History

Fact Explanation
A positive family history Adenosine deaminase deficiency is an autosomal recessive genetic condition that causes systemic purine metabolism, [1] results in varying degrees of immunodeficiency, ranging from neonatal onset Severe Combined Immunodeficiency (SCID) to an adult onset immunodeficiency disorder, so there is a possibility of having members of the family who had been diagnosed before. [2] [3]
An infant Severe combined immunodeficiency disease is often diagnosed by the age of six months to 12 months. [1, 4]
A young child Less severe delayed onset combined immune deficiency is usually diagnosed between the age of one to ten years. [1, 5]
A young adult Late or adult onset combined immunodeficiency disorder is usually diagnosed in patients of the age of twenty to forty years. [6]
Growth retardation The infants with SCID exhibit severe failure to thrive. Older children also show growth retardation. [1] The reasons are there is an osteoblast insufficiensy in ADA deficiency, malabsorption and contribution from recurrent infections. [7, 8, 9, 10]
Recurrent infections by opportunistic organisms In ADA deficiency, there is a combined deficiency of T-lymphocyte and B-lymphocyte function (and in many cases also natural killer, or NK, lymphocyte function). [10] It is due to the growth inhibitory action on lymphocyte colonies. [11] Both humoral and cellular immune functions are absent. [1] Severe infection is the most common presenting symptom of patients with SCID. (i.e. pneumonia, meningitis or bloodstream infections) [10] Patients with delayed onset often experience recurrent infections. [12, 13] The organisms are most of the time opportunistic. i.e. Pneumocystis jiroveci, chicken pox virus, Cytomegalovirus, Herpes simplex virus, adenovirus, parainfluenza 3, Epstein-Barr virus, polioviruses, measles virus, rotavirus, candida fungal infections. [10]
Persistent diarrhea and vomiting A very common presentation. [1, 14, 15, 16] The resultant malabsorption can cause growth retardation. [10]
Progressive difficulty in breathing Due to interstitial pneumonitis. [15, 16, 17] Patients with delayed onset of ADA deficiency are more prone to present with chronic pulmonary insufficiency. [1]
History of associated other conditions Some autoimmune conditions have been associated with ADA deficiency since the immune dysregulation. I.e. autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia. [1, 18]
Early sudden deaths Sudden deaths during the first year of life is common in SCID. [1, 19, 20]
References
  1. HERSHFIELD M, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Adenosine Deaminase Deficiency [online] 1993 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301656
  2. JIANG C, HONG R, HOROWITZ SD, KONG X, HIRSCHHORN R. An adenosine deaminase (ADA) allele contains two newly identified deleterious mutations (Y97C and L106V) that interact to abolish enzyme activity. Hum Mol Genet [online] 1997 Dec, 6(13):2271-8 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/9361033
  3. ARREDONDO-VEGA FX, SANTISTEBAN I, DANIELS S, TOUTAIN S, HERSHFIELD MS. Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am J Hum Genet [online] 1998 Oct, 63(4):1049-59 [viewed 18 September 2014] Available from: doi:10.1086/302054
  4. RATECH H, GRECO MA, GALLO G, RIMOIN DL, KAMINO H, HIRSCHHORN R. Pathologic findings in adenosine deaminase-deficient severe combined immunodeficiency. I. Kidney, adrenal, and chondro-osseous tissue alterations. Am J Pathol [online] 1985 Jul, 120(1):157-169 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1887960
  5. ROSSBERG S., SCHWARZ K., MEISEL C., HOLZHAUER S., KüHL J., EBELL W., WAHN V., BERNUTH H. VON. Delayed Onset of (Severe) Combined Immunodeficiency (S)CID (T-B+NK+): Complete IL-7 Receptor Deficiency in a 22 Months Old Girl. Klin Padiatr [online] December, 221(06):339-343 [viewed 18 September 2014] Available from: doi:10.1055/s-0029-1239537
  6. MALPHETTES M, GéRARD L, CARMAGNAT M, MOUILLOT G, VINCE N, BOUTBOUL D, BéREZNé A, NOVE-JOSSERAND R, LEMOING V, TETU L, VIALLARD JF, BONNOTTE B, PAVIC M, HAROCHE J, LARROCHE C, BROUET JC, FERMAND JP, RABIAN C, FIESCHI C, OKSENHENDLER E, DEFI STUDY GROUP. Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect. Clin Infect Dis [online] 2009 Nov 1, 49(9):1329-38 [viewed 18 September 2014] Available from: doi:10.1086/606059
