INTRODUCTION — Purine nucleoside phosphorylase (PNP) deficiency (MIM #613179) is a rare, autosomal recessive, inborn error of immunity (IEI) [1-3]. It is characterized by progressive immune abnormalities ranging from severe to nonsevere combined immunodeficiency (table 1) and neurologic symptomatology that includes ataxia, developmental delay, and spasticity. Autoimmunity, especially autoimmune hemolytic anemia, is also frequently present.
This topic reviews the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of PNP deficiency. The related immunodeficiency, adenosine deaminase (ADA) deficiency, which also affects purine degradation, is discussed separately. (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis" and "Adenosine deaminase deficiency: Treatment and prognosis".)
EPIDEMIOLOGY — PNP deficiency constitutes approximately 1 to 2 percent of all combined immunodeficiencies. A literature review in 2011 found 67 patients from 49 families , and an update at the end of 2014 reported that there were close to 80 patients [1,5-13]. Subsequently, additional patients have been described [14,15]. Heightened awareness coupled with the use of next-generation sequencing for patients with suspected inborn errors of immunity (IEI) have led to increased identification of patients with PNP deficiency [16-22].
PATHOGENESIS — PNP deficiency is caused by pathogenic variants in the PNP gene (MIM #164050) at 14q13.1 (figure 1) [9-13,23-30]. This gene encodes the protein PNP, one of the ubiquitous enzymes involved in the purine salvage pathway . Adenosine deaminase (ADA) deaminates adenosine to yield inosine, which is then converted to hypoxanthine by PNP. PNP also converts guanosine to guanine.
A number of metabolites are elevated in the plasma and urine in PNP deficiency, including deoxyguanosine and deoxyinosine. There is an intracellular accumulation of their deoxy triphosphate compounds, particularly deoxyguanosine triphosphate (dGTP). The latter is toxic to T cells, a property similar to deoxyadenosine triphosphate in ADA deficiency [32-34]. (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".)
The number and function of B cells in PNP deficiency are less severely affected than T cells and are often normal. This may be due to the selective toxicity and variability of intracellular accumulation of dGTP in different tissues. It has been postulated that the high apoptotic rate of thymocytes generates markedly increased levels of dGTP in the thymic milieu, which may account for the predominant destruction of these cells.
PNP-deficient mice exhibit impaired thymocyte differentiation, as well as a decreased number of maturing thymocytes, particularly double-positive cells, and peripheral T cells [33,35]. The mitogenic and allogeneic response of T cells in these mice is decreased, T cell apoptosis is increased in vivo, and a higher sensitivity to irradiation is seen in vitro. An age-dependent attrition of thymocytes and impaired thymocyte differentiation is also seen in these mice . From this mouse model, it was further postulated that there is an inhibition of mitochondrial deoxyribonucleic acid (DNA) repair due to the accumulation of dGTP in mitochondria. Similar findings were observed in a patient with PNP deficiency and dysplastic marrow morphology [33,34]. This patient's marrow stroma and lymphocytes showed a hypersensitivity to irradiation similar to that observed in PNP-deficient mice.
PNP-deficient mice exhibit neurologic abnormalities reminiscent of those observed among patients . PNP-deficient mice were also found to have smaller than normal cerebellum with increased numbers of apoptotic Purkinje cells. Using induced pluripotent stem cells from infants with PNP deficiency that were differentiated into neuronal cells, increased spontaneous and induced intrinsic apoptosis as well as p53 expression were identified, possibly explaining some of the neurologic abnormalities observed among patients .
CLINICAL MANIFESTATIONS — All patients with PNP deficiency are symptomatic, although the onset of symptoms may be delayed for years, with age at presentation ranging from four months to six years . Symptom onset may be much later in patients with partial PNP deficiency .
The clinical variability may depend in part upon whether the causative pathogenic variant(s) allow a degree residual protein expression and function. However, clear genotype-phenotype correlation has not been established. Severe cases may be detectable by newborn screening for severe combined immunodeficiency (SCID) using the T cell receptor excision circle (TREC) assay , which is now widely used to identify neonatal T cell lymphopenia . (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)
Patients typically present with frequent bacterial, viral, and opportunistic infections. Sinopulmonary infections are most common, but patients may also have liver abscesses and lymphadenitis. Patients are particularly prone to disseminated varicella and progressive vaccinia. Pulmonary tuberculosis due to disseminated Bacillus Calmette-Guérin (BCG) infection after vaccination and progressive multifocal leukoencephalopathy due to polyomavirus JC (JC virus) infection have been reported [9,41].
