MED-NERD

Severe combined immunodeficiency disorder SCID

Outline:

• Introduction
• Epidemiology
• Etiology
• Pathophysiology
• Histopathology
• Clinical presentation

Introduction:

Combined immunodeficiency disorder is due to T and B lymphocyte deficiency. The disorder is characterized by recurrent infections occurring early in life due to multiple organisms both ordinary and opportunistic pathogens. The most severe form of this disorder is known as Severe combined immunodeficiency disease (SCID) which is a group of potentially life threatening disorders. The disorder may be autosomal, sporadic, or the X-linked. More than 20 genetic defects were found in SCID. About 1 in 40,000 to 75,000 per live birth are diagnosed as SCID. Manifestations begin at the age of 6 months or earlier with multiple recurrent infections that may lead to early death in the severe form of the disease.

SCID is classified into T-B- SCID or T-B + SCID phenotypes based on B cell status whether defected or not. Further sub-classification is based on the natural killer cells status. Immunotherapy may not always be available to treat the manifestations of SCID. In 1968, the first successful bone marrow transplant from healthy HLA-matched sibling was performed to a male infant. Over years, research in allogeneic hematopoietic cell transplantation (HCT) was performed with progress in reaching effective treatment and restoration of T cell numbers and function form both matched siblings and alternative donors. Different methods of treatment have been used including Haplo-identical parental bone marrow or mobilized peripheral blood hematopoietic stem cells (PBSC) depleted of T cells in addition to closely matched bone marrow or cord blood from donors. For adenosine deaminase (ADA) deficient SCID, enzyme replacement therapy (ERT) was developed. Moreover, an autologous hematopoietic cell correction by gene therapy (GT) was developed for ADA deficient and X-linked SCID.
Early treatment can improve the outcome by avoiding infectious complication which can be achieved by newborn screening program. However, it is a rare disease without family history in apparently healthy newborns.

Epidemiology:

In 2003, a public awareness and physician education about primary immunodeficiency were implemented by the Jeffrey Modell Foundation. A population-based newborn screening for SCID and T cell deficiency over 96% of the US newborns.
About 89% of patients were 6 months of age and presented with the first symptoms. Recurrent pneumonia was reported in 66% of the cases, failure to thrive in 60%, and chronic diarrhoea in 35% of patients.
A study in the US showed that the incidence of SCID is about in 58,000 live births. Consanguinity increases the incidence of autosomal-recessive SCID.

Etiology:

-Reticular dysgenesis due to stem cell deficiency may lead to T-B-NK-SCID.

-Adenosine deaminase (ADA) deficiency may cause toxic metabolites in T,B, and NK cells leading to T-B-NK-SCID phenotype.

- RAG1/2 enzymes to snip DNA for VDJ rearrangement for TCR and BCR in addition to Artemis deficiency that causes failure of DNA repair after RAG1/2 snips. Both causes may lead to T-B-NK+ SCID (RAG1/2 defect).

-SCID may be X-linked and due to common gamma chain deficiency leading to absent Interleukin (IL) receptor for cytokines therefore leading to T-B+NK- SCID.

-Jak 3 kinase deficiency may also lead to T-B+NK- SCID.

-Lack of IL-7 alpha chains leading to IL-7 deficiency and therefore leading to failure of T cell differentiation Which may cause T-B+NK+ SCID.

-Failure of CD3 activation and defective signal transduction such as ZAP-70 deficiency may also lead to T-B+NK+ SCID.

-MHC class I deficiency which is known as “bare lymphocyte syndrome” is caused by defect in TAP-2 transcription leading to failure of MHC class I expression may cause T+B+NK+ SCID.

- MHC class II deficiency which is caused by defected MHC class II proteins transcription may also lead to T+B+NK+ SCID.

-Leaky-SCID is due to hypomorphic mutations in classical genes of SCID which is less severe phenotype presents with infections in addition to autoimmunity.

Pathophysiology:

Mutations in the genes of T and B cell functions are the main cause of SCID. B cell function depends on T cells as it requires signals from T cells for antibodies production. Therefore, profound T cell abnormalities can lead to B cell abnormalities and functional deficiency. NK cell can be protective in cases of T and B cell deficiency as its development is not related to T and B cells. Detection of the presence of these immunity cells especially NK cells can be used for assessment of the severity and prognosis of SCID.

