PNP-associated immunodeficiency

PNP-associated immunodeficiency occurs when an alteration in the PNP gene causes a block of the enzyme purine nucleoside phosphorylase (PNP). This rare genetic condition leads to T-cell depletion, causing clinical features of severe combined immunodeficiency (SCID). It typically presents in early childhood.

PNP-associated immunodeficiency is primarily characterised by profound progressive T-cell lymphopaenia. This leads to susceptibility to severe, life-threatening infections, including bacterial, viral, fungal and parasitic pathogens.

Typical infections include severe pneumonia or sepsis due to opportunistic pathogens such as Pneumocystis jiroveci, Pseudomonas sp, Candida sp and cytomegalovirus. Infections tend to be persistent, invasive and life-threatening, despite conventional treatment. Recurrent meningitis and persistent urine infections are also reported. Vaccine-strain infection following administration of live vaccinations, such as BCG or rotavirus, may also occur.

Other features can include:

• failure to thrive;
• chronic diarrhoea;
• sensorineural hearing loss;
• neurodevelopmental delay;
• autoimmune manifestations; and
• splenomegaly.

Patients typically present within the first three years of life with recurrent infections.

Hypomorphic variants in PNP are seen in up to 20% of patients. As a result of partial PNP activity, such patients may present later in life with milder immune anomalies, variable neurological involvement and less frequent infections.

PNP-associated immunodeficiency is caused by biallelic pathogenic variants in the PNP gene. The gene encodes purine nucleoside phosphorylase, an enzyme in the purine salvage pathway.

PNP frameshift, nonsense, splice site and missense variants, along with deletions, duplications, indels and insertions have all been reported in association with this condition.

Complete PNP deficiency is caused by biallelic null variants and results in a more severe phenotype, while hypomorphic variants resulting in a partial deficiency may have later onset with milder immunodeficiency.

PNP-associated immunodeficiency can be diagnosed following clinical evaluation or through newborn blood spot screening using the T-cell receptor excision circles assay. Where either is suggestive of SCID, laboratory evaluation is required. Patients may have a family history of immunodeficiency.

PNP-associated immunodeficiency causes a T-B+NK+ immunophenotype. In addition, the following features may be noted:

• full blood count may show reduced lymphocyte count;
• lymphocyte subset testing may show low levels of B and NK cells, alongside T-cell lymphopaenia;
• PNP levels will be very low; and
• uric acid levels may also be low.

Genomic testing will confirm the diagnosis and differentiate PNP SCID from other types of T-B+NK+ SCID.

According to the European Society for Immunodeficiencies, PNP-associated immunodeficiency can be diagnosed in the presence of at least one of the following:

• invasive bacterial, viral or fungal/opportunistic infection;
• persistent diarrhoea and failure to thrive; and/or
• an affected family member; and
• manifestation in the first year of life; and
• HIV excluded; and
• two of the following four T-cell criteria fulfilled:
  • low or absent CD3 or CD4 or CD8 T cells;
  • reduced naive CD4 and/or CD8 T cells;
  • elevated γδ T cells; and/or
  • reduced or absent proliferation to mitogen or TCR stimulation.

For information about testing, see ‘Patient with suspected severe combined immunodeficiency with PNP deficiency‘.

PNP-associated immunodeficiency may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

PNP-associated immunodeficiency follows an autosomal recessive inheritance pattern and is a rare primary immunodeficiency, accounting for about 4% of all SCID cases.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. De novo variants may also arise. Carriers do not appear to be affected by the disease.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier; and
  • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

SCID is a fatal condition unless definitive treatment to reconstitute the immune system is undertaken.

Immediate management principles involve treating infection and the prevention of opportunistic infections. This includes:

• no live vaccinations;
• aggressive treatment of infections, including with antifungal and antiviral agents;
• isolation from exposure to pathogens;
• immunoglobulin replacement;
• parenteral nutrition; and
• irradiated, cytomegalovirus negative blood products, if required.

The primary curative treatment is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients require long-term monitoring following HSCT to assess immune reconstitution and monitor for potential complications.

PNP-associated immunodeficiency may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• European Society for Immunodeficiencies: Diagnosis criteria
• Jeffrey Modell Foundation: 10 warning signs of primary immunodeficiency
• OMIM: 613179 Purine nucleoside phosphorylase deficiency

References:

• Karaaslan BG, Turan I, Aydemir S and others. ‘Neurologic status of patients with purine nucleoside phosphorylase deficiency before and after hematopoetic stem cell transplantation‘. Journal of Clinical Immunology 2023: volume 43, issue 8, pages 2,062–2,075. DOI: 10.1007/s10875-023-01585-6
• Schejter YD, Even-Or E, Shadur B and others. ‘The broad clinical spectrum and transplant results of PNP deficiency‘. Journal of Clinical Immunology 2020: volume 40, issue 1, pages 123–130. DOI: 10.1007/s10875-019-00698-1
• Torun B, Bilgin A, Orhan D and others. ‘Combined immunodeficiency due to purine nucleoside phosphorylase deficiency: Outcome of three patients‘. European Journal of Medical Genetics 2022: volume 65, issue 3, page 104428. DOI: 10.1016/j.ejmg.2022.104428

For patients

• Great Ormond Hospital for Children NHS Foundation Trust: Severe combined immunodeficiency (SCID)
• Immunodeficiency UK: Combined immunodeficiency in children