Combined immunodeficiency

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Overview

Classification

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]

Overview

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

X-linked thrombocytopenia (XLT)

  • XLT is a less severe variant of WAS that presents. It presents as a benign disease with good long-term survival compared with classic WAS.[5][6][7]
  • There is a relationship between XLT and WAS caused by different type of mutations of the same gene.[8]
  • WAS gene is mutated in XLT Wiskott-Aldrich syndrome.[8]
  • It usually inherits as a X linked-recessive pattern.
  • It is characterized by mild-to-moderate eczema, mild infrequent infections and small-sized platelets.
  • Treatment for patients with XLT is still not determined.[5]

WIP Deficiency

ARPC1B DEFICIENCY

ATAXIA-TELANGIECTASIA

  • Ataxia-telangiectasia (AT) is an autosomal recessive disorder caused by defective gene in AT which is located on chromosome 11q22.3.
  • Common manifestations of AT include followings:[16]
  • It leads to increased risk of development of lymphoid malignancies and immunodeficiency.
  • The ATM gene isinvolved in cell responses to DNA damage and cell cycle control.[17]
    • Neurologic abnormalities
    • Dermatologic manifestations
      • Hypopigmented macules
      • Melanocytic nevi
      • Facial papulosquamous rash
    • Oculocutaneous Telangiectasia
    • Radiosensitivity
    • 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:[18][19][20]
    • 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
  • The diagnosis is made by cytogenetics and molecular testing.
  • MRI and CT scans show signs of cerebellar atrophy.
  • Diagnosis can also be made by rapid immunoblotting assay for ATM protein because its levels are greatly reduced.[19]

Nijmegen breakage Syndrome

  • Nijmegen breakage syndrome (NBS) is caused by mutation in the NBS1 gene.
  • NBS1 gene is located on chromosome 8q21.
  • It is inherited as an autosomal recessive disorder.
  • The main manifestations of the syndrome are:
    • Microcephaly
    • Dysmorphic facial features
    • Mild growth retardation
    • Mild-to-moderate intellectual disability
    • Hypergonadotropic hypogonadism in females.[21]
    • Combined cellular and humoral immunodeficiency with 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.[22]
  • Nijmegen breakage syndrome is also known as Ataxia-telangiectasia variant-1.
  • There is no specific treatment for NBS.

Bloom Syndrome

  • Bloom syndrome is caused by the mutation in the BLM gene.
  • BLM gene encodes DNA helicase RecQ protein-like-3 (RECQL3).
  • BLM gene is located on chromosome 15q26.[23]
  • Bloom syndrome is also called as Bloom-Torre-Machacek syndrome or congenital telangiectatic erythema.
  • It is inherited as an autosomal recessive inherited disorder.
  • The most prominent features includes:
    • Growth deficiency of prenatal onset
    • Mild immunodeficiency
    • 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.[24]

PMS2 Deficiency

  • PMS2 stands for 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.[25]
  • It is inherited as autosomal recessive pattern.[26]
  • Deficency of PMS2 leads to colorectal cancer and hereditary nonpolyposis.[27]

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.
  • ICF4 is caused by mutation in the HELLS gene on chromosome 10q23.
  • It is an autosomal recessive disease.
  • Presents with immunodeficiency, mild facial dysmorphism, growth retardation, failure to thrive, and psychomotor retardation.[28]
  • Recurrent infections are the presenting symptom, usually in early childhood.
  • Generally, at least two immunoglobulin classes are affected in each patient, and agammaglobulinemia can occur.
  • .T cell number and response to mitogen may be decreased.[29][30][31]
  • The centromeric instability most frequently involves chromosomes 1 and 16, often 9, and rarely 2 and 10.
  • The differentials include Bloom syndrome, ataxia-telangiectasia, and Nijmegen breakage syndrome.
  • Early diagnosis of ICF syndrome is critical since early immunoglobulin supplementation can improve the course of disease.[28]
  • Allogeneic hematopoietic cell transplantation (HCT) in patients with severe disease corrects the immunodeficiency and improves growth.[32]