  7. SAUER A. V., MRAK E., JOFRA HERNANDEZ R., ZACCHI E., CAVANI F., CASIRAGHI M., GRUNEBAUM E., ROIFMAN C. M., CERVI M. C., AMBROSI A., CARLUCCI F., RONCAROLO M. G., VILLA A., RUBINACCI A., AIUTI A.. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood [online] December, 114(15):3216-3226 [viewed 19 September 2014] Available from: doi:10.1182/blood-2009-03-209221
  8. LEE C.D. Adenosine deaminase deficiency and treatment. [web] [viewed 19 September 2014] Available from: http://www.bio.davidson.edu/courses/Immunology/Students/spring2000/lee/restricted/adadeficiency.html
  9. SAUER A. V., MRAK E., JOFRA HERNANDEZ R., ZACCHI E., CAVANI F., CASIRAGHI M., GRUNEBAUM E., ROIFMAN C. M., CERVI M. C., AMBROSI A., CARLUCCI F., RONCAROLO M. G., VILLA A., RUBINACCI A., AIUTI A.. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood [online] December, 114(15):3216-3226 [viewed 19 September 2014] Available from: doi:10.1182/blood-2009-03-209221
  10. Severe Combined Immune Deficiency and Combined Immune Deficiency. [web] [viewed 19 September 2014] Available from: http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/severe-combined-immune-deficiency-and-combined-immune-deficiency/
  11. KUBOTA M. et al. Characterization of an Adenosine Deaminase-deficient Human Histiocytic Lymphoma Cell Line (DHL-9) and Selection of Mutants Deficient in Adenosine Kinase and Deoxycytidine Kinase. Cancer Res [online] 1983;43:2606-2610 [viewed 19 September 2014] Available from: http://cancerres.aacrjournals.org/content/43/6/2606.full.pdf
  12. ARREDONDO-VEGA FRANCISCO X., SANTISTEBAN INES, DANIELS SHANNON, TOUTAIN STEPHAN, HERSHFIELD MICHAEL S.. Adenosine Deaminase Deficiency: Genotype-Phenotype Correlations Based on Expressed Activity of 29 Mutant Alleles. The American Journal of Human Genetics [online] 1998 October, 63(4):1049-1059 [viewed 19 September 2014] Available from: doi:10.1086/302054
  13. OZSAHIN H. et al. Adenosine Deaminase Deficiency in Adults. Blood [online] April 15, 1997: 89 (8). [viewed 19 September 2014] Available from: http://www.bloodjournal.org/content/89/8/2849?sso-checked=true
  14. ÖZDEMIR O. Severe combined immune deficiency in an adenosine deaminase-deficient patient. Allergy and Asthma Proceedings [online] Volume 27, Number 2, March-April 2006, pp. 172-174(3) [viewed 19 September 2014] Available from: http://www.ingentaconnect.com/content/ocean/aap/2006/00000027/00000002/art00018?token=004e1785257879c7b76504c486646255c493e2f2a6c7b425b6a332b25757d5c4f6d4e227a80137
  15. ZIEGLER JB, LEE CH, VAN DER WEYDEN MB, BAGNARA AS, BEVERIDGE J. Severe combined immunodeficiency and adenosine deaminase deficiency: failure of enzyme replacement therapy. Arch Dis Child [online] 1980 Jun, 55(6):452-7 [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7436484
  16. FISCHER A. Severe combined immunodeficiencies (SCID) Clin Exp Immunol [online] 2000 Nov, 122(2):143-149 [viewed 19 September 2014] Available from: doi:10.1046/j.1365-2249.2000.01359.x
  17. BLACKBURN MR, VOLMER JB, THRASHER JL, ZHONG H, CROSBY JR, LEE JJ, KELLEMS RE. Metabolic Consequences of Adenosine Deaminase Deficiency in Mice Are Associated with Defects in Alveogenesis, Pulmonary Inflammation, and Airway Obstruction J Exp Med [online] 2000 Jul 17, 192(2):159-170 [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193256
  18. SAUER AV, BRIGIDA I, CARRIGLIO N, AIUTI A. Autoimmune Dysregulation and Purine Metabolism in Adenosine Deaminase Deficiency Front Immunol [online] :265 [viewed 19 September 2014] Available from: doi:10.3389/fimmu.2012.00265
  19. BOISON D, SCHEURER L, ZUMSTEG V, RüLICKE T, LITYNSKI P, FOWLER B, BRANDNER S, MOHLER H. Neonatal hepatic steatosis by disruption of the adenosine kinase gene Proc Natl Acad Sci U S A [online] 2002 May 14, 99(10):6985-6990 [viewed 19 September 2014] Available from: doi:10.1073/pnas.092642899
  20. BLACKBURN MR, KELLEMS RE. Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation. Adv Immunol [online] 2005:1-41 [viewed 19 September 2014] Available from: doi:10.1016/S0065-2776(04)86001-2

