Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis

INTRODUCTION — Adenosine deaminase (ADA) deficiency (MIM #102700) was the first immunodeficiency in which the specific molecular defect was identified. This autosomal-recessive genetic disorder typically leads to a severe combined immunodeficiency (SCID) (table 1) 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. The wide spectrum of the ADA deficiency phenotype is largely related to the variability in genetic mutations and the amount of residual ADA enzyme activity.

The pathogenesis, clinical manifestations, and diagnosis of ADA deficiency are presented in this topic review. The treatment of ADA deficiency is discussed separately, as is the related combined immunodeficiency disorder, purine nucleoside phosphorylase deficiency. (See "Adenosine deaminase deficiency: Treatment and prognosis" and "Purine nucleoside phosphorylase deficiency".)

An overview of SCID and detailed discussions on other SCID syndromes and combined immunodeficiencies are also covered separately (table 1). (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "Combined immunodeficiencies: An overview" and "Combined immunodeficiencies: Specific defects".)

ADA2 is another enzyme that has partial structural homology with ADA1 and is able to convert adenosine and 2-deoxyadenosine, albeit at a much lower affinity. Autosomal-recessive defects in ADA2 cause autoinflammatory disease and autoimmunity and are discussed separately. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Etiology' and "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors".)

EPIDEMIOLOGY — ADA deficiency has an overall incidence of 1 in 200,000 livebirths, with a much higher rate among some populations such as the Somali [1] and Amish/Mennonites [2]. ADA deficiency accounts for approximately one-third of all cases of autosomal-recessive severe combined immunodeficiency (SCID) and approximately 10 to 15 percent of all cases of SCID [3-5].

PATHOGENESIS — ADA is a ubiquitous enzyme found in all cells, including red and white blood cells, and in the serum. It catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, which are converted to waste products and excreted. ADA deficiency is an autosomal-recessive disorder caused by pathogenic variants in the ADA1 gene at 20q13.11 (MIM *608958) [6-9]. As little as 3 percent of residual enzyme activity can maintain nearly functional immunity into adulthood. Thus, a few patients have maintained normal immune function until immunologic decompensation occurs in adulthood and infectious complications bring attention to the diagnosis. There are also some people with "partial" ADA deficiency, who have enzyme activity ranging from 5 to 80 percent of normal but who otherwise have normal immunologic features [10].

In the absence of functional ADA, there is systemic accumulation of adenosine and deoxyadenosine. The replicative activity of the cell dictates the level of sensitivity to these toxic metabolites. Adenosine and deoxyadenosine are also converted to 5'-deoxyadenosine triphosphate (dATP), which inhibits ribonucleotide reductase and prevents de novo synthesis of nucleotides and deoxynucleotides. There is a decrease in deoxyribonucleic acid (DNA) synthesis in replicating cells because of the depletion of deoxynucleotides. In addition, deoxyadenosine irreversibly binds to and inhibits S-adenosylhomocysteine hydrolase, which also contributes to abnormal DNA synthesis [11,12].

ADA concentration is highest in the thymus, which probably accounts for the dependence of T cell development and maturation upon this enzyme. The absence of ADA and/or the presence of purine toxic metabolites may therefore be responsible for the early involution and dysplasia of the thymus observed with this disorder.

Several in vitro and animal models have attempted to unravel the mechanisms by which ADA deficiency causes this immune aberration. The in vitro models have relied upon two competitive inhibitors of ADA, erythro-9-(2hydroxy-3nonyl) adenine (EHNA) and 2'deoxycoformycin (dCF). In vitro, both compounds suppress lymphocyte mitogenic and antigenic responses that are partially reversed by exogenous ADA [13]. In addition, disease modeling with patient-derived induced pluripotent stem cells has shown that ADA deficiency impairs neutrophil development and differentiation [14].

The effect of ADA inhibition was studied in a chimeric human/mouse fetal thymic organ culture that mimicked an in vivo environment in which toxic metabolites accumulated [15]. Thymocyte expansion and differentiation were impaired by ADA inhibition. The decrease in mature thymocytes was primarily due to apoptosis that was associated with accumulation of intracellular dATP. Inhibition of adenosine kinase and deoxycytidine kinase prevented accumulation of dATP and restored thymocyte proliferation and differentiation.

