased eosinophils, B cells, IgA and IgE, and autoantibodies [6]


  • Ataxia-telangiectasia (AT) is an autosomal recessive characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, radiosensitivity, predisposition to lymphoid malignancies and immunodeficiency
  • The ATM gene is related to a family of genes involved in cellular responses to DNA damage and/or cell cycle control with defects in both cellular and humoral immunity [7].
  • ATM gene is located on 11q22.3.
  • Diagnosis is usually achieved by physical examination and identification of both ataxia and oculo-cutaneous telangiectasia, this is then followed by laboratory tests for low levels of IgA, IgG2, IgG4, and IgE.
  • They may also have a low lymphocyte count and other immunological abnormalities.
  • This can then be followed by cytogenetic and molecular testing to confirm the diagnosis.
  • MRI and CT scans may show signs of cerebellar atrophy.

Nijmegen breakage Syndrome

  • Nijmegen breakage syndrome (NBS) is caused by mutation in the NBS1 gene on chromosome 8q21 which is inherited as an Autosomal Recessive disorder.
  • It is characterized by microcephaly, growth retardation, immunodeficiency, and predisposition to cancer.
  • It is phenotypically indistinguishable from Berlin breakage syndrome.Both are autosomal recessive chromosomal instability syndromes.
  • Ataxia-telangiectasia variant-1 is the designation applied to the Nijmegen breakage syndrome.


  • It is caused by the mutation in the BLM gene encoding DNA helicase RecQ protein-like-3 (RECQL3) on chromosome 15q26.
  • also called Bloom-Torre-Machacek syndrome or congenital telangiectatic erythema, is a rare autosomal recessive inherited disorder characterized by genomic instability and predisposition to the development all types of cancer.
  • The most prominent features include growth deficiency of prenatal onset, mild immunodeficiency, excessive photosensitivity with facial lupus-like skin lesions, type 2 diabetes mellitus and hypogonadism.
  • Laboratory diagnosis of Bloom syndrome by detecting mutations in BLM .

PMS2 deficiency

  • PMS2 gene is located on chromosome 7p22.1
  • PMS2 is a gene that encodes for DNA repair proteins involved in mismatch repair
  • Its Deficiency is inherited as Autosomal Recessive pattern which leads to Colorectal cancer, hereditary nonpolyposis akaMismatch repair cancer syndrome[8]

Immunodeficiency with centromeric instability and facial anomalies(ICF1, ICF2, ICF3, ICF4)

  • ICF is caused by mutation in the ZBTB24 gene on chromosome 6q21; ICF3 is caused by mutation in the CDCA7 gene on chromosome 2q31; and ICF4 is caused by mutation in the HELLS gene on chromosome 10q23.
  • It is an autosomal recessive disease presenting with immunodeficiency, mild facial dysmorphism, growth retardation, failure to thrive, and psychomotor retardation.
  • Serum levels of IgG, IgM, IgE, and/or IgA are low.
  • Recurrent infections are the presenting symptom, usually in early childhood.
  • The differentials include Bloom syndrome, ataxia-telangiectasia, and Nijmegen breakage syndrome
  • Treatment almost always includes regular infusions of immunoglobulins, mostly intravenously
  • Recently, bone marrow transplantation has been tried.

MCM4 deficiency

  • Deficiency caused by homozygous mutation in the MCM4 gene located on 8q11.21 [9]
  • Tt is a variant of familial glucocorticoid deficiency (FGD), an autosomal recessive form of adrenal failure
  • MCM4 is one part of a MCM2-7 complex whic functions as the replicative helicase essential for normal DNA replication and genome stability in all eukaryotes
  • It characterized by adrenal insufficiency, short stature, and NK cell deficiency.
  • The NK cell deficiency accounts for the patients' recurrent viral illnesses
  • Patients have typical biochemical features of FGD, with isolated glucocorticoid deficiency, raised ACTH, and normal renin and aldosterone.
  • Affected individuals with adrenal insufficiency requiring corticosteroid replacement therapy