Examination

Fact Explanation
Wasting and stunting Due to growth retardation. [1, 2, 3, 4, 5]
Features of malabsorption Apart from loss of weight, abdominal distension due to accumulated fluid and gas [6], signs of anemia (stomatitis, cheilosis, mucoconjunctival pallor) [7], signs of fat soluble vitamin deficiencies (conjunctival xerosis, Bitot spots, corneal xerosis, corneal ulcerations in Vit A deficiency [8, 9], bleeding diathesis in Vit K deficiency) [10], peripheral neuropathy in Vit B12 deficiency [11] should also be looked for.
Features of dehydration i.e. i.e. decreased peripheral perfusion (indicated by capillary refilling time) , deep breathing, decreased skin turgor, sunken eyes, dry mouth, sunken fontanelle and absence of tears. Due to recurrent vomiting and diarrhea. [12, 13]
Features of a concurrent infective focus i.e. pneumonia (signs of lung consolidation: reduced breath sounds, reduced lung expansion, crepitations) , meningitis (neck stiffness, altered behaviour), or a skin infection. Because patients with ADA deficiency are prone to have recurrent infections. [14, 15, 16]
Features of lung fibrosis Due to chronic pulmonary inflammation. [17, 18, 19, 20]
Features of autoimmune conditions i.e. vitiligo, goitre (autoimmune thyroiditis), dermatitis (autoimmune dermatitis), small joint swelling and tenderness (rheumatoid arthritis or connective tissue disorder). Due to immune dysregulation. [1, 21]
References
  1. HERSHFIELD M, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Adenosine Deaminase Deficiency [online] 1993 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301656
  2. SAUER A. V., MRAK E., JOFRA HERNANDEZ R., ZACCHI E., CAVANI F., CASIRAGHI M., GRUNEBAUM E., ROIFMAN C. M., CERVI M. C., AMBROSI A., CARLUCCI F., RONCAROLO M. G., VILLA A., RUBINACCI A., AIUTI A.. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood [online] December, 114(15):3216-3226 [viewed 19 September 2014] Available from: doi:10.1182/blood-2009-03-209221
  3. LEE C.D. Adenosine deaminase deficiency and treatment. [web] [viewed 19 September 2014] Available from: http://www.bio.davidson.edu/courses/Immunology/Students/spring2000/lee/restricted/adadeficiency.html
  4. SAUER A. V., MRAK E., JOFRA HERNANDEZ R., ZACCHI E., CAVANI F., CASIRAGHI M., GRUNEBAUM E., ROIFMAN C. M., CERVI M. C., AMBROSI A., CARLUCCI F., RONCAROLO M. G., VILLA A., RUBINACCI A., AIUTI A.. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood [online] December, 114(15):3216-3226 [viewed 19 September 2014] Available from: doi:10.1182/blood-2009-03-209221
  5. Severe Combined Immune Deficiency and Combined Immune Deficiency. [web] [viewed 19 September 2014] Available from: http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/severe-combined-immune-deficiency-and-combined-immune-deficiency/
  6. SIMMONS CW. The Malabsorption Syndrome J Natl Med Assoc [online] 1962 Sep, 54(5):597-605 [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642123
  7. LUBY SP, KAZEMBE PN, REDD SC, ZIBA C, NWANYANWU OC, HIGHTOWER AW, FRANCO C, CHITSULO L, WIRIMA JJ, OLIVAR MA. Using clinical signs to diagnose anaemia in African children. Bull World Health Organ [online] 1995, 73(4):477-482 [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2486784
  8. GILBERT C. The eye signs of vitamin A deficiency Community Eye Health [online] 2013, 26(84):66-67 [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936686
  9. PITCHON E, SAHLI O, BORRUAT F.-X. Night Blindness, Yellow Vision, and Yellow Skin: Symptoms and Signs of Malabsorption. Klin Monatsbl Augenheilkd [online] 2006 May, 223(5):443-446 [viewed 19 September 2014] Available from: doi:10.1055/s-2006-926830
  10. WOODS CHRISTOPHER W., WOODS AMANDA G., CEDERHOLM CARMEN K.. Vitamin K Deficiency Bleeding. Advances in Neonatal Care [online] 2013 December, 13(6):402-407 [viewed 19 September 2014] Available from: doi:10.1097/ANC.0000000000000026
  11. PFEIFFER RF. Neurologic manifestations of malabsorption syndromes. Handb Clin Neurol [online] 2014:621-32 [viewed 19 September 2014] Available from: doi:10.1016/B978-0-7020-4087-0.00042-5
  12. MACKENZIE A, BARNES G, SHANN F. Clinical signs of dehydration in children. Lancet [online] 1989 Sep 9, 2(8663):605-7 [viewed 14 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/2570294
  13. BAILEY BENOIT, GRAVEL JOCELYN, GOLDMAN RAN D., FRIEDMAN JEREMY N., PARKIN PATRICIA C.. External Validation of the Clinical Dehydration Scale for Children With Acute Gastroenteritis. [online] 2010 May, 17(6):583-588 [viewed 14 September 2014] Available from: doi:10.1111/j.1553-2712.2010.00767.x
  14. Severe Combined Immune Deficiency and Combined Immune Deficiency. [web] [viewed 19 September 2014] Available from: http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/severe-combined-immune-deficiency-and-combined-immune-deficiency/
  15. ARREDONDO-VEGA FRANCISCO X., SANTISTEBAN INES, DANIELS SHANNON, TOUTAIN STEPHAN, HERSHFIELD MICHAEL S.. Adenosine Deaminase Deficiency: Genotype-Phenotype Correlations Based on Expressed Activity of 29 Mutant Alleles. The American Journal of Human Genetics [online] 1998 October, 63(4):1049-1059 [viewed 19 September 2014] Available from: doi:10.1086/302054
  16. OZSAHIN H. et al. Adenosine Deaminase Deficiency in Adults. Blood [online] April 15, 1997: 89 (8). [viewed 19 September 2014] Available from: http://www.bloodjournal.org/content/89/8/2849?sso-checked=true
  17. BLACKBURN MR, KELLEMS RE. Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation. Adv Immunol [online] 2005:1-41 [viewed 19 September 2014] Available from: doi:10.1016/S0065-2776(04)86001-2
  18. ZIEGLER JB, LEE CH, VAN DER WEYDEN MB, BAGNARA AS, BEVERIDGE J. Severe combined immunodeficiency and adenosine deaminase deficiency: failure of enzyme replacement therapy. Arch Dis Child [online] 1980 Jun, 55(6):452-7 [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7436484
  19. ISCHER A. Severe combined immunodeficiencies (SCID) Clin Exp Immunol [online] 2000 Nov, 122(2):143-149 [viewed 19 September 2014] Available from: doi:10.1046/j.1365-2249.2000.01359.x
  20. BLACKBURN MR, VOLMER JB, THRASHER JL, ZHONG H, CROSBY JR, LEE JJ, KELLEMS RE. Metabolic Consequences of Adenosine Deaminase Deficiency in Mice Are Associated with Defects in Alveogenesis, Pulmonary Inflammation, and Airway Obstruction J Exp Med [online] 2000 Jul 17, 192(2):159-170 [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193256
  21. SAUER AV, BRIGIDA I, CARRIGLIO N, AIUTI A. Autoimmune Dysregulation and Purine Metabolism in Adenosine Deaminase Deficiency Front Immunol [online] :265 [viewed 19 September 2014] Available from: doi:10.3389/fimmu.2012.00265