Failure to thrive is reported in most cases [9,12]. The tonsillar tissues are often absent, and lymph nodes are not palpable. Some patients have splenomegaly.
Approximately two-thirds of the patients also present with progressive neurologic symptoms, including developmental delay, muscle spasticity, ataxia, and disequilibrium syndrome with pyramidal signs [6,29,42-44]. Ataxia can be the initial presenting symptom.
There is an increased incidence of autoimmune disorders . They include hemolytic anemia, thrombocytopenia, neutropenia, thyroiditis, cerebral vasculitis, and sclerosing cholangitis. Systemic lupus erythematosus has also been reported [17,20], suggesting an associated interferonopathy in some patients with PNP deficiency . Alternatively, the autoimmunity may be due to impaired Toll-like receptor 7 signaling in B cells and macrophages . (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)
Uncontrolled hematologic cell proliferation that can lead to hemophagocytic lymphohistiocytosis [16,46] and lymphoma [18,47], often in association with Epstein-Barr virus (EBV) infection, is seen more frequently in patients with PNP deficiency. (See "Malignancy in inborn errors of immunity".)
LABORATORY FINDINGS — PNP activity is typically <5 percent of normal to absent in erythrocytes, leukocytes, and fibroblasts [7,8,29]. In one family with partial PNP deficiency, enzyme activity in various cells was 8 to 11 percent of normal levels .
If the patient recently received red blood cell transfusions, measurement of PNP activity should be delayed by three to four months, or it should be performed in leukocytes separated from the patient's blood. Carriers have approximately half-normal levels of PNP. Decreased plasma and urine levels of uric acid are also characteristic.
There is often a marked lymphopenia with low T cells (CD3+, CD4+, CD8+ cells). CD19+ B cell numbers are typically normal, although patients with low or absent B cells have been reported [17,48]. The delayed-type hypersensitivity response is absent to a variety of antigens, such as Candida, tetanus, mumps, and trichophyton. Lymphocyte proliferative responses to various mitogens and antigens may be initially normal but decrease and become abnormal over time. Serum immunoglobulins are usually normal or elevated with normal specific antibody titers, although occasionally they are low to absent.
DIAGNOSIS — The diagnosis of PNP deficiency should be suspected in patients suffering from a wide range of immune abnormalities. These include infants undergoing assessment for severe combined immunodeficiency (SCID), toddlers evaluated for increased susceptibility to viral infections, or teenagers and adults with possible common variable immune deficiency (CVID) [22,49]. The possibility of PNP deficiency should also be entertained among the causes for autoimmune manifestations, particularly hematologic cytopenias, because of the high frequency of immune dysregulation. Additionally, PNP deficiency should be considered among infants and children with progressive neurologic deficits, such as spasticity or ataxia. The association of increased susceptibility to infections and lymphopenia together with neurologic abnormalities is an important clue. Primary immunodeficiency diseases associated with neurologic manifestations including DiGeorge syndrome (DGS), ataxia-telangiectasia (AT), adenosine deaminase (ADA) deficiency, and DNA ligase IV (LIG4) deficiency should be excluded .
Initial screening studies in such patients should include T cell enumeration, evaluation of T cell function (proliferative response to mitogens and antigens), and serum uric acid, as well as tests to exclude alternative diagnoses. Low uric acid (<2 mg/dL) with an associated T cell deficiency is suggestive of PNP deficiency  and should be followed by measurement of PNP enzyme activity or PNP gene sequencing. Few laboratories perform PNP activity measurements, while many commercial vendors offer gene sequencing . Prenatal diagnosis is available if the condition has been diagnosed in a relative.
T cell excision circle (TREC) newborn screening may identify severe cases but not late-onset patients. Tandem mass spectrometry (TMS) can be set up to detect elevated levels of purine nucleosides and 2'-deoxy-nucleosides in dried blood spots .