RNF168 deficiency

  • Gene is located on chromosome 3q29
  • It codes E3 ubiquitin ligase which is critical for Double strand DNA breaks repair.[10]
  • Mutation of this gene leads to RIDDLE syndrome.
  • This sydrome is inherited as an Autosomal Recessive pattern
  • RIDDLE (radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties) syndrome is an immunodeficiency disorder that primarily manifests as an immunoglobulin deficiency,also present with nonimmunological characteristics including short stature and motor control problems

POLE1 deficiency

  • Gene location: 12q24.33
  • gene function: POLE gene encodes the catalytic subunit of DNA polymerase epsilon
  • Inheritance pattern: AR
  • Disease:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (FILS syndrome)[11]
  • If the pole gene mutation is inherited as an autosomal dominant patter then it leads to COLORECTAL CANCER, SUSCEPTIBILITY TO, 12

POLE2 deficiency

POLYMERASE, DNA, EPSILON-2; POLE2 14q21.3 involved in both DNA replication and DNA repair, AR Mutation in the POLE2 Gene Causing Combined Immunodeficiency

NSMCE3 deficiency

  • The NSMCE3 gene encodes a component of the SMC5/SMC6complex, which is essential for responses to DNA damage and chromosome segregation during cell division
  • 15q13.1
  • AR
  • Lung disease, immunodeficiency, and chromosome breakage syndrome
  • Defective T and B cell function and acute respiratory distress syndrome in early childhood.


ERCC6L2(Hebo deficiency)

  • ERCC6L2 gene is located on 9q22.32 ERCC6L2 belongs to a family of helicases
  • the gene is involved inchromatin unwinding, transcription regulation, and DNA recombination, translocation, and repair
  • Mutation of this gene leads to Bone marrow failure syndrome 2
  • It is inherited as an autosomal pattern
  • Characterized by trilineage bone marrow failure, learning disabilities, and microcephaly


Ligase 1 deficiency

LIGASE I, DNA, ATP-DEPENDENT; LIG1 19q13.33 LIG1 functions at the replication fork to join Okazaki fragments during replication of lagging strand DNA mutation of this gene leads to RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE (formerly called as DNA LIGASE I DEFICIENCY Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents. [14]

GINS1 deficiency

  • gene :GINS1
  • location : 20p11.21
  • protein: GINS complex
  • Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency


Immuno-osseous dysplasias

Cartilage Hair Hypoplasia  !

  • It is caused by homozygous or compound heterozygous mutation in the RMRP gene on chromosome 9p13.
  • The gene endoribonuclease RNase MRP consists of an RNA molecule bound to several proteins
  • It has two functions :cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of pre-rRNA.[16]
  • Muatation is nherited as an Autosomal Recessive pattern characterized by short-limbed short stature and fine, sparse hair
  • It also includes ligamentous laxity, defective immunity, hypoplastic anemia, and neuronal dysplasia of the intestine.
  • CHH is diagnosed clinically by observing fine and often sparse hair in an individual with short stature with disproportionally short limbs.
  • Radiographic findings are helpful in the work-up of an individual with suspected skeletal dysplasia.
  • The metaphyseal ends are abnormal in CHH and appear as scalloped, irregular surfaces that may contain cystic areas on routine radiographs[17]
  • Genetic analysis of the RMRP gene confirms the diagnosis

Schimke Syndrome

  • Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive spondylo-epiphyseal dysplasia Schimke immunoosseous dysplasia (SIOD) is caused by homozygous or compound heterozygous mutation in the SMARCAL1 gene on chromosome 2q25.
  • Mutations in the gene encoding the chromatin remodeling protein, SMARCAL1 (SWI/SNF2-related matrix-associated, actin-dependent regulator of chromatin


  • it is autosomal recessive condition, which features skeletal, renal, and immune abnormalities.[19]
  • characterized by short stature (often with prenatal growth deficiency), spondyloepiphyseal dysplasia, defective cellular immunity, and 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.

MYSM1 deficiency !