Differential Diagnoses

Fact Explanation
Other causes for Severe Combined Immunodeficiency There are other causes of SCID that results in absence of T cells and adaptive immunity. There are multiple genes involved, and some have been identified so far. Some are autosomal linked, some are X-linked. i.e. JAK 3 mutations, RAg 1/2 mutations, gamma-c mutations. Enzyme assays and specific immunofluorescence tests can help to differentiate. [1, 2, 3, 6]
Other causes for immunodeficiency The spectrum of causes for profound immunocompromised state should be carefully evaluated and excluded. i.e. HIV (by serological testing), liver diseases (by liver profile), chromosomal instability or genetic mutations, hypoproteinemia (by serum total protein and albumin levels). [4, 5, 7, 8, 9, 10, ]
References
  1. BUCKLEY RH. The multiple causes of human SCID J Clin Invest [online] 2004 Nov 15, 114(10):1409-1411 [viewed 24 September 2014] Available from: doi:10.1172/JCI23571
  2. HERSHFIELD MICHAEL S. Genotype is an important determinant of phenotype in adenosine deaminase deficiency. Current Opinion in Immunology [online] 2003 October, 15(5):571-577 [viewed 24 September 2014] Available from: doi:10.1016/S0952-7915(03)00104-3
  3. SCHMOLDT A, BENTHE HF, HABERLAND G. Digitoxin metabolism by rat liver microsomes. Biochem Pharmacol [online] 1975 Sep 1, 24(17):1639-41 [viewed 24 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10
  4. KAHN JAMES O., WALKER BRUCE D.. Acute Human Immunodeficiency Virus Type 1 Infection. N Engl J Med [online] 1998 July, 339(1):33-39 [viewed 24 September 2014] Available from: doi:10.1056/NEJM199807023390107
  5. WHALEN C, HORSBURGH C R, HOM D, LAHART C, SIMBERKOFF M, ELLNER J. Accelerated course of human immunodeficiency virus infection after tuberculosis.. Am J Respir Crit Care Med [online] 1995 January, 151(1):129-135 [viewed 24 September 2014] Available from: doi:10.1164/ajrccm.151.1.7812542
  6. DUESBERG PH. Human immunodeficiency virus and acquired immunodeficiency syndrome: correlation but not causation. Proc Natl Acad Sci U S A [online] 1989 Feb, 86(3):755-64 [viewed 24 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/2644642
  7. BESTOR TIMOTHY H., XU GUO-LIANG, BOURC'HIS DéBORAH, HSIEH CHIH-LIN, TOMMERUP NIELS, BUGGE MERETE, HULTEN MAJ, QU XIAOYAN, RUSSO JAMES J., VIEGAS-PéQUIGNOT EVANI. . Nature [online] 1999 November, 402(6758):187-191 [viewed 24 September 2014] Available from: doi:10.1038/46052
  8. HODGE D. Proteus syndrome and immunodeficiency. [online] 2000 March, 82(3):234-235 [viewed 24 September 2014] Available from: doi:10.1136/adc.82.3.234
  9. WALDMANN TA, TERRY WD. Familial hypercatabolic hypoproteinemia. A disorder of endogenous catabolism of albumin and immunoglobulin. J Clin Invest [online] 1990 Dec, 86(6):2093-2098 [viewed 24 September 2014] Available from: doi:10.1172/JCI114947
  10. BADENOCH J. The malabsorption syndromes. Some clinical problems. Ulster Med J [online] 1973 Winter, 42(1):63-73 [viewed 24 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/4572160