Histopathology:

Histopathologic studies of SCID through mictoscopic examination show the following:

-Absence of lymphoid cells in the stroma of thymus gland.

-Absence of Hassall's corpuscles.

-Fetal appearance of thymus gland.

-The presence of multiple Giardia lamblia in the gastrointestinal tract mainly in the mucosa of the jejunum due to defective immunity against multiple intestinal parasites.

-Biopsy of intestinal tract may show absence of plasma cells.

-Lymph node biopsy reveals severe depletion, absence of follicle formation, absence of cortico-medullary differentiation.

Clinical presentation:

-Symptoms of SCID present in the first few weeks or months of life mainly 6 months of age or even before with multiple recurrent infections whether ordinary with bacteria or opportunistic infection with viral, fungal or protozoal organisms.

-Infection with Cytomegalovirus (CMV) may affect liver, intestine, lung, heart, retina, and central nervous system.

-Immune dysregulation whether autologous (Omenn syndrome) or allogeneic (maternal GvHD) T cells

-Recurrent respiratory infections caused by multiple viruses such as Respiratory Syncytial Virus, Adenovirus, Myxovirus) and Frequent cough

-Severe pneumonias requiring mechanical ventilation caused by Pneumocystis jirovecii (PJP)

-Bronchiectasis

-Recurrent tonsillitis and sore throat, Aphthous stomatitis

-Oral candidiasis

-Arthritis

-Extensive cutaneous infections, Recurrent abscess

-Infection of internal organs

-Using multiple antimicrobials without improvement

-Lymphopenia, Anemia, Thrombocytopenia with bleeding

-Failure to thrive and short stature, Malnutrition, loss of weight

-Autoimmunity and Graft versus host reaction

-Bacteremia, Septicemia

-Fever or Hypothermia, Malaise, Anorexia, Cachexia

-Symptoms of meningitis, convulsions, headache, Late-onset primary encephalopathy, Microcephaly, Mental retardation

-Purulent conjunctivitis

-Skin manifestations including pyodermatitis, Eczema, Pruritus, Erythroderma

-Intestinal malabsorption, Chronic diarrhea due to intestinal infections with Rota-, Noro or Adenovirus

-Tuberculosis, Granuloma

-Lymphoproliferative disorders, Lymphocytic interstitial pneumonitis

-Hypoparathyroidism, Dwarfism, Thymic aplasia or hypoplasia, Thyroiditis

-Exocrine pancreatic insufficiency

-Mutiple maignencies

-Cardiac abnormalities such as cardiac murmur and conotruncal malformation

-Intrauterine growth retardation, Hydrops fetalis, Fetal demise, Delayed cord separation,

-Glomerulonephritis, hemolytic-uremic syndrome, Urinary sepsis, Urogenital abnormalities

-Amyloidosis

-Angioedema, Cafe-au-lait spots, Albinism, Vasculitis

-Poor wound healing, Nail dystrophy

-Hearing impairment, deafness

-Osteoporosis and fractures, Scoliosis, Chondrodysplasia

-Serositis, Periodontitis

-Denture abnormalities

-Myopathy, Tetany, Lupus-like syndrome

-Macroglossia

-Venous telangiectasias of trunk and limbs

-Atypical infection or following chronic swelling or ulceration at the injection site of live attenuated vaccines such as Bacille Calmette-Guérin (BCG) or Rotavirus vaccines, require further investigations to exclude T-lymphocyte deficiency.

According to the genes affected, the presentation varies as the following:

-ADA deficiency: patients present with bone abnormalities (cupping of osteochondral junctions), alveolar proteinosis

-DNA repair defects: patients present with delayed neurological development and microcephalia

-Hypomorphic mutations of SCID: patients present with Omenn syndrome (lymphadenopathy, hepato-/splenomegaly, eosinophilia, generalized exanthema, intractable diarrhea, and alopecia)

References:

(1)Justiz Vaillant AA, Mohseni M. Severe Combined Immunodeficiency. 2023 Jan 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–.
https://www.ncbi.nlm.nih.gov/books/NBK539762/
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063414/
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041706/
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lymphopenia. Immunol Rev. 2019 Jan;287(1):241-252.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324582/
(5)Haddad E, Hoenig M. Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency (SCID). Front Pediatr. 2019 Nov 19;7:481.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877719/