  • MYSM1 gene is located on 1p32.1
  • Myb-like, SWIRM, and MPN domain 1 (MYSM1) is a transcriptional regulator mediating histone deubiquitination[20]
  • Its deficiency leads to Bone marrow failure syndrome 4.
  • MYSM1 deficiency is associated with developmental aberrations, progressive Bone maarow failure with myelodysplastic features, and increased susceptibility to genotoxic stress.
  • Hematopoiteic stem cell transplant is a curative therapy for patients with MYSM1 deficiency.

MOPD1 deficiency

  • akaTaybi-Linder syndrome
  • RNU4ATAC gene ,encoding a small nuclear RNA (snRNA) component of the U12-dependent(minor) spliceosome on chromosome 2q14.
  • It is caused by mutations in the RNU4ATAC gene and is inherited in an autosomal recessive manner
  • Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is a genetic condition that is mainly characterized by intrauterine and post-natal growth retardation[21]
  • An abnormally small head size (microcephaly); abnormal bone growth (skeletal dysplasia); distinctive facial features; and brain anomalies
  • Diagnosis is made on the basis of the clinical and radiological phenotype, with common radiological features including short tubular bones, enlarged metaphyses, vertebral and pelvic anomalies, elongated clavicles, bowing of the long bones and cleft vertebral arches
  • There are no specific treatments for MOPD1
  • Treatment is supportive only.
  • The prognosis is poor with most affected individuals dying within the first year of life

EXTL3 deficiency

  • EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs)
  • Missense mutations in the EXTL3 gene located on chromosome 8p21.1
  • Mutation of this gene leads to a syndrome called immunoskeletal dysplasia with neurodevelopmental abnormalities
  • Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects.


Thymic Defects with additional congenital anomalies

DiDeorge Syndrome

  • Haploinsufficiency of the TBX1 gene,in particular is responsible for most of the physical malformations
  • This deletion leads to efective development of the 3rd and 4th pharyngeal pouch system
  • Haploinsufficiency of the TBX1 gene,in particular is responsible for most of the physical malformations
  • Chromosome 22q11.2 deletion syndrome (22qDS) includes DGS and other similar syndromes, such as velocardiofacial syndrome
  • The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia, although the phenotype is variable.
  • Palatal abnormalities and developmental delay are common Immunodeficiency is common in patients with DGS and can range from recurrent sinopulmonary infections (partial DGS) to severe combined immunodeficiency (SCID; complete DGS).
  • The severity of the immunodeficiency is The diagnosis of and evaluation for DGS should occur for any neonate with a conotruncal heart lesion, hypocalcemia, and/or cleft palaterelated to the degree of thymic hypoplasia[23]
  • The diagnosis of DGS is based upon reduced numbers of CD3+ T cells, combined with either characteristic clinical findings or a demonstrated deletion in chromosome 22q11.2
  • Also detected by SCID newborn screening (NBS) using an assay for T cell receptor excision circles (TRECS), a biomarker of T cell development[24]
  • Treatment includes supplementation with vitamin D or calcium and with parathyroid hormone
  • Thymus tissue transplantation, bone marrow transplant, stem cell transplant, or transplant of disease-fighting blood cells may be necessary.
  • Hematopoietic cell transplantation (HCT) is a suitable, technically easier, and more readily available alternative to thymic transplantation in the patient with complete DGS who has an HLA-identical donor

TBX1 deficiency

  • TBX1 gene is located on 22q11.21
  • T-box transcription factor TBX1 also known as T-box protein 1
  • The TBX1 gene provides instructions for making a protein called T-box 1
  • Genes in the T-box family play important roles in the formation of tissues and organs during embryonic development

Chromosome 10p13-p14 deletion Syndrome

  • Chromosome 10, monosomy 10p is a rare chromosomal disorder in which the end (distal) portion of the short arm (p) of chromosome 10 is missing (deleted or monosomic)
  • The severity of symptoms may be variable, depending upon the exact size or location of the deletion on chromosome 10p.
  • Clinical features often include severe intellectual disability; postnatal growth retardation, distinctive malformations of the skull and craniofacial region.
  • A short neck and/or congenital heart defects are also present.
  • Monosomy 10p is also frequently associated with growth delays after birth, resulting in short stature
  • Several cases have also been reported in which affected individuals have some features of DiGeorge syndrome (DGS)
  • A diagnosis of chromosome 10, monosomy 10p may be suggested before birth (prenatally) by tests such as amniocentesis or chorionic villus sampling (CVS)
  • The treatment of affected individuals is symptomatic and supportive.

