Successful haploidentical stem cell transplantation in a 3-month-old child with reticular dysgenesis using post-transplant cyclophosphamide: A case report & literature review from Pakistan

Successful haploidentical stem cell transplantation in a 3-month-old child with reticular dysgenesis using post-transplant cyclophosphamide: A case report & literature review from Pakistan | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Successful haploidentical stem cell transplantation in a 3-month-old child with reticular dysgenesis using post-transplant cyclophosphamide: A case report & literature review from Pakistan ZAINAB GHIAS, RABAB ZEHRA JAFRI, SHAFAQ SAMAD, SAIMA SIDDIQUI, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3323241/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Reticular dysgenesis is the most severe and rarest form of primary immunodeficiency disorder. Children with severe combined immunodeficiency mainly have lymphopenia. But this rare variant has an additional feature of neutropenia not responding to growth factor. There should be a high index of suspicion for this disease if any infant is presenting with recurrent infections with persistently low myeloid and lymphoid cell lines. A late preterm and low birth weight baby was found to have bi cytopenia incidentally. Presumed sepsis was treated but there was persistent lymphopenia and neutropenia. He had recurrent infections that raised the suspicion of immunodeficiency. He was a product of consanguineous marriage. He was diagnosed with reticular dysgenesis on whole exome sequencing homozygous mutation in mitochondrial AK2 gene variant c.94-2A > G. At 3.5 months of age, he underwent a haploidentical bone marrow transplant using myeloablative conditioning. He had neutrophil and platelet engraftment on post-transplant day + 14 and day + 16 respectively. He maintained full donor chimerism (> 90%) at post-transplant D + 30, + 60 and + 120. Nine months after the transplant his blood counts dropped and he developed severe neutropenia not responding to GCSF. He was given a CD34 booster dose (6.6 x 10^6 cells per kg/recipient body weight). Then eventually his blood count recovered. After, twenty months of transplant, he presented with grade 3 chronic GVHD of nails. At post-transplant 2.5 years both T and B cell immune reconstitution have been achieved with full donor chimerism. Any child with repeated infections and combination of lymphopenia and neutropenia should have high index of suspicion for reticular dysgenesis. Reticular dysgenesis haploidentical transplant post-transplant cyclophosphamide case report Figures Figure 1 INTRODUCTION Severe combined immunodeficiency (SCID) is a pediatric emergency. Reticular dysgenesis is a rare and unique variety of SCID, comprising less than 2% of cases. ( 1 ) It results from the mitochondrial dysfunction of the adenylate kinase AK2 gene located on the 1p5.1 locus. Patients present with agranulocytosis, lymphopenia, and sensorineural hearing loss ( 2 ) the only curative treatment for this otherwise fatal condition is a bone marrow transplant. ( 3 , 4 ). Suitable donor selection is very critical and every effort should be made to expedite the patient for bone marrow transplant. CASE PRESENTATION 3.5 months-old baby boy with a primary diagnosis of Reticular Dysgenesis was referred to our hospital for a haploidentical bone marrow transplant. He was a late preterm (36 weeks) born to a primigravida with uneventful pregnancy. However, mother’s third-trimester growth scans revealed intrauterine growth restriction and marked pericardial effusion. A fetal echocardiogram was performed, which showed normal cardiac functions. He was born through an elective cesarean section due to placental insufficiency. His birth weight was 2 kg (low birth weight/ intrauterine growth restriction) and he was born with good APGARS. After birth, he was kept in the nursery for observation. A complete blood count was performed, which revealed severe leukopenia with agranulocytosis, lymphopenia, and thrombocytopenia, Table 1 . Septic workup was sent and he was treated in the lines of presumed sepsis. After antibiotic course his blood counts did not recover and all his cultures were negative. Hence there was a high index of suspicion for immunodeficiency. He was given escalating doses of GCSF but remained unresponsive. He was not vaccinated and his mother's feed was discontinued after a month as advised by the infectious disease team, as she was positive for CMV IgG. Intravenous immunoglobulin and pentamidine prophylaxis were given. He was the first child of consanguineous marriage and there was no family history of immunodeficiency. Socioeconomic history was fair. Table 1 Hematological Findings: Hb 13 BUN 7.4mmol/L Tot bili 29.4micm/L