Combined immunodeficiency

# Overview
Please see Common variable immunodeficiency. There are a variety of syndromic conditions related to immunodeficiency. Some syndromic conditions are inherited.

# Classification

# Wiskott-Aldrich Syndrome
- Wiskott Aldrich syndrome (WAS) is X-Linked recessive primary immunodeficiency disorder.
- The classic triad of Wiskott-Aldrich syndrome include followings:
Eczema
Thrombocytopenia
Recurrent infections
- Eczema
- Thrombocytopenia
- 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
- Mild-to-moderate eczema
- Mild infrequent infections
- Small-sized platelets
- Treatment for patients with XLT is still not determined.

# WIP Deficiency
- 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:
Recurrent infections
Eczema
Thrombocytopenia
- Recurrent infections
- Eczema
- Thrombocytopenia
- 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 Deficiency
- 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: 
Recurrent infections
Vasculitis
Thrombocytopenia
- Recurrent infections
- Vasculitis
- Thrombocytopenia
- 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-telangietectasia
- 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
Choreoathetosis
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
Bronchiectasis
Interstitial lung disease
Pulmonary fibrosis
Neuromuscular abnormalities
Dysphagia
Aspiration
Respiratory muscle weakness
- Neurologic abnormalities
Progressive cerebellar ataxia
Abnormal eye movements
Oculomotor apraxia
Mild to moderate cognitive impairment
Choreoathetosis
- Progressive cerebellar ataxia
- Abnormal eye movements
- Oculomotor apraxia
- Mild to moderate cognitive impairment
- Choreoathetosis
- Dermatologic manifestations
Telangiectasias on exposed areas including pinnae, nose, face, and neck
Hypopigmented macules
Melanocytic nevi
Facial papulosquamous rash
- Telangiectasias on exposed areas including pinnae, nose, face, and neck
- Hypopigmented macules
- Melanocytic nevi
- Facial papulosquamous rash
- Oculocutaneous Telangiectasia
- Pulmonary disease
Recurrent sinopulmonary infections
Bronchiectasis
Interstitial lung disease
Pulmonary fibrosis
- Recurrent sinopulmonary infections
- Bronchiectasis
- Interstitial lung disease
- Pulmonary fibrosis
- Neuromuscular abnormalities
Dysphagia
Aspiration
Respiratory muscle weakness
- Dysphagia
- Aspiration
- Respiratory muscle weakness
- 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
Increased radiation-induced chromosomal breakage in cultured cells
Progressive cerebellar ataxia and who has disabling mutations on both alleles of ATM
- 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
- 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
- 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:
Microcephaly
Dysmorphic facial features
Mild growth retardation
Mild-to-moderate intellectual disability
Cafe-au-lait spots and depigmented skin lesions
Ovarian dysgenesis and premature ovarian failure in females
Hypergonadotropic hypogonadism and infertility in males
Recurrent sinopulmonary infections
- Microcephaly
- Dysmorphic facial features
- Mild growth retardation
- Mild-to-moderate intellectual disability
- Cafe-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
- 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
Immunodeficiency
Cafe-au-lait spots or hypopigmented skin lesions
Excessive photosensitivity with facial lupus-like skin lesions
Type 2 diabetes mellitus
Hypogonadism
Predisposition to the development of all types of cancers
- Growth deficiency of prenatal onset
- Immunodeficiency
- Cafe-au-lait spots or hypopigmented skin lesions
- Excessive photosensitivity with facial lupus-like skin lesions
- Type 2 diabetes mellitus
- Hypogonadism
- 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 Deficiency
- 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:
Immunodeficiency
facial dysmorphism
Ocular hypertelorism
Flat nasal bridge
Epicanthal fold
Low-set ears
Growth retardation
Failure to thrive
Psychomotor retardation
- Immunodeficiency
- facial dysmorphism
Ocular hypertelorism
Flat nasal bridge
Epicanthal fold
Low-set ears
- Ocular hypertelorism
- Flat nasal bridge
- Epicanthal fold
- Low-set ears
- Growth retardation
- Failure to thrive
- Psychomotor retardation
- 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.

# MCM4 Deficiency
- 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
- 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 Deficiency
- 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:
Radio-sensitivity
Immunodeficiency
Dysmorphic features
Learning difficulties
Short stature
Motor control problems
- Radio-sensitivity
- Immunodeficiency
- Dysmorphic features
- Learning difficulties
- Short stature
- Motor control problems
- It is pathologically similar to the ataxia-telangiectasia syndrome.

# POLE1 deficiency
- 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
Immunodeficiencies
Livedo on the skin since birth
Short stature
- Facial dysmorphism
- Immunodeficiencies
- 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 deficiency
- 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:
Combined immunodeficiencies
Facial dysmorphism
Autoimmunity
- Combined immunodeficiencies
- Facial dysmorphism
- Autoimmunity

# NSMCE3 Deficiency
- 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
Immunodeficiencies
Chromosome breakage syndrome
- Lung disease
- Immunodeficiencies
- Chromosome breakage syndrome
- Other features include:
Defective T cells and B cell
Acute respiratory distress syndrome in early childhood
- 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:
Trilineage bone marrow failure
Learning disabilities
Microcephaly
- Trilineage bone marrow failure
- Learning disabilities
- Microcephaly

# 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:
Immunodeficiency
Cellular hypersensitivity to DNA-damaging agents
- Immunodeficiency
- Cellular hypersensitivity to DNA-damaging agents

# GINS1 deficiency
- 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
- 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
- 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
- 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 deficiency
- 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
- Developmental aberrations
- Progressive bone marrow failure with myelodysplastic features
- Increased susceptibility to genotoxic stress
- Hematopoietic stem cell transplant is a curative therapy.

