Severe Combined Immunodeficiency - SCID

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS

Professor, University of Utah

Vice Chair and Chief of the Division of Clinical Pathology, Executive Vice President, ARUP Laboratories

Contributor

Lin

Leo Lin, MD, PhD

Assistant Professor (Clinical), University of Utah

Medical Director, Immunology, ARUP Laboratories

Contributor

Moscon

Justin D. Moscon, MD

Anatomic and Clinical Pathology Resident, University of Utah and ARUP Laboratories

Severe combined immunodeficiencies (SCIDs) are genetic disorders characterized by blocked T-lymphocyte differentiation or function and are often associated with abnormal development of other lymphocyte lineages (e.g., B cells and natural killer [NK] cells). These disorders lead to a complete absence of lymphocyte-dependent adaptive immunity. Infants with SCID may appear healthy at birth but characteristically present with severe infections early in life. Newborn screening for SCIDs is now recommended for all newborns in the United States. Early diagnosis is critical to begin treatment before serious complications develop.

Quick Answers for Clinicians

How are severe combined immunodeficiency subtypes classified?

Historically, severe combined immunodeficiency (SCID) subtypes were classified according to the presence or absence of T, B, and natural killer (NK) cells. With the growing availability of gene sequencing, patients with SCID are increasingly classified by their specific SCID genotype. In addition to specific gene variants, the Primary Immune Deficiency Treatment Consortium (PIDTC) has updated its definitions of three categories of SCID originally defined by T-cell counts and the presence of transplacental maternal engrafted (TME) T cells. These categories include typical SCID, leaky/atypical SCID, and Omenn syndrome. In general, leaky/atypical SCID and Omenn syndrome present with less profound T-cell deficiencies as compared to typical SCID. Previously, reticular dysgenesis was considered a fourth major SCID subtype; however, the revised definitions recommend categorizing patients with reticular dysgenesis into one of the three major subtypes listed above. For SCID subtype diagnostic criteria, refer to the Diagnosis section.

How are newborns screened for severe combined immunodeficiency?

Newborn screening for severe combined immunodeficiency (SCID) is performed by quantifying T-cell receptor excision circles (TRECs) in dried blood spots using polymerase chain reaction (PCR). TRECs are DNA fragments produced during T-cell maturation. Low neonatal TREC concentrations can indicate impaired T-cell development, which is highly sensitive for most forms of SCID. If the results are abnormal, the provider may recommend taking certain precautions to protect the infant from infection while further testing is performed. Such precautions may include isolation, immunoglobulin replacement therapy, avoiding live vaccines, and using commercial formula or pasteurized breast milk. In the United States, each state department of health has a protocol for management of newborns with suspected SCID.

Indications for Testing

Due to the widespread adoption of newborn screening, most patients with SCID in the U.S. are now assessed following abnormal screening results, before clinical symptoms present.

Infants and children presenting with recurrent, persistent, or severe bacterial, viral, or fungal infections or failure to thrive should be evaluated for SCID. Suspected SCID is a medical emergency and laboratory testing should be expedited. Other clinical findings suspicious for SCID include chronic diarrhea, Pneumocystis infection, and thrush. In some patients, exposure to maternal lymphocytes during delivery or a nonirradiated blood transfusion causes graft-versus-host disease (GVHD). GVHD in patients with SCID may manifest as rash, diarrhea, elevated liver enzymes, and hematologic findings, including thrombocytopenia and eosinophilia.

Laboratory Testing

A thorough laboratory workup to establish a diagnosis of SCID includes ruling out alternative causes of immunodeficiency and confirming T-cell absence or dysfunction.

Screen for Other Causes of Immunodeficiency

Testing for underlying diseases associated with immunodeficiency should include a CBC with differential and HIV testing. A normal lymphocyte count does not rule out SCID. Lymphocyte phenotyping should be performed, including an evaluation of T, B, and NK cells and T-cell subsets such as naïve and memory CD3/CD4 helper T cells. Phenotyping should be repeated at least 1 week after initial testing if a pathogenic SCID gene variant is confirmed, or at least 8 weeks after initial testing in the absence of confirmed genetic etiology. Other immunodeficiencies should be ruled out by quantitative immunoglobulin testing, evaluation of phagocytic cells, and complement testing.

Characterize T-Cell Abnormalities

T-cell abnormalities should be assessed by several specialized tests. These include T-cell receptor excision circle (TREC) quantification and testing for transplacental maternal engrafted (TME) T cells, either in whole blood or isolated CD3 T cells. Any detected level of TME is diagnostic of typical SCID. If T cells are present, T-cell receptor diversity should be measured by flow cytometry, spectratyping, or high-throughput sequencing.

Lymphocyte proliferation testing by mitogen stimulation may be performed but may not be necessary if the patient meets criteria for typical SCID. Reduced proliferation may be observed with either low numbers of T cells or normal numbers of dysfunctional T cells; these can be distinguished by standard lymphocyte subset counts. Anti-CD3/anti-CD28/IL-2-induced lymphocyte proliferation testing may be especially useful in the context of IL-2-receptor signaling defects. Proliferation test results are not available for at least 4-5 days.