CPK 100 TLC 0.2 Cr 140micm/L Direct 20micm/L Homocysteine normal Neut 12% Na 132 Alkphos 282 IU/L Coombs negative Lympho 50% K 4.2 GammaGT 192 IU/L G6PD Not def ANC 0.06 Cl 98 SGPT 10 CMV DNA Negative PLT 115 HCO3 14 SGOT 15 CMV IgG Positive Retic 0.8% Anion Gap 18 Albumin 3.7 CMV IgM Negative EBV DNA by PCR, Anti-HIV, Parvovirus, and Coxsackie virus were all negative. Lymphocyte subset analysis showed absent T, B, and NK cells. Immunoglobulin IgG was also low. Eye examination showed bilateral optic disc pallor, right optic nerve smaller than left most likely secondary to persistent hyaloid artery. Table 2 Radiological Findings: Chest x-ray and ultrasound absent thymic shadow Ultrasonography of the head normal midline structures Ultrasound KUB Mild to moderate hydronephrosis and presence of right non-communicating hydrocoele. Bone marrow biopsy Reversed M: E ratio, along with relative erythroid hyperplasia, karyorrhexis, and mild megaloblastic changes. Myeloid elements were profoundly decreased and showed maturation arrest at the promyelocyte stage with an absence of neutrophilic granulocytes. Cytogenetics normal male karyotype 46XY FISH for lymphoblastic leukemia panel Negative Molecular studies Normal Whole Exon Sequencing homozygous mutation (loss of function) of AK2 gene variant c.94-2A > G (pathogenic variants in the AK2 gene). When the child presented in our BMT unit, he was a failure-to-thrive child, weighing 3.4 kg, length of 52 cm, and frontal occipital circumference of 35 cm with all growth parameters below the third centile. On abdominal examination, his liver and spleen were three fingers palpable below the right and left costal margins respectively. Table 2 : A right hydrocele was present. The rest of the systemic examination was unremarkable. He was planned for a haploidentical stem cell transplant (5/10) with his donor (father). The blood group of the child was B negative and the donor's blood group was O positive. Conditioning consisted of injection of thymoglobulin (2.5mg/kg/day) for 4 days, injection of fludarabine 30mg/m2 for 4 days, and oral Busulfan 3.5mg/kg/day for 4 days. Post-transplant GVHD prophylaxis consisted of cyclophosphamide 50mg/kg/day on days + 3 & +4, mycophenolate mofetil (600 mg/m2) and tacrolimus (0.15 mg/kg/day) added on day + 5. A hematopoietic stem cell transplant was done on Thursday 3rd December 2020 . The stem cell source was peripheral blood stem cells. Product Volume was 194 ml with an HPC count of 92.1x 10 3 /microliter per kg of recipient weight, MNC 87.41 X 10 8 /kg body weight of the recipient, and CD34 was 10.5 x 10^6 cells/kg body weight of recipient. Tacrolimus levels were measured once weekly. During his stay in BMTU, on D + 6 he became sick and irritable, although afebrile, septic workup was sent and tazobactam and amikacin were started. On D + 11 he had a fever spike, hence antibiotic escalated to meropenem which was discontinued after pan cultures were negative. Neutrophil engraftment was achieved on day + 14, and platelet engraftment on day + 16. On day + 21, his metabolic profile was deranged. He developed hyponatremia, hyperkalemia, and normal anion gap metabolic acidosis. It was most likely drug-induced and tacrolimus was temporarily discontinued. On day + 22, the biochemistry profile showed persistent high anion gap metabolic acidosis, most likely due to isoniazid, which was subsequently stopped. BKV was Negative. On day + 30, lymphocyte subset analysis revealed the following: CD3 + cells were 1114 cells/mic L(73%), CD 4 + cells were 493 cells/mic L( 33%), CD 8 + cells were550 cells/mic L( 37%), NK cells were 361 cells/mic L(23%) and B cells were 21 cells/mic L(1%). Donor Chimerism has been more than 90% throughout his post-transplant period. He was admitted twice, once on day + 43 for a lower respiratory tract infection which was managed with antibiotics and inhalers. His second admission was on day + 103 with suspected gut GVHD, which turned out to be an infective etiology. Figure 1 His Brainstem auditory evoked potential was done four months post-transplant, which revealed a severe bilateral sensorineural hearing defect. His successful cochlear implantation was done 18 months after transplant after which his hearing is remarkably improved. Nine months after the transplant his blood counts dropped and he developed severe neutropenia not responding to GCSF. He was given a CD34 booster dose (6.6 x 10^6 cells per kg/recipient body weight). Then eventually his blood count recovered. After twenty months of transplant, he presented with grade 3 chronic GVHD of nails.