Initial attempts to create animal models of ADA deficiency failed since mice lacking ADA died perinatally from hepatocellular necrosis, although their lymphoid tissue was largely not affected [16]. Subsequently, an ADA-deficient mouse model with a combined immunodeficiency and many of the other features seen in humans was created using a two-stage genetic engineering strategy [17]. These ADA-deficient mice were rescued from perinatal lethality by restoring Ada expression to trophoblast cells. In another study of this mouse model, T cell apoptosis was abundant in thymi, but no increase in apoptosis was detected in the spleen and lymph nodes, suggesting that the defect is specific to developing thymocytes [18]. In contrast, human studies in five patients with ADA deficiency showed that in vitro peripheral blood lymphocyte treatment with ADA metabolites induced a three- to fourfold higher proportion of apoptotic cells in ADA^–/– T cells compared with normal cells, suggesting that mature ADA-deficient T cells are also prone to increased apoptosis [19].

CLINICAL MANIFESTATIONS

Clinical spectrum — The clinical spectrum of ADA deficiency has broadened over time as patients with atypical or milder forms due to the variability of specific genetic mutations have been identified. In addition, the ubiquitous expression of ADA and the important role that ADA substrates and products have in many biologic processes result in diverse nonimmune abnormalities.

Age at presentation — Approximately 90 percent of patients with ADA deficiency have a classic severe combined immunodeficiency (SCID) phenotype in which the disease presents in the first months of life. Most of the remainder have a "delayed" (6 to 24 months) or "late" (four years to adulthood) onset form [20,21]. Such patients may initially have variable numbers of circulating lymphocytes and some humoral immunity that quickly wanes.

Immunodeficiency — Most patients with ADA deficiency have SCID, but the degree of the immune defect can vary widely. (See 'Pathogenesis' above.)

Severe combined immunodeficiency phenotype — Most patients with ADA deficiency present with life-threatening infections, chronic persistent diarrhea, and failure to thrive in the first months of life. This phenotype is almost indistinguishable from that of patients with SCID due to other etiologies. The disease in these early-onset patients is invariably fatal in the first year or two of life without treatment. Maternal T cell engraftment may occur and can impede the diagnosis [22]. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations' and "Severe combined immunodeficiency (SCID): An overview", section on 'Detection of maternal T cell engraftment'.)

Some neonates present with prolonged hyperbilirubinemia and hepatitis [23]. In others, a severe neonatal Omenn syndrome is the initial manifestation [24]. This is characterized by a maculopapular rash that becomes desquamative, acute necrotizing hepatitis with jaundice, interstitial pneumonitis, and massive diarrhea.

Initial infections may affect the lungs, gastrointestinal tract, and skin [25], with acute and recurrent infections caused by bacterial, protozoal, fungal, and viral agents. The most frequent organisms and sites of infection are:

●Pneumocystis jirovecii (carinii) pneumonia

●Oral, esophageal, and intestinal candidiasis

●Candidal dermatitis of the diaper region

●Herpes virus infections, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV)

●Parainfluenza and enterovirus infections

Immunization with live vaccines, such as Bacille Calmette-Guérin (BCG), can lead to disseminated infection and sometimes death [26]. Similarly, persistent diarrhea often develops after rotavirus vaccination in patients with ADA deficiency [27].

Transfusion of nonirradiated blood will invariably result in a fatal graft-versus-host reaction. (See "Transfusion-associated graft-versus-host disease".)

The physical examination in patients with a SCID phenotype frequently reveals small tonsils and the absence of palpable lymph nodes. Additional findings may include hepatosplenomegaly and possibly other features of Omenn syndrome [24]. Prominence of the costochondral junctions similar to rachitic rosary is sometimes observed. Skin findings of dermatofibrosarcoma protuberans (DFSP) (picture 1), atrophic plaques, or protuberant lesions may be present.

Milder immunologic phenotypes — Patients who present later in life can have symptoms and signs similar to those presenting in childhood. However, milder forms of the disease have also been identified. The severity depends upon the extent of the quantitative and qualitative ADA deficiency. (See 'Pathogenesis' above.)

The following observations indicate that ADA deficiency can manifest later in childhood into adulthood and partial ADA deficiency can lead over time to a deterioration of immune function. Thus, ADA deficiency should be considered in the differential diagnosis in patients of any age who present with unexplained lymphopenia and immune deficiency.

●Four children with partial ADA deficiency were described in one case series [10]. These children lacked ADA in red blood cells but retained variable ADA activity in lymphoid cells. Three of these patients had heat-labile ADA mutations that are seen with greater prevalence in the Caribbean and may have a selective advantage with regard to malaria and Babesia infections.

