Combined immunodeficiency

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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] Shyam Patel [2]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[3]; Anum Gull M.B.B.S.[4]; Farman Khan, MD, MRCP [5]; Sadaf Sharfaei M.D.[6]

Overview

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

Classification

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

NSMCE3 deficiency

ERCC6L2(Hebo deficiency)

Ligase 1 deficiency

GINS1 deficiency

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
• 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.

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
• 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
• 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
• 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
• 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
  • 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

• 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
  • Café-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
• 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
• 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
• 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
• 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

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
• 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:
  • 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

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

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 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
• 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
• 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
• 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
• 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
• 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

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
• 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.

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

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

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

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
• 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

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
• 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
• 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
• 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
• 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

• 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

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

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

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

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

• 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

• 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