Repercussions of inborn errors of immunity on growth

Goudouris, Ekaterini Simões; Segundo, Gesmar Rodrigues Silva; Poli, Cecilia

doi:10.1016/j.jped.2018.11.006

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Reviews articles • J. Pediatr. (Rio J.) 95 (Suppl 1) • 2019 • https://doi.org/10.1016/j.jped.2018.11.006 copy

Repercussions of inborn errors of immunity on growth^☆ ☆ Please cite this article as: Goudouris ES, Segundo GR, Poli C. Repercussions of inborn errors of immunity on growth. J Pediatr. 2019;95:S49-S58.

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objectives:

This study aimed to review the literature on the repercussions of the different inborn errors of immunity on growth, drawing attention to the diagnosis of this group of diseases in patients with growth disorders, as well as to enable the identification of the different causes of growth disorders in patients with inborn errors of immunity, which can help in their treatment.

Data sources:

Non-systematic review of the literature, searching articles since 2000 in PubMed with the terms "growth", "growth disorders", "failure to thrive", or "short stature" AND "immunologic deficiency syndromes", "immune deficiency disease", or "immune deficiency" NOT HIV. The Online Mendelian Inheritance in Man (OMIN) database was searched for immunodeficiencies and short stature or failure to thrive.

Data summary:

Inborn errors of immunity can affect growth in different ways, and some of them can change growth through multiple simultaneous mechanisms: genetic syndromes; disorders of the osteoarticular system; disorders of the endocrine system; reduction in caloric intake; catabolic processes; loss of nutrients; and inflammatory and/or infectious conditions.

Conclusions:

The type of inborn errors of immunity allows anticipating what type of growth disorder can be expected. The type of growth disorder can help in the diagnosis of clinical conditions related to inborn errors of immunity. In many inborn errors of immunity, the causes of poor growth are mixed, involving more than one factor. In many cases, impaired growth can be adjusted with proper inborn errors of immunity treatment or proper approach to the mechanism of growth impairment.

KEYWORDS
Diseases of the immune system; Immune deficiency syndromes; Growth; Growth disorders