●A child with a partial ADA deficiency was described in whom immune functions deteriorated over time [28].

●A 12-year-old child was diagnosed with ADA deficiency after presenting with Heck disease (human papilloma virus-induced focal epithelial hyperplasia of the oral mucosa) [29].

●In one report, an adult form of ADA deficiency was described in 34- and 35-year-old sisters who had been lymphopenic from age 17 and 20 years, respectively [20]. Both had severe CD4-positive lymphopenia, with recurrent bacterial, fungal, and viral infections and chronic lung disease.

●In another report, a 39-year-old woman was reported with a combined immunodeficiency and lymphopenia [30]. She succumbed to a viral leukoencephalopathy at the age of 40 years. A 28-year-old male described in the same report was diagnosed after his niece died of a SCID [30]. He was healthy and had normal immune function. Both the 28-year-old male and the 39-year-old woman lacked red blood cell ADA activity but had only modestly elevated deoxyadenosine nucleotides [30].

Autoimmunity — Diverse autoimmune abnormalities have been reported among patients with ADA deficiency, particularly in those with milder forms of the disease. Manifestations include autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia. The immune dysregulation has been attributed to impaired function of regulatory T cells [31]. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

Malignancy — The two most common malignancies reported in patients with ADA deficiency are lymphoma and DFSP.

Lymphoma — Lymphoma most commonly occurs in patients with ADA deficiency treated with enzyme replacement therapy for extensive periods. It is often EBV induced, although EBV-negative lymphoma has also been described [32]. One review identified nine patients with ADA deficiency (out of an unknown total) who developed lymphoma, with 89 percent mortality [33]. The only surviving patient, who was treated with three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by six cycles of rituximab, was in remission for more than 12 years until recurrence of disseminated EBV-negative lymphoma [34]. (See "Malignancy in inborn errors of immunity".)

Dermatofibrosarcoma protuberans — DFSP is a rare malignant skin tumor associated with a t(17;22)(q22;q13) translocation that results in a type 1 collagen alpha-1 chain (COL1A1) platelet-derived growth factor beta (PDGFB) fusion gene (picture 1). A high incidence of DFSP, usually with multicentric involvement, is seen in patients with ADA-SCID [35]. Since this malignancy was first reported in association with ADA-SCID in 2011, there have been no reports of progression of the lesions to dissemination, and it remains uncertain whether excision or careful serial observation is best. (See "Dermatofibrosarcoma protuberans: Epidemiology, pathogenesis, clinical presentation, diagnosis, and staging".)

Somatic chromosomal abnormalities — Somatic chromosome anomalies were identified in a patient with ADA deficiency found to have an asymptomatic large lipoid abdominal tumor [36] and another with myeloid abnormalities and trisomy 8 mosaicism [37]. The frequent chromosomal abnormalities may be related to impaired adenosine homeostasis.

Pulmonary abnormalities — The primary pulmonary disorder seen in patients with ADA deficiency is pulmonary alveolar proteinosis (PAP). Asthma and bronchiectasis are seen in older patients.

Pulmonary alveolar proteinosis — PAP is a rare disorder caused by accumulation of surfactant-derived components in the lungs that is seen with high frequency in infants with ADA deficiency [38]. It often presents with tachypnea, hypoxia, and hazy pulmonary infiltrates at the time of disease recognition, making distinction from infectious etiologies such as P. jirovecii pneumonia difficult. Studies in ADA-deficient mice suggest that impaired function of alveolar macrophages, important for the clearance of surfactant, causes PAP [39,40]. PAP is reversible with enzyme replacement therapy and hematopoietic cell transplantation (HCT). (See "Adenosine deaminase deficiency: Treatment and prognosis".)

Asthma and bronchiectasis — Older patients with ADA deficiency also frequently suffer from pulmonary abnormalities including asthma and bronchiectasis [41]. In one series, 7 out of 10 patients had abnormal baseline pulmonary function, and half had significant reversible airway obstruction [42].