Investigations - for Diagnosis

Fact Explanation
Complete blood count Anemia and leucopenia is expected. [1]
Lymphocyte count There is very low T, B, and NK lymphocyte counts in peripheral blood. [2, 3] Lymphopenia is an early diagnostic sign. [1]
Serum immunoglobulins All types are low. [1, 2, 3, 4, 5]
Adenosine deaminase catalytic activity Less than 1% of normal ADA catalytic activity in hemolysates (in un-transfused patients) or in extracts of other cells (e.g., blood mononuclear cells, fibroblasts) is diagnostic. [2, 6]
References
  1. RATECH H, HIRSCHHORN R, GRECO MA. Pathologic findings in adenosine deaminase deficient-severe combined immunodeficiency. II. Thymus, spleen, lymph node, and gastrointestinal tract lymphoid tissue alterations. Am J Pathol [online] 1989 Dec, 135(6):1145-1156 [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1880483
  2. HERSHFIELD M, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Adenosine Deaminase Deficiency [online] 1993 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301656
  3. APASOV SG, BLACKBURN MR, KELLEMS RE, SMITH PT, SITKOVSKY MV. Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest [online] 2001 Jul, 108(1):131-41 [viewed 19 September 2014] Available from: doi:10.1172/JCI10360
  4. Immunobiology: The Immune System in Health and Disease. 5th edition. Inherited immunodeficiency diseases. [web] [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/books/NBK27109/
  5. SAUER AISHA VANESSA, BRIGIDA IMMACOLATA, CARRIGLIO NICOLA, AIUTI ALESSANDRO. Autoimmune Dysregulation and Purine Metabolism in Adenosine Deaminase Deficiency. Front. Immun. [online] 2012 December [viewed 19 September 2014] Available from: doi:10.3389/fimmu.2012.00265
  6. ARREDONDO-VEGA FX, SANTISTEBAN I, DANIELS S, TOUTAIN S, HERSHFIELD MS. Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am J Hum Genet [online] 1998 Oct, 63(4):1049-1059 [viewed 19 September 2014] Available from: doi:10.1086/302054

Investigations - Followup

Fact Explanation
Immunoglobin levels Total or specific immunoglobulin rise should be observed in adequate management. [1, 2, 3, 4]
References
  1. KAWAMURA NOBUAKI, ARIGA TADASHI, OHTSU MAKOTO, YAMADA MASAFUMI, TAME ATSUSHI, FURUTA HIROFUMI, KOBAYASHI ICHIRO, OKANO MOTOHIKO, YANAGIHARA YUKIYOSHI, SAKIYAMA YUKIO. Elevation of serum IgE level and peripheral eosinophil count during T lymphocyte-directed gene therapy for ADA deficiency: implication of Tc2-like cells after gene transduction procedure. Immunology Letters [online] 1998 November, 64(1):49-53 [viewed 19 September 2014] Available from: doi:10.1016/S0165-2478(98)00083-2
  2. CANDOTTI F., SHAW K. L., MUUL L., CARBONARO D., SOKOLIC R., CHOI C., SCHURMAN S. H., GARABEDIAN E., KESSERWAN C., JAGADEESH G. J., FU P.-Y., GSCHWENG E., COOPER A., TISDALE J. F., WEINBERG K. I., CROOKS G. M., KAPOOR N., SHAH A., ABDEL-AZIM H., YU X.-J., SMOGORZEWSKA M., WAYNE A. S., ROSENBLATT H. M., DAVIS C. M., HANSON C., RISHI R. G., WANG X., GJERTSON D., YANG O. O., BALAMURUGAN A., BAUER G., IRELAND J. A., ENGEL B. C., PODSAKOFF G. M., HERSHFIELD M. S., BLAESE R. M., PARKMAN R., KOHN D. B.. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood [online] December, 120(18):3635-3646 [viewed 19 September 2014] Available from: doi:10.1182/blood-2012-02-400937
  3. RICH KC, RICHMAN CM, MEJIAS E, DADDONA P. Immunoreconstitution by Peripheral Blood Leukocytes in Adenosine Deaminase-deficient Severe Combined Immunodeficiency J Clin Invest [online] 1980 Aug, 66(2):389-395 [viewed 19 September 2014] Available from: doi:10.1172/JCI109868
  4. HAMMARSTRöM L, VORECHOVSKY I, WEBSTER D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID) Clin Exp Immunol [online] 2000 May, 120(2):225-231 [viewed 19 September 2014] Available from: doi:10.1046/j.1365-2249.2000.01131.x