MCM4 Deficiency

  • MCM stands for minichromosome maintenance complex component 4.
  • Deficiency caused by homozygous mutation in the MCM4 gene located on 8q11.21. [33]
  • It is a variant of familial glucocorticoid deficiency (FGD), an autosomal recessive form of adrenal failure.[34]
  • MCM4 is one part of a MCM2-7 complex which functions as the replicative helicase.
  • Helicase is essential for normal DNA replication and genome stability in all eukaryotes.
  • It characterized by adrenal insufficiency, short stature, and NK cell deficiency.[35]
  • The NK cell deficiency accounts for recurrent viral illnesses.[36][34]
  • 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

  • It stands for Ring finger protein 168(RNF168).
  • Gene is located on chromosome 3q29.[37]
  • It codes E3 ubiquitin ligase which is critical for Double strand DNA breaks repair.[38]
  • Mutation of this gene leads to RIDDLE syndrome.[39]
  • This syndrome is inherited as an autosomal recessive pattern.
  • RIDDLE (radio-sensitivity, immunodeficiency, dysmorphic features, and learning difficulties) syndrome is an immunodeficiency disorder.[39]
  • Manifests as an immunoglobulin deficiency.
  • pathologic similarities to the ataxia-telangiectasia syndrome.[38]
  • It also presents with non immunological characteristics including short stature and motor control problems.

POLE1 Deficiency

  • POLE1 stands for DNA polymerase,epsilon subunit 1.
  • The POLE1 gene is located on 12q24.33.
  • POLE1 gene encodes the catalytic subunit of DNA polymerase epsilon.
  • It is inherited as an autosomal recessive pattern.
  • Disease:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (FILS syndrome)[40]
  • FILS syndrome is characterized by mild facial dysmorphism, mainly malar hypoplasia, livedo on the skin since birth, immunodeficiency resulting in recurrent infections, and short stature[41]
  • Colorectal cancer-12 is an autosomal dominant disorder characterized by a high-penetrance predisposition to the development of colorectal adenomas and carcinomas[42]

POLE2 Deficiency

  • POLE2 stands for DNA polymerase epsilon subunit 2.[43]
  • This gene is located on 14q21.
  • It is nvolved in both DNA replication and DNA repair.
  • Mutation in the POLE2 gene causes combined Immunodeficiency.
  • It is chaharacterized by combined immunodeficiency, facial dysmorphisms, and autoimmunity.[44]
  • It is inherited as an autosomal recessive pattern.

NSMCE3 Deficiency

ERCC6L2(Hebo deficiency)

  • HEBO stands for Helicase mutated in bone marrow failure.
  • ERCC6L2 gene is located on 9q22.32 ERCC6L2 belongs to a family of helicases.
  • The gene is involved in chromatin unwinding, transcription regulation, and DNA recombination, translocation, and repair.[47]
  • Mutation of this gene leads to bone marrow failure syndrome 2.[47]
  • Characterized by bone marrow failure, learning disabilities, and microcephaly.[47]

Ligase 1 Deficiency

  • LIG1 gene is located on 19q13.33
  • DNA ligase is encoded by LIG1 gene.
  • LIG1 functions at the replication fork to join Okazaki fragments during replication of lagging strand DNA.[48]
  • Mutation of this gene leads reclassified -variant of unknown significance(formerly called as DNA LIGASE I DEFICIENCY).
  • characterized by immunodeficiencies and cellular hypersensitivity to DNA-damaging agents.[49]

GINS1 deficiency

  • GINS1 gene is located on 20p11.2
  • This gene encodes for GINS complex.
  • Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency.[50]

Cartilage Hair Hypoplasia

  • Also known as Metaphyseal chondroplasia.
  • 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.[51]
  • It has two functions :cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of pre-rRNA.[51]
  • Mutation is inherited as an autosomal recessive pattern.
  • Characterized by short-limbed, short stature and fine, sparse hair.[52]
  • It also includes ligamentous laxity, defective immunity, hypoplastic anemia, and neuronal dysplasia of the intestine.[51]
  • CHH is diagnosed clinically by observing fine and often sparse hair in an individual with short stature with disproportionally short limbs.[53]
  • Radiographic findings are helpful in the work-up of an individual with suspected skeletal dysplasia.
  • The metaphyseal ends are abnormal and appear as scalloped, irregular surfaces that may contain cystic areas on routine radiographs.[54]
  • Genetic analysis of the RMRP gene confirms the diagnosis.