(Fig. 1 ) It was initially treated with cyclosporine 25 mg BD and mycophenolate mofetil 30 mg BD were added. Later on, ruxolitinib was started with the local application of steroid and tacrolimus creams. Currently, he is Two years and three months post-transplant he is well thriving and active child with age-appropriate growth parameters. His post-transplant donor chimerism at 2 years is more than 90%. Both T and B cell immune reconstitution has been achieved. Table 3 : His current T cell subset analysis is as follows Table 3 Subset analysis Lymphocytes 3.1x10^9/L CD 8 T cell % 21.2% CD 3 Tcell 2.6121x10^9/L CD 19 B cell 0.4x10^9/L CD 3 Tcell% 80.2% CD 19 B cell % 15% CD 4 Tcell 1.2x10^9/L NK Cell 0.12x10^9/L CD 4 Tcell % 47% NK Cell % 5% CD 8 Tcell 0.53x10^9/L CD 4/ CD 8 2.2x10^9/L DISCUSSION Reticular dysgenesis, the rarest form of SCID, is a unique clinical entity incompatible with life without an allogeneic bone marrow transplant. ( 5 ) It is characterized by a combination of lymphopenia and neutropenia with variable degrees of anemia and thrombocytopenia in more than 50% of cases. There is limited retrospective data of 32 patients available regarding the disease spectrum and transplant outcome in patients with reticular dysgenesis across the globe over thirty years from 1982 to 2011. ( 6 ) Since then, there has been a paucity of data for the last ten years which is a major limitation. Agranulocytosis is accountable for the lethal nature of this disease. Overwhelming sepsis due to bacterial infections is the major culprit of the life-threatening state and very early death. Opportunistic infections like Pneumocystis jiroveci pneumonia or systemic infections with cytomegalovirus are mostly uncommon in children with reticular dysgenesis. ( 6 ) Our patient also encountered Pseudomonas sepsis at two months of age which was adequately treated with broad-spectrum antibiotics. Reticular dysgenesis is associated with children who are born prematurely and are small for gestational age and low birth weight. ( 7 ) Our child was late preterm (36 weeks), with intrauterine growth restriction (IUGR) and a low birth weight of 2 kg. This suggests that AK2 deficiency may cause in-utero fetal distress leading to premature birth. The success of the transplant of reticular dysgenesis lies in the fact that they require both immune reconstitutions of the myeloid as well as the lymphoid components. Conditioning and alloreactive donor T cells are important factors promoting stem cell engraftment. Conditioning with a myeloablative regimen is the key to a successful transplant. ( 8 ) After conditioning with busulfan, no graft failure was reported with T cell-replete grafts. Busulfan has shown effectiveness in combination with cyclophosphamide. Rapid T cell reconstitution is beneficial to treat viral and fungal infections and delayed T cell reconstitution after haploidentical transplant is a major disadvantage. Early and timely neutrophil engraftment is critical in overcoming bacterial infections. ( 9 ) For benign diseases, unaffected HLA-matched sibling donors and bone marrow harvesting are the gold standards. However, matched unrelated donors result in the lowest rate of graft failure for non-malignant diseases. ( 7 ) T cell depletion in mismatched related donors used to be an important aspect to overcome the HLA barrier until the advent of post-transplant cyclophosphamide. There is a paucity of data for post-transplant cyclophosphamide in haploidentical transplants in patients with primary immunodeficiency disorders. To the best of our knowledge, our case is the first one to receive post-transplant cyclophosphamide in haploidentical reticular dysgenesis. However, this new approach of T cell graft repletion with post-transplant cyclophosphamide is now a standard of care in haploidentical transplants. ( 9 , 10 ) Furthermore, a non-hematological manifestation of the disease is sensorineural hearing loss. ( 10 ) The molecular pathology is still unclear. Cochlear implants correct hearing disability. Hearing impairment is virtually always present in all cases of Reticular dysgenesis. Before the transplant hearing assessment of our child could not be assessed. Four months after the transplant brainstem auditory evoked potential (BAEP) was done that revealed bilateral severe sensorineural hearing loss. His bilateral cochlear implant has been successfully done and his hearing is markedly improved. It has been two years after the hematopoietic stem cell transplant and his graft is maintained quite well with the issue of skin GVHD under good control on ruxolitinib. There is a paucity of these cases in the literature and to the best of our knowledge this is the first-ever diagnosed case of Reticular dysgenesis that has survived two years after a successful haploidentical stem cell transplant. Many children with reticular dysgenesis develop fulminant sepsis and succumb to death without being diagnosed due to limitations of resources