Bare lymphocyte syndrome type II

Overview

Bare lymphocyte syndrome type II (BLS II) is a rare and severe primary immunodeficiency disorder caused by the absence or significantly reduced expression of major histocompatibility complex (MHC) class II molecules on the surface of antigen-presenting cells. This condition severely impairs the immune system’s ability to activate CD4+ T cells, which are essential for coordinating immune responses. As a result, affected individuals suffer from recurrent, life-threatening infections early in life. BLS II is one of the most severe forms of combined immunodeficiency and is considered a medical emergency in infancy.

Causes

Bare lymphocyte syndrome type II is caused by mutations in genes that regulate the expression of MHC class II molecules. These include:

• CIITA – the master regulator of MHC class II gene transcription

• RFXANK, RFX5, and RFXAP – which encode components of the RFX transcription complex necessary for MHC class II expression

Key genetic features:

• Autosomal recessive inheritance – both copies of the affected gene must be mutated

• Consanguinity increases the risk due to inheritance of the same mutation from both parents

Symptoms

Symptoms of BLS II typically present in infancy or early childhood and resemble those of severe combined immunodeficiency (SCID):

• Severe, recurrent bacterial, viral, and fungal infections

• Chronic diarrhea and failure to thrive

• Persistent respiratory infections such as pneumonia or bronchitis

• Lymphopenia – low levels of circulating lymphocytes, especially CD4+ T cells

• Delayed or absent immune responses to vaccinations

• General failure to develop effective adaptive immunity

Diagnosis

Early diagnosis is critical due to the syndrome’s rapid progression and life-threatening nature. Key diagnostic steps include:

• Flow cytometry – shows absence or marked reduction of MHC class II expression on B cells and monocytes

• Immunophenotyping – reveals low or absent CD4+ T cells

• Genetic testing – confirms mutations in CIITA, RFXANK, RFX5, or RFXAP genes

• Delayed-type hypersensitivity tests – typically show no response

• Family history and consanguinity screening

Treatment

There is no cure for BLS II other than hematopoietic stem cell transplantation (HSCT), which is the only potentially life-saving treatment. Management options include:

• Hematopoietic stem cell transplantation (HSCT) – ideally performed as early as possible for better outcomes

• Antibiotic prophylaxis – to prevent bacterial infections

• Antifungal and antiviral medications – for recurrent opportunistic infections

• Immunoglobulin replacement therapy – to boost humoral immunity

• Supportive care – including nutritional support, infection monitoring, and protective isolation if necessary

Prognosis

The prognosis of Bare lymphocyte syndrome type II is poor without early and aggressive treatment:

• Untreated children typically do not survive beyond early childhood

• Survival improves significantly with early hematopoietic stem cell transplantation

• Infections and complications can still occur even after transplant, requiring lifelong monitoring

• Carrier parents are unaffected but may pass the condition to offspring

Early detection through newborn screening and genetic counseling in high-risk families can help improve outcomes and support timely treatment.