X-Linked Severe Combined Immunodeficiency

Clinical characteristics: The phenotypic spectrum of X-linked severe combined immunodeficiency (X-SCID) ranges from typical X-SCID (early-onset disease in males that is fatal if not treated with hematopoietic stem cell transplantation [HSCT] or gene therapy) to atypical X-SCID (later-onset disease comprising phenotypes caused by variable immunodeficiency, immune dysregulation, and/or autoimmunity).

1. Typical X-SCID. Prior to universal newborn screening (NBS) for SCID most males with typical X-SCID came to medical attention between ages three and six months because of recurrent infections, persistent infections, and infections with opportunistic organisms. With universal NBS for SCID, the common presentation for typical X-SCID is now an asymptomatic, healthy-appearing male infant.

2. Atypical X-SCID, which usually is not detected by NBS, can manifest in the first years of life or later with one of the following: recurrent upper and lower respiratory tract infections with bronchiectasis; Omenn syndrome, a clinical phenotype caused by immune dysregulation; X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis); immune dysregulation and autoimmunity; or Epstein-Barr virus-related lymphoproliferative complications.

Diagnosis/testing: The diagnosis of typical and atypical X-SCID is established in a male proband with suggestive findings and a hemizygous pathogenic variant in IL2RG identified by molecular genetic testing.

Management: Treatment of manifestations:

1. Typical X-SCID. Newborns with an abnormal NBS require immediate subspecialty immunology evaluation at a center with expertise in the diagnosis of SCID and its genetic causes, and in SCID treatment protocols, including HSCT or gene therapy. While clinical practices and protocols can vary depending on the center, treatment goals include ensuring the safety of the infant/child, prophylaxis for infections, and preemptive HSCT to establish a functional immune system prior to the development of symptoms.

2. Atypical X-SCID. Treatment depends on the degree of infectious complications and the presence of immune dysregulation and/or autoimmunity, and requires subspecialty immunologic care to assist in the diagnosis and choice of antimicrobial and immune-suppressive therapies.

Surveillance: After successful HSCT, routine monitoring of affected males every six to 12 months regarding lineage-specific donor cell engraftment; growth, immune, and lung function; and any gastrointestinal and/or dermatologic issues. If HSCT involved conditioning chemotherapy, long-term monitoring of vital organ function and neurodevelopmental progress is also warranted.

Agents/circumstances to avoid: To ensure the safety of affected individuals of all ages pending definitive treatment to achieve immunocompetence, parents and other care providers need to assure that the following are avoided: breast-feeding and breast milk (pending clarification of maternal CMV status); exposure to young children, sick persons, or individuals with cold sores; crowded enclosed spaces; live viral vaccines for the affected individual as well as household contacts; transfusion of non-irradiated blood products; areas of construction or soil manipulation.

Evaluation of relatives at risk: When the IL2RG pathogenic variant causing X-SCID in the family is known, prenatal testing of at-risk male fetuses may be performed to help prepare for optimal management of an affected infant at birth. If prenatal testing has not been performed, an at-risk newborn male should immediately be placed in a safe environment and tested for the familial IL2RG pathogenic variant to allow earliest possible diagnosis and treatment.

Genetic counseling: X-SCID is inherited in an X-linked manner. The chance that a female who is heterozygous (i.e., a carrier) for the familial IL2RG pathogenic variant will transmit the variant in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will be clinically asymptomatic. Affected males transmit the IL2RG pathogenic variant to all of their daughters and none of their sons. Once the IL2RG pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.