Genetic Sequencing

Genetic sequencing is now considered standard of care for patients with SCID. If initial panels are nondiagnostic, whole exome or whole genome sequencing is warranted. A trio analysis (i.e., using samples from the patient and both parents) is preferred. Refer to the Genotypes and Associated SCID Subtypes table for more information.

Diagnosis

Diagnostic criteria for SCID subtypes are adapted from the Primary Immune Deficiency Treatment Consortium (PIDTC).

Typical SCID

TME present

All of the following:
- T-cell counts of <0.05 x 10⁹/L on at least two occasions. The interval between tests must be at least 1 week if a pathogenic gene variant is identified, or 8 weeks in the absence of a known pathogenic gene variant.
- Either low TRECs OR <20% CD4-positive T cells with naïve surface markers
- Alternate explanations for low T-cell counts ruled out

Leaky/Atypical SCID

At least two of the following:
- Low T-cell count
- Oligoclonal T cells
- Abnormal TRECs OR <20% naïve CD4-positive T cells

AND

Either pathogenic gene variant(s) OR reduced proliferative response to mitogen or anti-CD3/CD28 stimulation
Alternate explanations for low T-cell counts ruled out, including other SCID subtypes

Omenn Syndrome

CD45RO-positive memory phenotype in >80% of CD4-positive T cells
Pathogenic gene variant(s)
Generalized rash
TME absent
At least two of the following:
- Eosinophilia
- Elevated immunoglobulin E (IgE)
- Abnormal TRECs
- Hepatomegaly or splenomegaly
- Lymphadenopathy
- Oligoclonal T cells

Genotypes and Associated SCID Subtypes^{a, b}
Gene	Typical SCID	Leaky/Atypical SCID	Omenn Syndrome	Lymphocyte Counts	Genetics and Associated Features
IL2RG	Most common	Common	—	T cells: Very low B cells: Normal to high NK cells: Low	XL
JAK3	Common	Unusual	—	T cells: Very low B cells: Normal to high NK cells: Low	AR
IL7R	Common	—	Very rare	T cells: Very low B cells: Normal to high NK cells: Normal	AR
CD3D	Unusual	Rare	—	T cells: Very low B cells: Normal NK cells: Normal	AR CD3-delta deficiency
RAG1	Common	Most common	Most common	T cells: Very low B cells: Very low NK cells: Normal	AR Elevated risk of graft rejection
RAG2	Unusual	Common	Common	T cells: Very low B cells: Very low NK cells: Normal	AR Elevated risk of graft rejection
DCLRE1C	Common	Rare	—	T cells: Very low B cells: Very low NK cells: Normal	AR Radiation sensitivity, elevated risk of graft rejection
NHEJ1	—	Rare	—	T cells: Very low B cells: Very low NK cells: Normal	AR Radiation sensitivity, microcephaly
LIG4	—	Rare	—	T cells: Very low B cells: Very low NK cells: Normal	AR Radiation sensitivity, microcephaly
AK2	Unusual	—	Very rare	T cells: Very low B cells: Normal to low	AR Granulocytopenia, deafness, reticular dysgenesis
ADA	Common	Common	—	T cells: Very low B cells: Low, decreasing NK cells: Low	AR Bone defects, pulmonary alveolar proteinosis, cognitive defects
PNP	Very rare	Rare	—	T cells: Progressive decrease B cells: Normal	AR Autoimmune hemolytic anemia, neurologic impairment
RMRP	Very rare	Common	Possible	T cells: Very low to normal B cells: Normal	AR Short-limbed dwarfism and metaphyseal dysostosis, sparse hair, bone marrow failure, autoimmunity, cancer/lymphoma susceptibility, impaired spermatogenesis, intestinal neuronal dysplasia
BCL11B	—	Very rare	—	T cells: Low B cells: Normal	AD Poor T-cell proliferation, congenital abnormalities, neonatal teeth, abnormal facies, absent corpus callosum, neurocognitive defects
MSN	Very rare	Very rare	—	T cells: Normal B cells: Low	XL Neutropenia, defective T-cell migration/proliferation, recurrent infections with bacteria, varicella
MAN2B2	—	Very rare	—	T cells: Low B cells: Low	AR Vasculitis, arthritis, microcephaly, neurodevelopmental delay, congenital disorder of glycosylation
RAC2	—	Very rare	—	T cells: Very low B cells: Very low	AD Neutropenia
TTC7A	—	Very rare	—	T cells: Variable, may be absent B cells: Normal to low	AR Multiple intestinal atresias, possibly with gestational polyhydramnios and early demise
^aAdapted from the 2022 International Union of Immunological Societies update on the classification of human inborn errors of immunity; refer to this source for additional detail and genotypes. ^bAssociated SCID subtypes based on 2022 PIDTC definitions; refer to this source for more detail on genotype frequencies. AD, autosomal dominant; AR, autosomal recessive; XL, X-linked