Investigations - Screening/Staging

Fact Explanation
Dried blood spot test The most cost-effective method of screening newborns is using a dried blood spot (DBS) as soon as the neonate is born. Adenosine and 2'-deoxyadenosine can be tested by using tandem mass spectrometry. [1, 2]
T-cell receptor excision circle (TREC) assay It has the highest sensitivity. It incorporates polymerase chain reaction (PCR). Normal newborns have TREC numbers at around 10% of their total T-cell numbers, whereas older children and adults have progressively lower ratios of TRECs to T cells, reflecting peripheral T-cell expansion. Infants with SCID were shown to have very low or undetectable TRECs. [3, 4, 5, 6, 7]
Absolute lymphocyte count (ALC) Requires a separate blood sample. Any ALC <2500/microL is potentially pathogenic in early infancy and should be evaluated. [8, 9]
Immunoassays i.e. IL-7 immunoassay for functional T cell immunity, CD3 as a marker for T cells, CD45 as a marker for total leukocytes. [9, 10]
References
  1. AZZARI CHIARA, LA MARCA GIANCARLO, RESTI MASSIMO. Neonatal screening for severe combined immunodeficiency caused by an adenosine deaminase defect: A reliable and inexpensive method using tandem mass spectrometry. Journal of Allergy and Clinical Immunology [online] 2011 June, 127(6):1394-1399 [viewed 19 September 2014] Available from: doi:10.1016/j.jaci.2011.03.040
  2. HUANG H, MANTON KG. Newborn screening for severe combined immunodeficiency (SCID): a review. Front Biosci [online] 2005 May 1:1024-39 [viewed 19 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15769602
  3. PUCK JM. Neonatal Screening for Severe Combined Immunodeficiency (SCID) Curr Opin Pediatr [online] 2011 Dec, 23(6):667-673 [viewed 19 September 2014] Available from: doi:10.1097/MOP.0b013e32834cb9b0
  4. CHAN KEE, PUCK JENNIFER M.. Development of population-based newborn screening for severe combined immunodeficiency. Journal of Allergy and Clinical Immunology [online] 2005 February, 115(2):391-398 [viewed 19 September 2014] Available from: doi:10.1016/j.jaci.2004.10.012
  5. PUCK JM. Laboratory Technology for Population-based Screening for SCID in Neonates: The Winner Is T-cell Receptor Excision Circles (TRECs) J Allergy Clin Immunol [online] 2012 Mar, 129(3):607-616 [viewed 19 September 2014] Available from: doi:10.1016/j.jaci.2012.01.032
  6. KWAN ANTONIA, ABRAHAM ROSHINI S., CURRIER ROBERT, BROWER AMY, ANDRUSZEWSKI KAREN, ABBOTT JORDAN K., BAKER MEI, BALLOW MARK, BARTOSHESKY LOUIS E., BONILLA FRANCISCO A., BROKOPP CHARLES, BROOKS EDWARD, CAGGANA MICHELE, CELESTIN JOCELYN, CHURCH JOSEPH A., COMEAU ANNE MARIE, CONNELLY JAMES A., COWAN MORTON J., CUNNINGHAM-RUNDLES CHARLOTTE, DASU TRIVIKRAM, DAVE NINA, DE LA MORENA MARIA T., DUFFNER ULRICH, FONG CHIN-TO, FORBES LISA, FREEDENBERG DEBRA, GELFAND ERWIN W., HALE JAIME E., HANSON I. CELINE, HAY BEVERLY N., HU DIANA, INFANTE ANTHONY, JOHNSON DAISY, KAPOOR NEENA, KAY DENISE M., KOHN DONALD B., LEE RACHEL, LEHMAN HEATHER, LIN ZHILI, LOREY FRED, ABDEL-MAGEED ALY, MANNING ADRIENNE, MCGHEE SEAN, MOORE THEODORE B., NAIDES STANLEY J., NOTARANGELO LUIGI D., ORANGE JORDAN S., PAI SUNG-YUN, PORTEUS MATTHEW, RODRIGUEZ RAY, ROMBERG NEIL, ROUTES JOHN, RUEHLE MARY, RUBENSTEIN ARYE, SAAVEDRA-MATIZ CARLOS A., SCOTT GINGER, SCOTT PATRICIA M., SECORD ELIZABETH, SEROOGY CHRISTINE, SHEARER WILLIAM T., SIEGEL SUBHADRA, SILVERS STACY K., STIEHM E. RICHARD, SUGERMAN ROBERT W., SULLIVAN JOHN L., TANKSLEY SUSAN, TIERCE MILLARD L., VERBSKY JAMES, VOGEL BETH, WALKER ROSALYN, WALKOVICH KELLY, WALTER JOLAN E., WASSERMAN RICHARD L., WATSON MICHAEL S., WEINBERG GEOFFREY A., WEINER LEONARD B., WOOD HEATHER, YATES ANNE B., PUCK JENNIFER M.. Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States. JAMA [online] 2014 August [viewed 19 September 2014] Available from: doi:10.1001/jama.2014.9132
  7. PUCK JENNIFER M. Neonatal screening for severe combined immune deficiency. Current Opinion in Allergy and Clinical Immunology [online] 2007 December, 7(6):522-527 [viewed 19 September 2014] Available from: doi:10.1097/ACI.0b013e3282f14a2a
  8. ADELI M. M., BUCKLEY R. H.. Why Newborn Screening for Severe Combined Immunodeficiency Is Essential: A Case Report. PEDIATRICS [online] December, 126(2):e465-e469 [viewed 19 September 2014] Available from: doi:10.1542/peds.2009-3659
  9. SOMECH R, ETZIONI A. A Call to Include Severe Combined Immunodeficiency in Newborn Screening Program Rambam Maimonides Med J [online] , 5(1):e0001 [viewed 19 September 2014] Available from: doi:10.5041/RMMJ.10135
  10. JANIK D. K., LINDAU-SHEPARD B., COMEAU A. M., PASS K. A.. A Multiplex Immunoassay Using the Guthrie Specimen to Detect T-Cell Deficiencies Including Severe Combined Immunodeficiency Disease. Clinical Chemistry [online] December, 56(9):1460-1465 [viewed 19 September 2014] Available from: doi:10.1373/clinchem.2010.144329