Schimke Syndrome

  • Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder.
  • SIODis caused by homozygous or compound heterozygous mutation in the SMARCAL1 gene on chromosome 2q25.[55]
  • Mutations in SMARCAL1 gene which encodes matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1).[55].[56]
  • 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.
  • Markedly improved marrow function afterbone marrow transplantation.[57][57]

MYSM1 deficiency

  • MYSM1 gene is located on 1p32.1
  • Myb-like, SWIRM, and MPN domain 1 (MYSM1) is a transcriptional regulator mediating histone deubiquitination[58]
  • Its deficiency leads to Bone marrow failure syndrome 4.
  • It is inherited as an autosomal recessive pattern.[59][60]
  • MYSM1 deficiency is associated with developmental aberrations, progressive bone marrow failure with myelodysplastic features, and increased susceptibility to genotoxic stress.
  • Hematopoiteic stem cell transplant is a curative therapy.

MOPD1 deficiency

  • aka Taybi-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.
  • Inherited in an autosomal recessive manner.[59]
  • Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is a genetic condition that is mainly characterized by intrauterine and post-natal growth retardation.[61]
  • Presentation includes an abnormally small head size (microcephaly); abnormal bone growth (skeletal dysplasia); distinctive facial features; and brain anomalies.[60]
  • 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 stands for EXOSTOSIN-LIKE GLYCOSYLTRANSFERASE 3.
  • 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.[62]

DiDeorge Syndrome

  • Haploinsufficiency of the TBX1 gene,in particular is responsible for most of the physical malformations.
  • This deletion leads to defective 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 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[63]
  • 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[64]
  • 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.
  • Mutations in the gene leads to CONOTRUNCAL ANOMALY FACE SYNDROME/VELOCARDIOFACIAL SYNDROME and DIGEORGE SYNDROME

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.
  • 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

  • CHARGE syndrome stands for CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIES
  • Caused by heterozygous mutation in the CHD7 on chromosome 8q12.
  • CHD7 is essential for the formation of multipotent migratory neural crest
  • Neural crest 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 Autosomal Dominant pattern.
  • Characterized by a pattern of congenital anomalies including choanal atresia and malformations of the heart, inner ear, and retina.

Job Syndrome

  • hyper-IgE recurrent infection syndrome is caused by heterozygous mutation in the STAT3 gene on chromosome 17q21
  • It is inherited as Autosomal Dominant pattern.
  • It 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

  • It is a Rare autosomal recessive disorder.
  • It is aused 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.

PGM3 deficiency

  • PGM 3 stands for PHOSPHOGLUCOMUTASE 3
  • PGM3 gene is located on chromosome 6q14.
  • Mutation of this gene leads to immunodeficiency-23 (IMD23)
  • It is also known as IMMUNODEFICIENCY-VASCULITIS-MYOCLONUS SYNDROME.
  • IMD23 is inherited as an autosomal recessive.
  • Characterized by recurrent respiratory and skin infections beginning in early childhood.
  • Affected individuals also show developmental delay or cognitive impairment of varying severity.
  • Laboratory studies includes increased serum IgE.

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.
  • It is 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

SAMD9

  • SMD9 stands for STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 9
  • It is encoded by the SAMD9 gene located on 7q21.2
  • MIRAGE syndrome is 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.

SAMD9L

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.
  • Characteized by hemolytic 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 gene (inhibitor of kappa polypeptide gene enhancer in B cells, kinase gamma/nuclear factor-kappa B essential modulator).
  • 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.
  • 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 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.
  • 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),particularly toxic to thymocytes and T cells
  • It is rare autosomal recessive immunodeficiency disorder
  • Characterized mainly by decreased T-cell function.
  • 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.
  • Diagnosis should 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

  • Also known as FAMILIAL INTESTINAL POLYATRESIA SYNDROME.
  • Gastrointestinal defects and immunodeficiency syndrome (GIDID) is caused by mutation in the TTC7A gene 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 on chromosome 2q37.
  • It 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).
  • EPG5 is 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
  • Characterized by 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

  • also known as HEME-OXIDIZED IRP2 UBIQUITIN LIGASE 1
  • The alternate title for this gene is RBCK1 ( RANBP-TYPE AND C3HC4-TYPE ZINC FINGER-CONTAINING 1).
  • PGBM1 (polyglucosan body myopathy-1) is caused by homozygous or compound heterozygous mutation in the RBCK1 gene (610924) on chromosome 20p13.
  • It is inherited as autosomal recessive disorder.
  • Polyglucosan body myopathy-1 is 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