CHARGE Syndrome

  • Caused by heterozygous mutation in the CHD7 on chromosome 8q12.
  • CHD7 is essential for the formation of multipotent migratory neural crest, a transient cell population that is ectodermal in origin but undergoes a major transcriptional reprogramming event to acquire a remarkably broad differentiation potential and ability to migrate throughout the body, giving rise to craniofacial bones and cartilages, the peripheral nervous system, pigmentation, and cardiac structures
  • Inherited as an Autonsomal Dominant pattern
  • Characterized by a pattern of congenital anomalies including choanal atresia and malformations of the heart, inner ear, and retina

Hyper-IgE syndromes

(HIES)Job Syndrome

  • Autosomal dominant hyper-IgE recurrent infection syndrome is caused by heterozygous mutation in the STAT3 gene on chromosome 17q21
  • Hyper-IgE recurrent infection syndrome is a primary immunodeficiency disorder characterized by chronic eczema, recurrent Staphylococcal infections, increased serum IgE, and eosinophilia.
  • Patients have a distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures
  • STAT3 is important in the signaling induced by multiple families of cytokines, hormones, and growth factors, although the precise mechanisms that unify the infectious, dermatologic, skeletal, and immunologic features of this disorder are not yet known
  • Laboratory abnormalities include elevated total serum IgE levels, typically ranging from 1000 to >50,000 int. units/mL, and variable eosinophilia.
  • The diagnosis of HIES is based upon the presence of suggestive clinical and laboratory findings.
  • The diagnosis can be confirmed by molecular testing.
  • Management of patients with HIES is focused on skin care, prevention of infection, prompt and complete treatment of infections, and control of pulmonary complications

Comel Netherton Syndrome

  • Rare autosomal recessive disorder of cornification caused by mutations in the serine protease inhibitor of Kazal type 5 gene (SPINK5)on chromosome 5q32.
  • SPINK5 encodes a multidomain serine protein kinase known as lymphoepithelial Kazal type inhibitor (LEKTI) expressed in epithelial and mucosal surfaces
  • Among the proteases it directly inhibits are several kallikreins, especially kallikrein 5 (KLK5). Kallikreins are critical epidermal proteases, important for regulating skin desquamation
  • It is clinically characterized by the classic triad of congenital ichthyosiform erythroderma, a specific hair shaft abnormality termed trichorrhexis invaginata ("bamboo hair"), and an atopic diathesis
  • Many NS 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 NS. it is mainly supportive The erythrodermic newborn with NS has a very high risk of potentially life-threatening complications, such as hypernatremic dehydration, sepsis, and hypothermia

PGM3 deficiency

Dyskeratosis congenita (DKC)

Dyskeratosis congenita

  • X-linked dyskeratosis congenita (DKCX) is caused by mutation in the DKC1 gene on chromosome Xq28
  • The disorder is caused by defects in the maintenance of telomeres
  • Mutations in genes that maintain telomere length in rapidly dividing cells lead to premature cell death, senescence, or genomic instability,
  • It is characterized as a triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa

COATS plus syndrome

  • cerebroretinal microangiopathy with calcifications and cysts-1 (CRMCC1) is also known as COATS plus syndrome
  • caused by compound heterozygous mutation in the CTC1 gene on chromosome 17p13.
  • Inherited as an Autoosomal recessive pattern
  • characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline


  • SMD9 stands for STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 9encoded by the SAMD9 gene located on 7q21.2
  • MIRAGE syndrome inherited as an Autosomal dominant pattern
  • it includes form of syndromic adrenal hypoplasia, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy
  • The condition is often fatal within the first decade of life, usually as a result of invasive infection
  • If the Mutation is inherited as an Autosomal Recessive Pattern then it leads to Tumoral calcinosis, familial, normophosphatemic characterized by normophosphatemic familial tumoral calcinosis