Management - General Measures

Fact Explanation
Patient and parent/ family education Educating the patient and the family about the nature of the condition, and the necessity of adherence to treatments since it's fatal but treatable condition. Here, inheritance of the condition should be stressed enough. [1]
Treat the concurrent infections i.e. with antibacterials, antivirals or antifungals as necessary. 90% of the patients have recurrent infections so prophylaxis is indicated as required. [1, 2, 3, 4, 5, 6]
Respiratory support i.e. high flow oxygen mask, intubation, ventilator as necessary. Adenosine deaminase deficiency causes chronic lung inflammation and insufficiency. [7, 8]
Prophylaxis against Pneumocystis jiroveci With twice weekly trimethoprim-sulfamethoxazole. [1, 9]
Genetic counselling Since ADA deficiency is inherited in an autosomal recessive manner, if two carriers reproduce, at conception, 25% of the offspring has a chance of being affected, 50% chance for being carriers, and 25% chance to being unaffected. [1]
References
  1. HERSHFIELD M, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Adenosine Deaminase Deficiency [online] 1993 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301656
  2. FLEISCHMAN A, HERSHFIELD MS, TOUTAIN S, LEDERMAN HM, SULLIVAN KE, FASANO MB, GREENE J, WINKELSTEIN JA. Adenosine Deaminase Deficiency and Purine Nucleoside Phosphorylase Deficiency in Common Variable Immunodeficiency Clin Diagn Lab Immunol [online] 1998 May, 5(3):399-400 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC104530
  3. Severe Combined Immune Deficiency and Combined Immune Deficiency. [web] [viewed 19 September 2014] Available from: http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/severe-combined-immune-deficiency-and-combined-immune-deficiency/
  4. KUBOTA M. et al. Characterization of an Adenosine Deaminase-deficient Human Histiocytic Lymphoma Cell Line (DHL-9) and Selection of Mutants Deficient in Adenosine Kinase and Deoxycytidine Kinase. Cancer Res [online] 1983;43:2606-2610 [viewed 19 September 2014] Available from: http://cancerres.aacrjournals.org/content/43/6/2606.full.pdf
  5. ARREDONDO-VEGA FRANCISCO X., SANTISTEBAN INES, DANIELS SHANNON, TOUTAIN STEPHAN, HERSHFIELD MICHAEL S.. Adenosine Deaminase Deficiency: Genotype-Phenotype Correlations Based on Expressed Activity of 29 Mutant Alleles. The American Journal of Human Genetics [online] 1998 October, 63(4):1049-1059 [viewed 19 September 2014] Available from: doi:10.1086/302054
  6. OZSAHIN H. et al. Adenosine Deaminase Deficiency in Adults. Blood [online] April 15, 1997: 89 (8). [viewed 19 September 2014] Available from: http://www.bloodjournal.org/content/89/8/2849?sso-checked=true
  7. BLACKBURN MR, KELLEMS RE. Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation. Adv Immunol. [online] 2005;86:1-41. [viewed 19 September 2014] Available from: DOI: 10.1016/S0065-2776(04)86001-2
  8. BLACKBURN MR, VOLMER JB, THRASHER JL, ZHONG H, CROSBY JR, LEE JJ, KELLEMS RE. Metabolic Consequences of Adenosine Deaminase Deficiency in Mice Are Associated with Defects in Alveogenesis, Pulmonary Inflammation, and Airway Obstruction J Exp Med [online] 2000 Jul 17, 192(2):159-170 [viewed 24 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193256
  9. AGRAWAL ANURAG K., CHANG PATRICK P., FEUSNER JAMES. Twice Weekly Pneumocystis jiroveci Pneumonia Prophylaxis With Trimethoprim-Sulfamethoxazole in Pediatric Patients With Acute Lymphoblastic Leukemia. Journal of Pediatric Hematology/Oncology [online] 2011 January, 33(1):e1-e4 [viewed 24 September 2014] Available from: doi:10.1097/MPH.0b013e3181fd6fca