Neurologic abnormalities — Neurologic abnormalities are frequently associated with ADA deficiency and include neurocognitive and learning deficits, behavioral problems, coordination and gait abnormalities, hypo- and hypertonia, sensorineural hearing loss, and seizures [43-45]. A retrospective study of the US Immunodeficiency Network (USIDNET) registry identified one or more of these neurologic conditions in 45 percent of 64 patients with ADA deficiency [46]. Many of these abnormalities are not reversed by treatment (enzyme replacement therapy or HCT). However, the absolute frequencies of neurologic complications in patients with ADA-SCID who are diagnosed and treated early without severe intervening infections have not been defined. (See "Adenosine deaminase deficiency: Treatment and prognosis".)

In a study of 12 patients with ADA deficiency who survived HCT, six demonstrated significant neurologic abnormalities. The central nervous system (CNS) abnormalities were probably due to the metabolic abnormalities of ADA deficiency and not to complications of transplantation [44]. Brain magnetic resonance imaging (MRI) evaluation in patients with ADA deficiency revealed leukoencephalopathy, enlargement of ventricles, and subarachnoid spaces [47].

In a cohort study of 105 patients who underwent HCT for severe congenital immunodeficiencies, ADA-SCID was associated with a lower intelligence quotient (IQ) and higher rates of emotional and behavioral difficulties compared with the other SCID groups [48]. Bilateral sensorineural hearing loss was reported in 7 of 12 patients (58 percent) in another series who all had received HCT [45]. Hearing deficits may contribute to significantly reduced verbal and total IQ assessments [47].

Kidney and urogenital abnormalities — Hemolytic uremic syndrome with acute kidney injury was identified in an increasing number of children with ADA deficiency who had no evidence of infection with Shiga-toxigenic organisms [49-51]. Whether the kidney disease, which was not reported to reoccur, is related to effects of adenosine on endothelia, adenosine-mediated signaling abnormalities, or the previously described mesangial sclerosis [52] is still not known. A high prevalence of cryptorchidism was reported among males with ADA deficiency in a retrospective study [53]. The majority of patients had spontaneous pubertal development, although a few cases of precocious or delayed puberty were reported. No patients were found to have elevated follicle-stimulating hormone (FSH) levels. (See "Overview of hemolytic uremic syndrome in children".)

LABORATORY, RADIOGRAPHIC, AND HISTOLOGIC FINDINGS — Patients with ADA deficiency typically have severely reduced numbers of T, B, and natural killer (NK) cells [3].

Metabolic abnormalities — In normal persons, levels of adenosine and other purine nucleosides and deoxynucleosides in the plasma and urine are extremely low or undetectable due to rapid equilibration across cell membranes and prompt metabolism.

With ADA deficiency, the normal metabolic routes for these compounds are unavailable. Thus, the levels of deoxyadenosine and deoxyadenosine triphosphate (dATP) rise sharply after birth since the "detoxification" by the in utero heterozygote levels of maternal ADA are no longer available, resulting in the following biochemical hallmarks of the disease:

●In red blood cells, there is a massive increase in adenosine, deoxyadenosine, and dATP concentrations and a decrease in adenosine triphosphate (ATP) values [54,55].

●The plasma concentrations of adenosine and deoxyadenosine are variable but are usually elevated to between 0.5 and 10 mM, respectively [54].

●In the urine, adenosine levels are lower than deoxyadenosine, reflecting the more efficient reutilization of adenosine than deoxyadenosine by phosphorylation in the cells [56].

●The activity of S-adenosylhomocysteine hydrolase in red blood cells is markedly decreased since this enzyme is inactivated by deoxyadenosine [11].

Immune laboratory values — In ADA-deficient severe combined immunodeficiency (SCID), the severe T cell deficiency is manifested by [3,25,41]:

●Severe lymphopenia, with low numbers of CD3+ and CD4+ T cells compared with age-matched controls

●Poor in vitro lymphocyte mitogenic and antigenic responses

●Absent mixed lymphocyte reactions (MLRs)

B and NK cells are typically also severely reduced in patients with ADA-SCID. However, some patients may retain NK cells and even B cells. B cell function is variable. Most patients are unable to mount specific antibody responses and have variable immunoglobulin deficiencies, including low or absent immunoglobulin A (IgA) or immunoglobulin M (IgM) levels and low total immunoglobulin G (IgG) or IgG subclasses, particularly IgG2. Several patients were found to have markedly increased serum immunoglobulin E (IgE) levels. Panhypogammaglobulinemia has also been observed.

Neutropenia occurs in the majority of patients [57]. Additional hematologic laboratory abnormalities may also include autoimmune hemolytic anemia, thrombocytopenia, and eosinophilia.