and the unavailability of genetic testing like whole genome sequencing and next-generation sequencing. Therefore, any sick neonate or infant with a combination of neutropenia and lymphopenia should have a high clinical suspicion of reticular dysgenesis. Every possible effort should be made to exclude the diagnosis. We require a longer follow-up to document the complete recovery of the disease. PATIENTS PERSPECTIVE Since our patient is a little child, his parents and grandparents are very grateful and ever thankful for well management of the challenging bone marrow transplant of this rare disease. They had lots of reservations and apprehensions in the beginning. But as the transplant progressed, all his events were managed pre-emptively and in a skillful manner. Undoubtedly it was an overwhelming and everlasting learning experience for the entire team. Declarations Consent for publication: Informed written consent was obtained from the parent of the child to publish the information and image in an online open-access publication. Ethical Approval Our Institution doesn’t require IRB for Case reports: Competing interests No conflict of interest. Authors' contributions ZAINAB GHIAS Chief contributor and final compilation of case report according to CARE checklist. RABAB JAFRI Tabulation, images and formatting of al laboratory workup SHAFAQ SAMAD Management of the hematopoietic stem cell transplantation and post-transplant care SAIMA MUNZIR Genetic workup (NGS) panel of Primary Immunodeficiency disease TASNEEM FARZANA Management of the hematopoietic stem cell transplantation and post-transplant care UZMA ZAIDI Management of the hematopoietic stem cell transplantation and post-transplant care Funding No funding was accessed for this article. Availability of data and materials: The data of the current study available from the corresponding author on reasonable request. References Hoenig M, Lagresle-Peyrou C, Pannicke U, Notarangelo LD, Porta F, Gennery AR, Slatter M, Cowan MJ, Stepensky P, Al-Mousa H, Al-Zahrani D. Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome. Blood, The Journal of the American Society of Hematology. 2017 May 25;129(21):2928-38. Small TN, Wall DA, Kurtzberg J, Cowan MJ, O’Reilly RJ, Friedrich W. Association of reticular dysgenesis (thymic alymphoplasia and congenital aleukocytosis) with bilateral sensorineural deafness. The Journal of pediatrics. 1999 Sep 1;135(3):387-9. De Santes KB, Lai SS, Cowan MJ. Haploidentical bone marrow transplants for two patients with reticular dysgenesis. Bone marrow transplantation. 1996 Jun 1;17(6):1171-3. Friedrich W, Goldmann SF, Ebell W, Blütters-Sawatzki R, Gaedicke G, Raghavachar A, Peter HH, Belohradsky B, Kreth W, Kubanek B, Kleihauer E. Severe combined immunodeficiency: treatment by bone marrow transplantation in 15 infants using HLA-haploidentical donors. European journal of pediatrics. 1985 Jul;144:125-30. Levinsky R, Tiedeman K. Successful bone-marrow transplantation for reticular dysgenesis. The Lancet. 1983 Mar 26;321(8326):671-3. Stephan JL, Vlekova V, Le Deist F, Blanche S, Donadieu J, De Saint-Basile G, Durandy A, Griscelli C, Fischer A. Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. The Journal of pediatrics. 1993 Oct 1;123(4):564-72. Kwan A, Puck JM. History and current status of newborn screening for severe combined immunodeficiency. InSeminars in perinatology 2015 Apr 1 (Vol. 39, No. 3, pp. 194-205). WB Saunders. Rissone A, Weinacht KG, la Marca G, Bishop K, Giocaliere E, Jagadeesh J, Felgentreff K, Dobbs K, Al-Herz W, Jones M, Chandrasekharappa S. Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress. Journal of Experimental Medicine. 2015 Jul 27;212(8):1185-202. Six E, Lagresle-Peyrou C, Susini S, De Chappedelaine C, Sigrist N, Sadek H, Chouteau M, Cagnard N, Fontenay M, Hermine O, Chomienne C. AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages. Cell Death & Disease. 2015 Aug;6(8):e1856-. Lagresle-Peyrou C, Six EM, Picard C, Rieux-Laucat F, Michel V, Ditadi A, Chappedelaine CD, Morillon E, Valensi F, Simon-Stoos KL, Mullikin JC. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nature genetics. 2009 Jan;41(1):106-11. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3323241","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":237112245,"identity":"4237511b-4d74-4b56-9fbb-3918962bb1ad","order_by":0,"name":"ZAINAB GHIAS","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYDCCA0CcAEISIIaNDQOYQYKWtDQitTDAtDCkHSashe/28YcfHu6wy5Of3fzsw4OE84n9s5sPPmCosYnGpUXyXEKyROKZ5GKDO8eMZyQk3E6ccedYsgHDsbTcBhxaDM4wHJBIbGNO3CCRYMyQ+ON2YsONHDMJxobDeLQwNv9IbKtPnD8j/TNDQsK5xPmEtTCzAW05DDLcGKjlQOIGQlokz7CxWSS2HS82uJFTDNSSbLzxRlqyQQIev/CdYX9882dbdZ78jPTNjD8S7GTn3Ug++OBDjQ1OLRjAEawygVjlIGBPiuJRMApGwSgYGQAA1gxkLeliVPAAAAAASUVORK5CYII=","orcid":"","institution":"National Institute Of Blood Disease and Bone Marrow Transplantation","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"ZAINAB","middleName":"","lastName":"GHIAS","suffix":""},{"id":237112246,"identity":"59e9b729-dda4-450f-b1d9-56037a8e74d2","order_by":1,"name":"RABAB ZEHRA JAFRI","email":"","orcid":"","institution":"Aga Khan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"RABAB","middleName":"ZEHRA","lastName":"JAFRI","suffix":""},{"id":237112247,"identity":"ce0d476f-6bcc-425d-ae2b-9de759ac8bb3","order_by":2,"name":"SHAFAQ SAMAD","email":"","orcid":"","institution":"National Institute Of Blood Disease and Bone Marrow Transplantation","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"SHAFAQ","middleName":"","lastName":"SAMAD","suffix":""},{"id":237112248,"identity":"e349963c-f30f-4a98-b305-05b24d78d251","order_by":3,"name":"SAIMA SIDDIQUI","email":"","orcid":"","institution":"National Institute Of Blood Disease and Bone Marrow Transplantation","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"SAIMA","middleName":"","lastName":"SIDDIQUI","suffix":""},{"id":237112249,"identity":"145c3043-2da8-461f-a3a2-a89390d3353b","order_by":4,"name":"TASNEEM FARZANA","email":"","orcid":"","institution":"National Institute Of Blood Disease and Bone Marrow Transplantation","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"TASNEEM","middleName":"","lastName":"FARZANA","suffix":""},{"id":237112250,"identity":"fc70dfd2-8d3e-4945-b23d-eabb3fcc8516","order_by":5,"name":"UZMA ZAIDI","email":"","orcid":"","institution":"National Institute Of Blood Disease and Bone Marrow Transplantation","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"UZMA","middleName":"","lastName":"ZAIDI","suffix":""}],"badges":[],"createdAt":"2023-09-04 06:59:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3323241/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3323241/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":44213471,"identity":"bcd0d915-33d5-4407-9d1d-258042af0a90","added_by":"auto","created_at":"2023-10-06 21:06:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2971614,"visible":true,"origin":"","legend":"\u003cp\u003eChronic nail GVHD\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3323241/v1/0aab2593edbc01226b2bd6ec.png"},{"id":68851003,"identity":"2a702a48-9419-4c9c-bd4a-14370de9f39c","added_by":"auto","created_at":"2024-11-12 17:16:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3163687,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3323241/v1/d886f9e9-7ee5-43ec-b982-6c1e619f2cb9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSuccessful haploidentical stem cell transplantation in a 3-month-old child with reticular dysgenesis using post-transplant cyclophosphamide: A case report \u0026amp; literature review from Pakistan\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSevere combined immunodeficiency (SCID) is a pediatric emergency. Reticular dysgenesis is a rare and unique variety of SCID, comprising less than 2% of cases. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIt results from the mitochondrial dysfunction of the adenylate kinase AK2 gene located on the 1p5.1 locus. Patients present with agranulocytosis, lymphopenia, and sensorineural hearing loss (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) the only curative treatment for this otherwise fatal condition is a bone marrow transplant. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Suitable donor selection is very critical and every effort should be made to expedite the patient for bone marrow transplant.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003e3.5 months-old baby boy with a primary diagnosis of Reticular Dysgenesis was referred to our hospital for a haploidentical bone marrow transplant.\u003c/p\u003e \u003cp\u003eHe was a late preterm (36 weeks) born to a primigravida with uneventful pregnancy. However, mother\u0026rsquo;s third-trimester growth scans revealed intrauterine growth restriction and marked pericardial effusion. A fetal echocardiogram was performed, which showed normal cardiac functions. He was born through an elective cesarean section due to placental insufficiency. His birth weight was 2 kg (low birth weight/ intrauterine growth restriction) and he was born with good APGARS.\u003c/p\u003e \u003cp\u003eAfter birth, he was kept in the nursery for observation. A complete blood count was performed, which revealed severe leukopenia with agranulocytosis, lymphopenia, and thrombocytopenia, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Septic workup was sent and he was treated in the lines of presumed sepsis. After antibiotic course his blood counts did not recover and all his cultures were negative. Hence there was a high index of suspicion for immunodeficiency. He was given escalating doses of GCSF but remained unresponsive. He was not vaccinated and his mother's feed was discontinued after a month as advised by the infectious disease team, as she was positive for CMV IgG. Intravenous immunoglobulin and pentamidine prophylaxis were given.