  • Located on 7q21.2
  • inherited as an autosomal Dominant pattern.
  • mutation of this gene leads to Ataxia-pancytopenia syndrome
  • It characterized by cerebellar ataxia, variable hematologic cytopenias, and presdisposition to bone marrow failure and myeloid leukemia

Transcobalmin 2 deficiency

  • TCN2 gene is located on chromosome 22q12.2
  • The TCN2 gene encodes transcobalamin II (TC II), a plasma globulin that acts as the primary transport protein for vitamin B12
  • Transcobalamin is also called as VITAMIN B12-BINDING PROTEIN 2
  • TC II as well as intrinsic factor (609342) is required for transport of cobalamin from the intestine to the blood
  • Mutation of this gene leads to TCN 2 deficiency which is inherited as an Autosomal Recessive pattern
  • It is characterized with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia.
  • Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea.
  • Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities

Deficiency causing hereditary folate malabsorption

  • hereditary folate malabsorption is caused by homozygous or compound heterozygous mutation in the SLC46A1 gene (611672) on chromosome 17q11.
  • Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth.
  • Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits.
  • Treatment with folate supplementation results in resolution of the signs and symptoms.
  • The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system

Methylene-tetrahydrofolate-dehydrogenase 1 deficiency

  • The MTHFD1 gene encodes a trifunctional protein comprising 5,10-methylenetetrahydrofolate dehydrogenase , 5,10-methenyltetrahydrofolate cyclohydrolase , and 10-formyltetrahydrofolate synthetase
  • These 3 sequential reactions are involved in the interconversion of 1-carbon derivatives of tetrahydrofolate (THF) which are substrates for methionine, thymidylate, and de novo purine syntheses.
  • Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia is an inborn error of folate metabolite
  • it is is an autosomal recessive disorder
  • it is characteized bymhemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild mental retardation, lymphopenia involving all subsets, and low T-cell receptor excision circles.
  • Folinic acid and hydroxycobalamin supplementation is an effective treatment

NEMO deficiency

  • NEMO, also known as IKBKG, (inhibitor of kappa polypeptide gene enhancer in B cells, kinase gamma/nuclear factor-kappa B essential modulator) gene
  • 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; 300248) on Xq28.
  • It is an X-linked recessive disorder characterized by variable ectodermal features, but most often including hypo/anhidrosis, and various immunologic and infectious phenotypes of differing severity.
  • Mutations in this gene also leads to anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema (OLEDAID).

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 (164008) on chromosome 14q13.
  • t 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
  • it is one of the enzymes involved in the purine salvage pathway Defects in this enzyme lead to intracellular accumulation of metabolites, including deoxyguanosine triphosphate (dGTP), thought to be particularly toxic to thymocytes and T cells
  • Rare autosomal recessive immunodeficiency disorder characterized mainly by decreased T-cell function. Some patients also have neurologic impairment
  • Patients typically present in infancy to early childhood with frequent bacterial, viral, and opportunistic infections and failure to thrive.
  • It also presents with progressive neurologic symptoms and autoimmune disease
  • Low serum uric acid associated with T cell deficiency is highly suggestive of PNP deficiency, and the diagnosis should then be 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

  • gastrointestinal defects and immunodeficiency syndrome (GIDID) is caused by homozygous or compound heterozygous mutation in the TTC7A gene (609332) on chromosome 2p21.
  • autosomal recessive inheritance.
  • Gastrointestinal defects and immunodeficiency syndrome (GIDID) is characterized by multiple intestinal atresia, in which atresia occurs at various levels throughout the small and large intestines.
  • Surgical outcomes are poor, and the condition is usually fatal within the first month of life.
  • Some patients exhibit inflammatory bowel disease (IBD), with or without intestinal atresia, and in some cases, the intestinal features are associated with either mild or severe combined immunodeficiency