Radiographs — The chest radiograph reveals the absence of a thymic shadow (image 1). Radiographs also display flaring of the anterior ribs, pelvic dysplasia, and shortening of the transverse vertebral processes with flattening of their ends (platyspondyly) and thick growth arrest lines (image 2) [58]. Other characteristic findings include squaring or spurring of the inferolateral margin of the scapula (image 1); cupping of the anterior rib ends, best viewed by lateral imaging; and diffuse osteopenia of the bones [59]. The bone abnormalities seen in patients have been attributed to imbalance in receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin, which were also identified in ADA-deficient mice [60].

Histology — Patients with ADA-SCID often have myeloid dysplasia and bone marrow hypocellularity [61]. Autopsy findings in eight patients with ADA deficiency demonstrated that thymus weights were 2 to 30 percent of expected [62]. Histologically, the thymus is dysplastic, with poor corticomedullary differentiation, small nests of undifferentiated epithelial cells, and absence of Hassall's corpuscles.

DIAGNOSIS

When to suspect the diagnosis — Infants can be detected on newborn screening (NBS) prior to onset of symptoms if the test is included on the panel. Children with ADA-deficient severe combined immunodeficiency (SCID) who are born in locales where testing for SCID is not included on the NBS panel most often present with typical signs and symptoms of SCID including failure to thrive, life-threatening infections, chronic mucocutaneous fungal infections, and/or opportunistic infections. Features that suggest ADA deficiency, but not most other forms of SCID, include earlier age of presentation with failure to thrive and noninfectious respiratory distress (often before four months of age), rib cage abnormalities, early neurologic abnormalities, and sensory-neural hearing loss. In late presenters, recurrent infection, opportunistic infections, and an unexplained lymphopenia may raise the suspicion of an unusual form of ADA deficiency. (See "Severe combined immunodeficiency (SCID): An overview" and 'Severe combined immunodeficiency phenotype' above and "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects' and 'Newborn screening' below.)

Newborn screening — NBS via quantification of T cell receptor excision circles (TRECs) has proven an important way to diagnose ADA deficiency early in infancy, prior to the onset of severe infections [41,63-65]. TRECs are formed during the differentiation of T cells in the thymus. They serve as a marker for naïve T cells in the peripheral blood and can be enumerated using dried blood spots on NBS cards [66]. TRECs are low to absent in over 90 percent of patients with ADA-SCID. However, T cells and TRECs may still be present if measured in the first few days of life in newborns with ADA deficiency because there is some degree of in utero detoxification by maternal ADA. In addition, TREC assays may not detect delayed or late-onset ADA deficiency, due to sufficient residual levels of ADA in the newborn period. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)

An alternative approach to NBS for ADA deficiency using tandem mass spectrometry can also correctly identify infants with residual ADA activity, although it has not been widely implemented [67,68]. This is particularly beneficial for situations of delayed- or late-onset ADA deficiency as these patients may have normal TREC levels at the time of NBS testing yet will already have elevated adenosine and deoxyadenosine that can be detected by tandem mass spectrometry [69,70].

Initial evaluation — The patient suspected of having SCID of any etiology requires the complete evaluation of specific humoral and cellular immunity. Studies include the measurement of immunoglobulin levels, absolute numbers and percentages of lymphocyte subsets (T, B, and natural killer [NK]), and assessment of T cell function. In this situation, T cell function is usually determined by in vitro measurement of responses to mitogens, such as phytohemagglutinin (PHA) and concanavalin A (ConA). The diagnostic evaluation for SCID is reviewed in greater detail separately. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Diagnosis' and "Laboratory evaluation of the immune system".)

ADA-SCID is suggested by finding severe pan lymphopenia with T cell deficiency, as expressed by lymphopenia with low numbers of CD3+ and CD4+ cells, poor in vitro lymphocyte mitogenic and antigenic responses, and absent mixed lymphocyte reactions (MLRs). Most patients also have marked reduction of B and NK cells (T-B-NK- SCID).

Other laboratory findings that assist in the diagnosis of ADA deficiency include the detection of nonhemolytic neutropenia [57], noninfectious mild-to-moderate hepatitis, and periodic acid-Schiff stain positive (PAS+) proteinaceous noninfectious alveolar lavage.

Tests specific for ADA deficiency — The major diagnostic metabolic laboratory findings specific for ADA deficiency, which are also used to monitor treatment results, are the following:

●Absent ADA levels in lysed erythrocytes from fresh blood samples or dried blood spots. This test is available at several commercial and research centers, while the remaining assays are only available at few specialized laboratories.