\u003c/p\u003e \u003cp\u003eHe was the first child of consanguineous marriage and there was no family history of immunodeficiency. Socioeconomic history was fair.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHematological Findings:\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBUN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.4mmol/L\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTot bili\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29.4micm/L\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCPK\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e140micm/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDirect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20micm/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHomocysteine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003enormal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAlkphos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e282 IU/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCoombs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLympho\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGammaGT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e192 IU/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eG6PD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNot def\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eANC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSGPT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCMV DNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHCO3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSGOT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCMV IgG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRetic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnion Gap\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAlbumin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCMV IgM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eEBV DNA by PCR, Anti-HIV, Parvovirus, and Coxsackie virus were all negative. Lymphocyte subset analysis showed absent T, B, and NK cells. Immunoglobulin IgG was also low. Eye examination showed bilateral optic disc pallor, right optic nerve smaller than left most likely secondary to persistent hyaloid artery.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRadiological Findings:\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChest x-ray and ultrasound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eabsent thymic shadow\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUltrasonography of the head\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003enormal midline structures\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUltrasound KUB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMild to moderate hydronephrosis and presence of right non-communicating hydrocoele.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReversed M: E ratio, along with relative erythroid hyperplasia, karyorrhexis, and mild megaloblastic changes. Myeloid elements were profoundly decreased and showed maturation arrest at the promyelocyte stage with an absence of neutrophilic granulocytes.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytogenetics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003enormal male karyotype 46XY\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFISH for lymphoblastic leukemia panel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular studies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhole Exon Sequencing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ehomozygous mutation (loss of function) of AK2 gene variant c.94-2A\u0026thinsp;\u0026gt;\u0026thinsp;G (pathogenic variants in the AK2 gene).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhen the child presented in our BMT unit, he was a failure-to-thrive child, weighing 3.4 kg, length of 52 cm, and frontal occipital circumference of 35 cm with all growth parameters below the third centile. On abdominal examination, his liver and spleen were three fingers palpable below the right and left costal margins respectively. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e: A right hydrocele was present. The rest of the systemic examination was unremarkable.