# MOPD1 deficiency
- 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:
Abnormally small head size
Abnormal bone growth (skeletal dysplasia)
Distinctive facial features
Brain anomalies
- Intrauterine growth retardation
- Post-natal growth retardation with the following features:
Abnormally small head size
Abnormal bone growth (skeletal dysplasia)
- Abnormally small head size
- Abnormal bone growth (skeletal dysplasia)
- Distinctive facial features
- Brain anomalies
- Diagnosis is made on the basis of the clinical and radiological phenotype.
- Common radiological features include:
Short tubular bones
Enlarged metaphyses
Vertebral and pelvic anomalies
Elongated clavicles
Bowing the long bones
- Short tubular bones
- Enlarged metaphyses
- Vertebral and pelvic anomalies
- Elongated clavicles
- Bowing the long bones
- 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 deficiency
- 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
- 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
Hypocalcemia
Palatal abnormalities
Developmental delay
T cell immunodeficiency presents with:
Recurrent sinopulmonary infections
Severe combined immunodeficiency
- Conotruncal cardiac anomalies
- Hypoplastic thymus
- Hypocalcemia
- Palatal abnormalities
- Developmental delay
- T cell immunodeficiency presents with:
Recurrent sinopulmonary infections
Severe combined immunodeficiency
- 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.

# TBX1 deficiency
- 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
- 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
- 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:
Coloboma
Heart anamoly
Choanal atresia
Retardation
Genital anamolies
Ear anamolies
- Coloboma
- Heart anamoly
- Choanal atresia
- Retardation
- Genital anamolies
- Ear anamolies

# Job Syndrome
- 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
Eosinophilia
Skeletal manifestation such as:
Distinctive coarse facial appearance
Abnormal dentition
Hyperextensibility of the joints
Bone fractures
- Chronic eczema
- Recurrent staphylococcal infections resulthing in cold abcess
- Increased serum IgE
- Eosinophilia
- Skeletal manifestation such as:
Distinctive coarse facial appearance
Abnormal dentition
Hyperextensibility of the joints
Bone fractures
- 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
- 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.

# PGM3 deficiency
- 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
Eczema
Increased serum IgE
- Recurrent respiratory and skin infections beginning in early childhood
- Developmental delay
- Cognitive impairment of varying severity
- Eczema
- Increased serum IgE

# Dyskeratosis congenita
- 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
- 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:
Retinal telangiectasias with exudates
Intracranial calcifications
Cerebellar movement disorder
Osteopenia
Leukoencephalopathy
Poor growth
Bone marrow failure
- Retinal telangiectasias with exudates
- Intracranial calcifications
- Cerebellar movement disorder
- Osteopenia
- Leukoencephalopathy
- Poor growth
- Bone marrow failure

# SAMD9 Mutation
- 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:
Myelodysplasia
Infection
Restriction of growth
Adrenal hypoplasia
Genital phenotypes
Enteropathy
- Myelodysplasia
- Infection
- Restriction of growth
- Adrenal hypoplasia
- Genital phenotypes
- Enteropathy
- 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 Mutation
- 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
- 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:
Failure to thrive
Megaloblastic anemia
Pancytopenia
Methylmalonic aciduria
Recurrent infections
Mental retardation
Neurologic abnormalities
- Failure to thrive
- Megaloblastic anemia
- Pancytopenia
- Methylmalonic aciduria
- Recurrent infections
- Mental retardation
- Neurologic abnormalities
- 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
Diarrhea
Immunodeficiency
Infections
Neurologic deficits
- Low blood and cerebrospinal fluid folate levels
- Megaloblastic anemia
- Diarrhea
- Immunodeficiency
- Infections
- Neurologic deficits
- Definitive treatment is folate supplementation.

# MTHFD1 deficiency
- 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
Macrocytosis
Epilepsy
Hearing loss
Retinopathy
Mild mental retardation
Lymphopenia
Low T-cell receptor excision circle
- Hemolytic uremic syndrome
- Macrocytosis
- Epilepsy
- Hearing loss
- Retinopathy
- Mild mental retardation
- Lymphopenia
- Low T-cell receptor excision circle
- MTHFD1 deficiency is treated by folinic acid and hydroxycobalamin supplementation.

# NEMO deficiency
- 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
- 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
- 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
- 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
Cataracts
Pigmentary defects
Progressive cardiomyopathy
Variable immunodeficiency
Profound psychomotor retardation
Hypotonia due to a myopathy
- Agenesis of the corpus callosum
- Cataracts
- Pigmentary defects
- Progressive cardiomyopathy
- Variable immunodeficiency
- Profound psychomotor retardation
- Hypotonia due to a myopathy

# HOIL1 deficiency
- 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.

# HOIP1 deficiency
- 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
- 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
- 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

# STIM1 deficiency
- 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:
Hypotonia
Hypohidrosis
Dental enamel hypoplasia consistent with amelogenesis imperfecta
- Hypotonia
- Hypohidrosis
- 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.
- Generalized lymphatic dysplasia
- Facial dysmorphism
- Cognitive impairment.

# STAT5b deficiency
- 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.
- Severe growth failure
- Elevated serum concentrations of GH
- Clinical phenotype that identical to congenital GH deficiency.

# Kabuki Syndrome
- 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
Scoliosis
Short fifth finger
Persistence of fingerpads
Radiographic abnormalities of the vertebrae, hands, and hip joints
Recurrent otitis media in infancy
- 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
- Scoliosis
- Short fifth finger
- Persistence of fingerpads
- Radiographic abnormalities of the vertebrae, hands, and hip joints
- Recurrent otitis media in infancy