Hepatic veno-occlusive disease with immunodeficiency

  • hepatic venoocclusive disease with immunodeficiency (VODI) is caused by homozygous mutation in the SP110 gene (604457) on chromosome 2q37.
  • Hepatic venoocclusive disease with immunodeficiency syndrome (VODI) is an autosomal recessive primary immunodeficiency associated with hepatic vascular occlusion and fibrosis.
  • The immunodeficiency is characterized by severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, and absent tissue plasma cells and and hepatic veno-occlusive disease
  • VODI is associated with an 85% mortality if unrecognized and untreated with intravenous immunoglobulin and Pneumocystis jerovici prophylaxis

Vici Syndrome

  • EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomesrome (VICIS)
  • It is caused by homozygous or compound heterozygous mutation in the EPG5 gene on chromosome 18q
  • Autosomal recessive inheritance
  • congenital multisystem disorder characterized by agenesis of the corpus callosum (ACC), cataracts, pigmentary defects, progressive cardiomyopathy, and variable immunodeficiency.
  • Affected individuals also have profound psychomotor retardation and hypotonia due to a myopathy

HOIL1 deficiency

  • the alternate title for this gene is RBCK1 ( RANBP-TYPE AND C3HC4-TYPE ZINC FINGER-CONTAINING 1)
  • polyglucosan body myopathy-1 (PGBM1) is caused by homozygous or compound heterozygous mutation in the RBCK1 gene (610924) on chromosome 20p13.
  • Tth autosomal recessive inheritance
  • Polyglucosan body myopathy-1 is an autosomal recessive disorder characterized by onset in childhood of progressive proximal muscle weakness, resulting in difficulties in ambulation.
  • Most patients also develop progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. A small subset of patients present with severe immunodeficiency and a hyperinflammatory state in very early childhood

HOIP1 deficiency

  • caused by the mutation in RNF31 gene to chromosome 14q11.2.
  • inherited, complete deficiency of human HOIL-1, a component of the linear ubiquitination chain assembly complex (LUBAC), underlies autoinflammation, infections, and amylopectinosis
  • A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC

Calcium Channel Defects(ORAI-1 deficiency, )

  • also known as ORAI calcium release-activated calcium modulator 1
  • primary immunodeficiency-9 (IMD9) is caused by homozygous or compound heterozygous mutation in the ORAI1 gene (610277), which encodes a subunit of the plasma membrane calcium channel CRAC, on chromosome 12q24
  • Immunodeficiency-9 is an autosomal recessive disorder characterized by early onset of recurrent infections due to defective T-cell activation.
  • Affected individuals also have congenital myopathy resulting in muscle weakness as well as features of ectodermal dysplasia, including soft dental enamel

STIM1 deficiency

  • primary immunodeficiency-10 (IMD10) is caused by homozygous mutation in the STIM1 gene (605921) on chromosome 11p15
  • Immunodeficiency-10 is an autosomal recessive primary immunodeficiency characterized by onset of recurrent infections in childhood due to defective T- and NK-cell function butthe severity is variable
  • Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta

Hennekam-lymphangiectasia-lymphedema syndrome

  • Hennekam lymphangiectasia-lymphedema syndrome-2 (HKLLS2) is caused by homozygous or compound heterozygous mutation in the FAT4 gene (612411) on chromosome 4q28.
  • FAT4 gene encodes a protein that is a member of a large family of protocadherins.
  • Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. * include facial dysmorphism and cognitive impairment

STAT5b deficiency

  • In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators
  • GHI caused by a homozygous missense mutation in the gene encoding signal transducer and activator transcription 5B (STAT5B), which is essential for normal signaling of the GH receptor .
  • The patients have severe postnatal growth failure and immune dysregulation, which is probably because STAT5B also mediates signal transduction triggered by various immune ligands, such as interleukin-2 (IL2), interleukin-4 (IL4), and colony-stimulating factor 1 (CSF1)
  • STAT5 proteins are components of the common growth hormone and interleukin 2 family of cytokines' signaling pathway

Kabuki Syndrome

  • The protein encoded by MLL2 gene (KMT2D) gene is a histone methyltransferase that methylates the Lys-4 position of histone H3.
  • Kabuki syndrome-1 (KABUK1) is caused by heterozygous mutation in the MLL2 gene (KMT2D
  • Autosomal Dominant
  • Kabuki syndrome is a congenital mental retardation syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by 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), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy


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