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for PNP deficiency is broad, with immunologic abnormalities ranging from other forms of severe combined immunodeficiency (SCID) to agammaglobulinemia and common variable immunodeficiency (CVID). The age at presentation can help direct the differential (SCID in a newborn; CVID in an older child or adult). The combination of immunologic and neurologic abnormalities narrows the differential further and includes DiGeorge syndrome (DGS), ataxia-telangiectasia (AT), adenosine deaminase (ADA) deficiency, and DNA ligase IV (LIG4) deficiency. Certain clinical and laboratory features may help differentiate these disorders from PNP deficiency, and the diagnosis can then be confirmed by PNP enzymatic activity, genetic testing, or both.
●DiGeorge syndrome – DGS is a constellation of signs and symptoms associated with defective development of the pharyngeal pouch system. Thymic hypoplasia in DGS results in a range of T cell deficits, from mild defects that do not result in clinical immunodeficiency to a form of SCID called complete DGS, similar to the wide range of immunodeficiency seen with PNP deficiency. In addition, both DGS and PNP deficiency can result in cognitive impairment or tonus abnormalities. However, the classic triad of features of DGS on presentation (conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia resulting from parathyroid hypoplasia) is not seen in PNP deficiency. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)
●Ataxia-telangiectasia – Children with AT suffer from progressive cerebellar ataxia, abnormal eye movements, other neurologic abnormalities, oculocutaneous telangiectasias, and a combined immunodeficiency with recurrent sinopulmonary infections. Associated features include pulmonary disease, an increased incidence of malignancy, radiation sensitivity, growth retardation, and diabetes mellitus caused by insulin resistance. AT is best differentiated from PNP deficiency by genetic testing since oculocutaneous telangiectasias do not appear until three to five years of age. (See "Ataxia-telangiectasia".)
●Adenosine deaminase deficiency – ADA deficiency typically leads to a SCID with dysfunction of T, B, and natural killer (NK) cells (T-B-NK- SCID) that presents in the first few months of life. However, there are also a few patients with a later onset and relatively milder disease. Neurologic abnormalities are prominent in ADA deficiency and include cognitive deficits, behavioral problems, gait abnormalities, hypo- and hypertonia, and sensorineural hearing loss. Unlike PNP deficiency, B cells are typically low to absent. Blood and urine testing for metabolic abnormalities can also help differentiate between ADA and PNP deficiencies. (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".)
●DNA ligase IV deficiency – LIG4 deficiency is a form of radiation-sensitive, T-B-NK+ SCID that has additional clinical manifestations outside of the immune system, including microcephaly, developmental and growth delay, and dysmorphic facial features. Unlike PNP deficiency, B cells are typically low to absent. (See "T-B-NK+ SCID: Management".)
TREATMENT — Patients with PNP deficiency benefit from supportive care, including Pneumocystis jirovecii pneumonia (PJP) prophylaxis, immunoglobulin replacement when abnormal antibody production is evident, and avoidance of live-viral and Bacillus Calmette-Guérin (BCG) vaccines. Hematopoietic cell transplantation (HCT) is the only curative option offered to patients with PNP deficiency. However, detailed information on such procedures has been reported for fewer than 20 patients. The paucity of data limits accurate assessment of the potential immune and neurologic benefits from HCT in patients with PNP deficiency, as well as clear guidance on the optimal conditioning regimens. Nevertheless, the success of HCT in PNP deficiency should prompt discussion of such curative procedures in all patients.
The majority of patients received HCT from human leukocyte antigen (HLA) matched or one-antigen-mismatched family members [15,16,21,43,44,54-58]. Few patients received HCT without conditioning because of disseminated herpes virus or cytomegalovirus (CMV) infections [15,54]. Follow-up of these patients demonstrated greater than 90 percent engraftment of donor T cells in some. However, repeated stem cell boosts and transplants were required in others. Few patients with PNP deficiency received HCT from HLA haploidentical family donors [6,59,60]. Outcome was often poor, with only two patients reported to have achieved long-term engraftment and survival. HCT with HLA-matched or closely matched, unrelated donors is used with increasing frequency for PNP deficiency .