●A marked increase in deoxyadenosine triphosphate (dATP) levels in erythrocyte lysates (with levels that vary by laboratory).

●A significant decrease in ATP concentration in red blood cells.

●Absent or extremely low levels of s-adenosylhomocysteine hydrolase in red blood cells.

●Increase in 2'-deoxyadenosine in urine and plasma, as well as in dried blood spots.

Genetic testing — The diagnosis is confirmed by identification of biallelic pathogenic variants in the ADA1 gene.

Prenatal diagnosis — Prenatal diagnosis can be made by mutational analysis or by evaluation of ADA activity in cultured fibroblasts from amniotic fluid [13] and from chorionic villus sampling [71]. Prenatal diagnosis via molecular genetic testing is an option for those families in which the mutations causing ADA deficiency have been identified [72]. Amniocentesis is indicated in any pregnancy that follows the birth of a child with ADA deficiency.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of ADA deficiency includes all other forms of autosomal-recessive severe combined immunodeficiency (SCID), complete DiGeorge syndrome, and purine nucleoside phosphorylase deficiency.

●Several clinical characteristics can help differentiate ADA deficiency from other forms of SCID. (See 'When to suspect the diagnosis' above and "Severe combined immunodeficiency (SCID): An overview", section on 'Diagnosis' and "Severe combined immunodeficiency (SCID): Specific defects".)

●The lack of associated facial and structural anomalies can help distinguish between ADA deficiency and DiGeorge syndrome. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis".)

●The presence of normal uric acid helps differentiate ADA deficiency from purine nucleoside phosphorylase deficiency. (See "Purine nucleoside phosphorylase deficiency".)

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

●Genetics and pathogenesis – Adenosine deaminase (ADA) deficiency (MIM #102700) is a rare, autosomal-recessive genetic disorder caused by pathogenic variants in the ADA1 gene at 20q13.11 (MIM *608958). In the absence of functional ADA, there is an intracellular accumulation of adenosine and deoxyadenosine. These products are toxic to lymphocytes and lead to dysfunction of T, B, and natural killer (NK) cells that can range in severity from T-B-NK- severe combined immunodeficiency (SCID) to milder phenotypes. The wide spectrum of the ADA deficiency phenotype is largely related to the variability in genetic mutations. (See 'Pathogenesis' above.)

●Clinical manifestations – ADA deficiency typically leads to a severe combined immunodeficiency (SCID) (table 1) that presents in the first few months of life, unless identified prior to onset of symptoms by newborn screening (NBS). However, there are also a few patients with a later onset and relatively milder disease. Typical signs and symptoms of SCID include failure to thrive, life-threatening infections, chronic mucocutaneous fungal infections, and/or opportunistic infections. Features that suggest ADA deficiency, but not most other forms of SCID, include earlier age of presentation with failure to thrive and noninfectious respiratory distress (often before four months of age), rib cage abnormalities, early neurologic abnormalities, and sensory-neural hearing loss. In late presenters, recurrent infection, opportunistic infections, and an unexplained lymphopenia may raise the suspicion of an unusual form of ADA deficiency. (See 'Clinical manifestations' above.)

●Diagnosis – SCID is suspected when there is a positive NBS or the infant presents with typical features. Additional findings that aid in diagnosis of ADA deficiency include (see 'Laboratory, radiographic, and histologic findings' above and 'Diagnosis' above):

•Absent ADA in lysed erythrocytes and elevated levels of adenosine and deoxyadenosine levels in the urine and plasma.

•Severe T cell deficiency manifested by lymphopenia and poor T cell responses to mitogens and antigens; inability to mount specific antibody responses in most patients, but immunoglobulin levels are variable.

•Absent thymic shadow on chest radiograph (image 1). Additional radiographic abnormalities seen in ADA deficiency but not other forms of SCID include flaring of the anterior ribs and squaring or spurring of the inferolateral margin of the scapula (image 2).

The diagnosis is confirmed by identification of biallelic pathogenic variants in the ADA1 gene.

●Differential diagnosis – The differential diagnosis of ADA deficiency includes all other forms of autosomal-recessive SCID, complete DiGeorge syndrome, and purine nucleoside phosphorylase deficiency. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Arye Rubinstein, MD, who contributed to earlier versions of this topic review.

The editorial staff at UpToDate also acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.