Mechanism	IEI	Main characteristics
Genetic syndrome
Genetic syndrome*	CHARGE	Coloboma, congenital heart disease, choanal atresia, mental retardation, growth retardation, genital hypoplasia, ear anomalies and/or deafness, and T-cell lymphopenia
	Kabuki	Mental retardation, postnatal dwarfism, bone abnormalities, characteristic facial dysmorphism with eversion of the distal third of lower eyelids and arched eyebrows, cleft palate, autoimmune cytopenias, hypothyroidism, hypogammaglobulinemia similar to common variable immunodeficiency
	Mulvihill-Smith	Multiple pigmented nevi, prematurity, poor facial fat, microcephaly, sensorineural deafness, pre- and postnatal failure to thrive, and T-cell lymphopenia
	Mulibrey nanism	Long bones with cortical thickening, shallow and elongated sella turcica, muscle hypotonia, hepatomegaly, retinal abnormalities, constrictive pericarditis, facial anomalies, low IgG and IgM, B lymphopenia without T-cell alteration
	Rubinstein-Taybi	Mental retardation, microcephaly, thumb and forefinger enlargement, facial dysmorphism, heart disease, T-cell lymphopenia and defect in the production of antibodies for polysaccharides
	Dubowitz	Mental retardation, microcephaly, scattered hair, eczema, facial anomalies (ptosis, ear dysplasia), neutropenia, and hyper IgE syndrome
	Hoyeraal-Hreidarsson	Aplastic anemia, cerebellar hypoplasia, enteropathy, development delay, combined immunodeficiency
	Shokeir	Absence of thumbs, anosmia, ichthyosiform dermatosis, mucocutaneous candidiasis, hypogammaglobulinemia, neutropenia, T-cell alteration
	Toriello	Cataract, microcephaly, mental retardation, dental hypoplasia, low IgG and IgM, neutropenia during infections
	Stoll	Development delay, congenital heart disease, vesicoureteral reflux, facial dysmorphisms (prominent forehead, central facial mass hypoplasia), neutropenia
	BILU (Hoffman syndrome)	B-cell defect, skeletal defects of feet and hands, urogenital malformations, hypogammaglobulinemia, B and T-cell lymphopenia
	Seckel	Microcephaly, mental retardation, typical facies (micrognathia, low-set ears, prominent and hooked nose), pancytopenia, and hypogammaglobulinemia
	Vici	Agenesis of the corpus callosum, cataract, myocardiopathy, hypopigmentation, mental retardation, from normal immune system to Severe Combined ImmuneDeficiency (SCID)
	Barth	Dilated cardiomyopathy with endocardial fibroelastosis, proximal myopathy, organic aciduria, and neutropenia
	DNA ligase IV deficiency	Bird-like facies, polydactyly, hypogonadism, combined T-cell and B-cell defects
	PIK3R1 mutation	Hyper IgM syndrome, lymphadenopathy, and SHORT syndrome (short stature, joint hypermotility, bone age delay, hernias, low body mass index, progeroid appearance)
DNA repair defects	Nijmegen syndrome	Microcephaly, high susceptibility to malignancies, facial dysmorphism (bird-like facies), Café-au-lait spots and/or vitiligo, T-cell lymphopenia or combined immunodeficiency
	Ligase IV syndrome	Microcephaly, facial dysmorphism (bird-like facies), developmental delay, pancytopenia, from normal immune system to SCID
	Cernunnos deficiency	Microcephaly, bird-like facies, osseous and/or urogenital malformations, T-cell lymphopenia or SCID
	Bloom syndrome	Hypo- or hyperpigmented or sun-induced telangiectatic skin lesions, bone marrow failure, hypogammaglobulinemia
	Bernard syndrome	Microcephaly, corticoid deficiency (hypoglycemia and hyperpigmentation), reduced NK cells
	RIDDLE	Radiosensitivity, facial dysmorphisms, learning disabilities, and defects in antibody production
Osteoarticular dysplasia	Schimke immuno-osseous dysplasia	Spondyloepiphyseal dysplasia, lumbar lordosis, chronic nephrotic syndrome with progressive kidney failure, and T-cell lymphopenia
	Cartilage-hair hypoplasia	Metaphyseal chondrodysplasia with short limbs, hypoplastic hair, bone marrow failure, varies from normal immune system to SCID
	Skeletal dysplasia of short limbs with humoral defect	Metaphyseal dysostosis with hypogammaglobulinemia without T-cell involvement.
	Spondylenchondrodysplasia with immune dysregulation	Metaphyseal radiolucent bone lesions, vertebral dysplasia, overall developmental delay, mild combined immunodeficiency and autoimmunity (cytopenias and thyroiditis)
	Kenny-Caffey syndrome	Cortical widening of long bones, spinal stenosis, hypoparathyroidism, facial dysmorphism, ophthalmic abnormalities, neutropenia, T-cell change
	Roifman syndrome (Roifman syndrome 1)	Spondyloepiphysial dysplasia, facial dysmorphisms, retinal dystrophy, mental retardation, microcephaly, and defects in antibody production
	Roifman-Costa syndrome (Roifman syndrome 2)	Spondylometaphyseal dysplasia, autoimmune disorders, and combined immunodeficiency in T and B-cells
	FILS (Facial dysmorphism, Immunodeficiency, Livedo, Short stature)	Facial dysmorphisms, livedo, and short stature, with bone dysplasia, humoral defect, and reduced T-cell proliferation.