Management - Specific Treatments

Fact Explanation
Bone marrow /stem cell transplantation (BMT/SCT) To restore a functional immune system. [1] The mainstay of treatment. [2, 3, 4] It only partially restores purine metabolites to normal. [5] Harvesting is done usually on an HLA-identical healthy sibling or a close relative. When individuals with ADA-deficient SCID lack an HLA-identical related donor, BMT/SCT from a "non-ideal" donor, which may be an HLA-matched unrelated donor, an HLA-haploidentical donor (usually a parent), or umbilical cord-derived stem cells can be used, [1]
Enzyme therapy Replacing the enzyme deficiency with polyethylene glycol-modified bovine adenosine deaminase. [1, 2, 6]
Gene therapy Periodic infusions of autologous culture-expanded T cells genetically corrected by insertion of a normal ADA gene using retroviral-mediated gene. Still in research level. [7, 8, 9]
References
  1. HERSHFIELD M, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Adenosine Deaminase Deficiency [online] 1993 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301656
  2. BOBBY GASPAR H.. Bone Marrow Transplantation and Alternatives for Adenosine Deaminase Deficiency. Immunology and Allergy Clinics of North America [online] 2010 May, 30(2):221-236 [viewed 24 September 2014] Available from: doi:10.1016/j.iac.2010.01.002
  3. CARBONARO D. A., JIN X., COTOI D., MI T., YU X.-J., SKELTON D. C., DOREY F., KELLEMS R. E., BLACKBURN M. R., KOHN D. B.. Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion. Blood [online] December, 111(12):5745-5754 [viewed 24 September 2014] Available from: doi:10.1182/blood-2007-08-103663
  4. GASPAR H. B., AIUTI A., PORTA F., CANDOTTI F., HERSHFIELD M. S., NOTARANGELO L. D.. How I treat ADA deficiency. Blood [online] December, 114(17):3524-3532 [viewed 24 September 2014] Available from: doi:10.1182/blood-2009-06-189209
  5. HIRSCHHORN R, ROEGNER-MANISCALCO V, KURITSKY L, ROSEN F S. Bone marrow transplantation only partially restores purine metabolites to normal in adenosine deaminase-deficient patients.. J. Clin. Invest. [online] 1981 December, 68(6):1387-1393 [viewed 24 September 2014] Available from: doi:10.1172/JCI110389
  6. CHAN BELINDA, WARA DIANE, BASTIAN JOHN, HERSHFIELD MICHAEL S., BOHNSACK JOHN, AZEN COLLEEN G., PARKMAN ROBERTSON, WEINBERG KENNETH, KOHN DONALD B.. Long-term efficacy of enzyme replacement therapy for Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (SCID). Clinical Immunology [online] 2005 November, 117(2):133-143 [viewed 24 September 2014] Available from: doi:10.1016/j.clim.2005.07.006
  7. DAMMACCO F, PESCE S, DAMMACCO A, ACQUAFREDDA A, CAVALLO T, BAFUNDI N. ARGININE INFUSION FOLLOWED BY ARGININE PLUS GROWTH HORMONE(GH) RELEASING HORMONE ADMINISTRATION: A TEST TO ASSESS GH SECRETION. Pediatr Res [online] 1993 May, 33:S49-S49 [viewed 24 September 2014] Available from: doi:10.1203/00006450-199305001-00278
  8. FERRUA FRANCESCA, BRIGIDA IMMACOLATA, AIUTI ALESSANDRO. Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency. Current Opinion in Allergy and Clinical Immunology [online] 2010 December, 10(6):551-556 [viewed 24 September 2014] Available from: doi:10.1097/ACI.0b013e32833fea85
  9. CANDOTTI F., SHAW K. L., MUUL L., CARBONARO D., SOKOLIC R., CHOI C., SCHURMAN S. H., GARABEDIAN E., KESSERWAN C., JAGADEESH G. J., FU P.-Y., GSCHWENG E., COOPER A., TISDALE J. F., WEINBERG K. I., CROOKS G. M., KAPOOR N., SHAH A., ABDEL-AZIM H., YU X.-J., SMOGORZEWSKA M., WAYNE A. S., ROSENBLATT H. M., DAVIS C. M., HANSON C., RISHI R. G., WANG X., GJERTSON D., YANG O. O., BALAMURUGAN A., BAUER G., IRELAND J. A., ENGEL B. C., PODSAKOFF G. M., HERSHFIELD M. S., BLAESE R. M., PARKMAN R., KOHN D. B.. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood [online] December, 120(18):3635-3646 [viewed 24 September 2014] Available from: doi:10.1182/blood-2012-02-400937