  • Alternate title is ZIBRA HOIL1-INTERACTING PROTEIN; HOIP
  • Caused by the mutation in RNF31 gene to chromosome 14q11.2.
  • 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)

  • It usually inherits as an autosomal recessive disorder.
  • It is 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. ORAI1 gene encodes a subunit of the plasma membrane calcium channel CRAC which is located on chromosome 12q24.
  • 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

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 2

  • It usually inherits as an autosomal recessive pattern.[65]
  • Homozygous or compound heterozygous mutation in the FAT4 gene on chromosome 4q28 lead to Hennekam lymphangiectasia-lymphedema syndrome-2(HKLLS2).
  • FAT4 gene encodes a protein which is a member of a large family of protocadherins.
  • It is characterized by generalized lymphatic dysplasia that affects different organs such as the intestinal tract, pericardium, and limbs. It also causes facial dysmorphism and cognitive impairment.[65]

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.
  • 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.[66]
  • GH insensitivity (GHI) is severe growth failure, associated with elevated serum concentrations of GH, resulting in a clinical phenotype that is essentially identical from that of congenital GH deficiency.[67]
  • GHI caused by a homozygousmutation in the gene encoding signal transducer and activator transcription 5B (STAT5B), that is required for normal signaling of the GH receptor .
  • They have severe postnatal growth failure and immune dysregulation, because STAT5B mediates signal transduction triggered by various immune ligands, such as interleukin-2 (IL2), interleukin-4 (IL4), and colony-stimulating factor 1 (CSF1).

Kabuki Syndrome

  • Kabuki syndrome-1 (KABUK1) is caused by heterozygous mutation in the MLL2 gene (KMT2D).
  • Histone methyltransferase is a protein that encoded by MLL2 gene (KMT2D) which methylates the Lys-4 position of histone H3.
  • It usually inherits as an autosomal dominant pattern.
  • Common manifestations of Kabuki syndrome include:[68][69][70]
    • 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

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  52. ↑ MCKUSICK VA, ELDRIDGE R, HOSTETLER JA, RUANGWIT U, EGELAND JA (May 1965). "DWARFISM IN THE AMISH. II. CARTILAGE-HAIR HYPOPLASIA". Bull Johns Hopkins Hosp. 116: 285–326. PMID 14284412.
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  54. ↑ Mäkitie O, Marttinen E, Kaitila I (1992). "Skeletal growth in cartilage-hair hypoplasia. A radiological study of 82 patients". Pediatr Radiol. 22 (6): 434–9. PMID 1437368.
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  60. ↑ 60.0 60.1 Bahrami E, Witzel M, Racek T, Puchałka J, Hollizeck S, Greif-Kohistani N, Kotlarz D, Horny HP, Feederle R, Schmidt H, Sherkat R, Steinemann D, Göhring G, Schlegelbeger B, Albert MH, Al-Herz W, Klein C (October 2017). "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations". J. Allergy Clin. Immunol. 140 (4): 1112–1119. doi:10.1016/j.jaci.2016.10.053. PMID 28115216.
  61. ↑ Pierce MJ, Morse RP (March 2012). "The neurologic findings in Taybi-Linder syndrome (MOPD I/III): case report and review of the literature". Am. J. Med. Genet. A. 158A (3): 606–10. doi:10.1002/ajmg.a.33958. PMID 22302400.
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  63. ↑ Davies EG (October 2013). "Immunodeficiency in DiGeorge Syndrome and Options for Treating Cases with Complete Athymia". Front Immunol. 4: 322. doi:10.3389/fimmu.2013.00322. PMC 3814041. PMID 24198816.
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  68. ↑ Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T (October 1981). "Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency". J. Pediatr. 99 (4): 565–9. PMID 7277096.
  69. ↑ Matsune K, Shimizu T, Tohma T, Asada Y, Ohashi H, Maeda T (January 2001). "Craniofacial and dental characteristics of Kabuki syndrome". Am. J. Med. Genet. 98 (2): 185–90. PMID 11223856.
  70. ↑ Petzold D, Kratzsch E, Opitz C, Tinschert S (February 2003). "The Kabuki syndrome: four patients with oral abnormalities". Eur J Orthod. 25 (1): 13–9. PMID 12608719. Vancouver style error: initials (help)
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