	SCID with ADA defect	Skeletal dysplasia with short limbs and severe combined immunodeficiency
	MacDermont syndrome	Short limbs, increased skinfolds, curved femur, neutropenia, and hypogammaglobulinemia (IgG2 and IgA), CD4 lymphopenia
	Kyphomelic dysplasia	Short and flat femur, sometimes with altered ulna, radius, and humerus, T- and B-cell lymphopenia
	Spondylo-mesomelic acrodysplasia	Dwarfism of short limbs with joint displacement and severe combined immunodeficiency
	MYSMI deficiency	Cataract, developmental delay, skeletal abnormalities, recurrent infections with T lymphopenia, and bone marrow failure/myelodysplasia
	MOPDI deficiency	Spondyloepiphysial dysplasia, very compromised intrauterine growth, retinal dystrophy, facial dysmorphisms, lymphadenopathy, change in the production of specific antibodies
	EXTL3 deficiency	Platyspondylia, kyphosis, skeletal dysplasias, developmental delay, T lymphopenia with change in antibody production
Endocrinopathies
Defects of the growth hormone (GH) pathway	STAT-5B deficiency	Insensitivity to GH (low IGF-1 with normal GH and increased prolactin) associated with immune dysregulation (arthritis, lymphocytic interstitial pneumonia, Idiopathic thrombocytopenic purpura-ITP), and T-cell and NK cell lymphopenia with compromised Treg function
	X-linked agammaglobulinemia associated with isolated GH deficiency	GH deficiency (IGF-α low) with panhypoglobulinemia and B lymphopenia, without mutation in BTK
	Ataxia-telangiectasia	GH deficiency, cerebellar-type ataxia, oculocutaneous telangiectasia, cellular and/or humoral immunodeficiency.
	Sutor syndrome	GH deficiency, hypogonadotrophic hypogonadism, hypogammaglobulinemia, reduced NK cells, change in T-cell function
Autoimmune endocrinopathies	IPEX	Early-onset autoimmune enteropathy, neonatal diabetes, hypothyroidism, food allergy
Autoimmune endocrinopathies	APECED	Autoimmune polyendocrinopathy, candidiasis, ectodermal dysplasia
Metabolic diseases
Glycosylation defects	PGM3	Glycosylation defect, short stature, brachydactyly, facial dysmorphisms, mental retardation, combined defect affecting B and NK cells
Glycosylation defects	LAD2	Disorder of glycosylation type IIc, developmental delay, growth retardation with short stature, leukocyte adhesion defect, milder than LAD1; minimal clinical changes may be observed
Low caloric intake
Low ingestion	Defects in several immune parts associated with neurological conditions	Swallowing disorders
Malabsorption	Humoral defects	Recurring or chronic gastrointestinal infection
	Immune dysregulation and humoral defects	Inflammatory bowel disease, autoimmune enteropathy
	Hyper IgE syndrome and immune dysregulation diseases	Food allergy
	Schwachman Diamond syndrome	Pancreatic insufficiency, pancytopenia
Hypercatabolic states
Chronic and/or recurrent infections	Combined T and B cells defecfts, humoral defects or innate immunity defects	Infections with various infectious agents and locations, depending on the immune sector impaired. Humoral defects with sinopulmonary infections caused by encapsulated germs and gastrointestinal infections caused by giardia, cryptosporidium, and enterovirus; combined defects with severeand widespread infections by fungi, virus, Gram negative bacteria and mycobacteria; defects of phagocytes with pulmonary, bone and cutaneous infections, caused by Gram-negative staphylococci, fungi, and mycobacteria; deficiencies in the complement system with meningitis and sinopulmonary infections caused by Neisseria.
Chronic inflammation	Defects with immune dysregulation or autoinflammatory disorders	Autoimmunity or chronic and/or recurring inflammation without evidence of infection or autoimmunity, with fever, specially affecting skin, serous membranes, and osteoarticular system.
Malignancies	Immune dysregulation associated with several immune defects, such as common variable immunodeficiency and ALPS	Malignant diseases, especially of the lymphoreticular system
Chronic pulmonary disease	Defects associated with recurrent pulmonary infections and immune dysregulation	Bronchiectasis, lymphocytic interstitial disease, pneumothorax
Cardiac insufficiency	Syndromes associated with congenital heart diseases	Uncorrected or incompletely corrected congenital heart diseases

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[1] * Corresponding author. E-mail:egoudouris@gmail.com (E.S. Goudouris).

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Repercussions of inborn errors of immunity on growth☆ ☆ Please cite this article as: Goudouris ES, Segundo GR, Poli C. Repercussions of inborn errors of immunity on growth. J Pediatr. 2019;95:S49-S58.

Abstract

Objectives:

Data sources:

Data summary:

Conclusions:

Repercussions of inborn errors of immunity on growth^☆ ☆ Please cite this article as: Goudouris ES, Segundo GR, Poli C. Repercussions of inborn errors of immunity on growth. J Pediatr. 2019;95:S49-S58.