Graft failure occurred in a patient who received an HLA-matched, unrelated-donor transplant following fludarabine, melphalan, and alemtuzumab conditioning . Repeat transplant using the same donor with fludarabine, treosulfan, and alemtuzumab conditioning resulted in mixed, yet stable, T cell lineage chimerism . Similarly, fludarabine, busulfan, and alemtuzumab conditioning prior to HCT with bone marrow from a 9 of 10 HLA loci-identical unrelated donor led to normal lymphocyte counts and subsets 21 months later .
Reduced-intensity conditioning consisting of fludarabine, melphalan, and antithymocyte globulins followed by transplant with peripheral blood CD34+ cells from an HLA-matched unrelated donor led to complete engraftment of donor cells . Two patients received umbilical cord blood cells from unrelated donors. One patient died three months after an HLA-matched, unrelated cord blood transplant that was performed after the patient failed a previous haploidentical transplant . The second patient achieved full donor chimerism and improved T lineage counts and function following an umbilical cord blood transplant with busulfan, cyclophosphamide, and antithymocyte globulins conditioning .
HCT should be performed when patients are young and preferably prior to development of irreversible damage from infections. However, success has also been reported when HCT was performed in the second decade of in life . In addition to reversal of the immune deficiency, HCT may benefit the neurologic abnormalities seen associated with PNP deficiency [5,21]. The neurologic status may improve in some patients following successful transplantations, possibly because of better clinical status [44,55], while, in other patients, further neurologic deterioration and developmental delay may be halted .
Frequent transfusions of red blood cells, which are rich in PNP, have been shown to improve metabolic and immune function in patients with PNP deficiency . However, the benefits are only transient, and complications from the transfusions have limited long-term use of this treatment. Studies in PNP-deficient mice also indicate that correction of purine metabolism early in life can prevent the development of neurologic abnormalities . These findings have prompted the use of red blood cell exchange transfusions in infants diagnosed with PNP deficiency at birth as a temporizing measure until HCT could be performed .
Gene therapy for PNP deficiency is under investigation. Preliminary in vitro human studies and in vivo murine studies using a lentiviral vector demonstrated increased PNP expression and partial correction of some of the abnormalities associated with PNP deficiency . However, the effect was transient. (See "Overview of gene therapy for inborn errors of immunity".)
Enzyme replacement therapy is also under investigation for PNP deficiency [66,67]. Thymic transplantation and transfer factor are not curative , although the approval of thymic transplants for patients with congenital athymia  raises the possibility that a combined HCT and thymic transplant may benefit older patients with PNP deficiency.
PROGNOSIS — Without successful transplantation, patients usually die within the first or second decade of life due to recurrent viral, fungal, or bacterial infections . There is one report of a patient with PNP deficiency who received only supportive care and gave birth to a healthy child at 21 years of age .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●Genetics and pathogenesis – Purine nucleoside phosphorylase (PNP) deficiency is caused by pathogenic variants in the PNP gene that encodes the protein PNP, one of the enzymes involved in the purine salvage pathway. Defects in this enzyme lead to intracellular accumulation of metabolites, including deoxyguanosine triphosphate (dGTP), thought to be particularly toxic to thymocytes and T cells. (See 'Pathogenesis' above.)
●Clinical manifestations – Patients typically present in infancy to early childhood with frequent bacterial, viral, and opportunistic infections and failure to thrive. Approximately two-thirds of the patients also present with progressive neurologic symptoms, and one-third develop autoimmune disease. Patients with partial PNP deficiency can present in adulthood. (See 'Clinical manifestations' above.)
●Diagnosis – Low serum uric acid associated with T cell deficiency is highly suggestive of PNP deficiency, and the diagnosis should then be confirmed by measurement of PNP enzyme activity or demonstration of pathogenic variants in the PNP gene. (See 'Diagnosis' above.)
●Treatment and prognosis – The only curative procedure for PNP deficiency is hematopoietic cell transplantation (HCT), with success reported following use of reduced-intensity conditioning. Without successful transplantation, patients usually die within the first or second decade of life due to recurrent viral, fungal, or bacterial infections. Enzyme and gene therapies are under investigation. (See 'Treatment' above and 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
The UpToDate editorial staff also acknowledges Arye Rubinstein, MD, who contributed as an author to earlier versions of this topic review.
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