\u003c/p\u003e \u003cp\u003eHe was planned for a haploidentical stem cell transplant (5/10) with his donor (father). The blood group of the child was B negative and the donor's blood group was O positive. Conditioning consisted of injection of thymoglobulin (2.5mg/kg/day) for 4 days, injection of fludarabine 30mg/m2 for 4 days, and oral Busulfan 3.5mg/kg/day for 4 days. Post-transplant GVHD prophylaxis consisted of cyclophosphamide 50mg/kg/day on days\u0026thinsp;+\u0026thinsp;3 \u0026amp; +4, mycophenolate mofetil (600 mg/m2) and tacrolimus (0.15 mg/kg/day) added on day\u0026thinsp;+\u0026thinsp;5.\u003c/p\u003e \u003cp\u003e \u003cb\u003eA hematopoietic stem cell transplant was done on Thursday 3rd December 2020\u003c/b\u003e. The stem cell source was peripheral blood stem cells. Product Volume was 194 ml with an HPC count of 92.1x 10\u003csup\u003e3\u003c/sup\u003e/microliter per kg of recipient weight, MNC 87.41 X 10\u003csup\u003e8\u003c/sup\u003e /kg body weight of the recipient, and CD34 was 10.5 x 10^6 cells/kg body weight of recipient. Tacrolimus levels were measured once weekly. During his stay in BMTU, on D\u0026thinsp;+\u0026thinsp;6 he became sick and irritable, although afebrile, septic workup was sent and tazobactam and amikacin were started. On D\u0026thinsp;+\u0026thinsp;11 he had a fever spike, hence antibiotic escalated to meropenem which was discontinued after pan cultures were negative. Neutrophil engraftment was achieved on day\u0026thinsp;+\u0026thinsp;14, and platelet engraftment on day\u0026thinsp;+\u0026thinsp;16. On day\u0026thinsp;+\u0026thinsp;21, his metabolic profile was deranged. He developed hyponatremia, hyperkalemia, and normal anion gap metabolic acidosis. It was most likely drug-induced and tacrolimus was temporarily discontinued. On day\u0026thinsp;+\u0026thinsp;22, the biochemistry profile showed persistent high anion gap metabolic acidosis, most likely due to isoniazid, which was subsequently stopped. BKV was Negative.\u003c/p\u003e \u003cp\u003eOn day\u0026thinsp;+\u0026thinsp;30, lymphocyte subset analysis revealed the following:\u003c/p\u003e \u003cp\u003eCD3\u0026thinsp;+\u0026thinsp;cells were 1114 cells/mic L(73%), CD 4\u0026thinsp;+\u0026thinsp;cells were 493 cells/mic L( 33%), CD 8\u0026thinsp;+\u0026thinsp;cells were550 cells/mic L( 37%), NK cells were 361 cells/mic L(23%) and B cells were 21 cells/mic L(1%). Donor Chimerism has been more than 90% throughout his post-transplant period.\u003c/p\u003e \u003cp\u003eHe was admitted twice, once on day\u0026thinsp;+\u0026thinsp;43 for a lower respiratory tract infection which was managed with antibiotics and inhalers. His second admission was on day\u0026thinsp;+\u0026thinsp;103 with suspected gut GVHD, which turned out to be an infective etiology. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003c/p\u003e \u003cp\u003eHis Brainstem auditory evoked potential was done four months post-transplant, which revealed a severe bilateral sensorineural hearing defect. His successful cochlear implantation was done 18 months after transplant after which his hearing is remarkably improved.\u003c/p\u003e \u003cp\u003eNine months after the transplant his blood counts dropped and he developed severe neutropenia not responding to GCSF. He was given a CD34 booster dose (6.6 x 10^6 cells per kg/recipient body weight). Then eventually his blood count recovered.\u003c/p\u003e \u003cp\u003eAfter twenty months of transplant, he presented with grade 3 chronic GVHD of nails.(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) It was initially treated with cyclosporine 25 mg BD and mycophenolate mofetil 30 mg BD were added. Later on, ruxolitinib was started with the local application of steroid and tacrolimus creams. Currently, he is Two years and three months post-transplant he is well thriving and active child with age-appropriate growth parameters. His post-transplant donor chimerism at 2 years is more than 90%. Both T and B cell immune reconstitution has been achieved. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e:\u003c/p\u003e \u003cp\u003eHis current T cell subset analysis is as follows\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubset analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocytes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.1x10^9/L\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCD 8 T cell %\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.2%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD 3 Tcell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.6121x10^9/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCD 19 B cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.4x10^9/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD 3 Tcell%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCD 19 B cell %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD 4 Tcell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2x10^9/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNK Cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.12x10^9/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD 4 Tcell %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNK Cell %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD 8 Tcell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.53x10^9/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCD 4/ CD 8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.2x10^9/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eReticular dysgenesis, the rarest form of SCID, is a unique clinical entity incompatible with life without an allogeneic bone marrow transplant. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) It is characterized by a combination of lymphopenia and neutropenia with variable degrees of anemia and thrombocytopenia in more than 50% of cases. There is limited retrospective data of 32 patients available regarding the disease spectrum and transplant outcome in patients with reticular dysgenesis across the globe over thirty years from 1982 to 2011. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Since then, there has been a paucity of data for the last ten years which is a major limitation.\u003c/p\u003e \u003cp\u003eAgranulocytosis is accountable for the lethal nature of this disease. Overwhelming sepsis due to bacterial infections is the major culprit of the life-threatening state and very early death. Opportunistic infections like Pneumocystis jiroveci pneumonia or systemic infections with cytomegalovirus are mostly uncommon in children with reticular dysgenesis. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Our patient also encountered Pseudomonas sepsis at two months of age which was adequately treated with broad-spectrum antibiotics.\u003c/p\u003e \u003cp\u003eReticular dysgenesis is associated with children who are born prematurely and are small for gestational age and low birth weight. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Our child was late preterm (36 weeks), with intrauterine growth restriction (IUGR) and a low birth weight of 2 kg. This suggests that AK2 deficiency may cause in-utero fetal distress leading to premature birth.\u003c/p\u003e \u003cp\u003eThe success of the transplant of reticular dysgenesis lies in the fact that they require both immune reconstitutions of the myeloid as well as the lymphoid components. Conditioning and alloreactive donor T cells are important factors promoting stem cell engraftment. Conditioning with a myeloablative regimen is the key to a successful transplant. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) After conditioning with busulfan, no graft failure was reported with T cell-replete grafts. Busulfan has shown effectiveness in combination with cyclophosphamide. Rapid T cell reconstitution is beneficial to treat viral and fungal infections and delayed T cell reconstitution after haploidentical transplant is a major disadvantage. Early and timely neutrophil engraftment is critical in overcoming bacterial infections. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eFor benign diseases, unaffected HLA-matched sibling donors and bone marrow harvesting are the gold standards. However, matched unrelated donors result in the lowest rate of graft failure for non-malignant diseases. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) T cell depletion in mismatched related donors used to be an important aspect to overcome the HLA barrier until the advent of post-transplant cyclophosphamide. There is a paucity of data for post-transplant cyclophosphamide in haploidentical transplants in patients with primary immunodeficiency disorders. To the best of our knowledge, our case is the first one to receive post-transplant cyclophosphamide in haploidentical reticular dysgenesis. However, this new approach of T cell graft repletion with post-transplant cyclophosphamide is now a standard of care in haploidentical transplants. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eFurthermore, a non-hematological manifestation of the disease is sensorineural hearing loss. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) The molecular pathology is still unclear. Cochlear implants correct hearing disability. Hearing impairment is virtually always present in all cases of Reticular dysgenesis. Before the transplant hearing assessment of our child could not be assessed. Four months after the transplant brainstem auditory evoked potential (BAEP) was done that revealed bilateral severe sensorineural hearing loss. His bilateral cochlear implant has been successfully done and his hearing is markedly improved. It has been two years after the hematopoietic stem cell transplant and his graft is maintained quite well with the issue of skin GVHD under good control on ruxolitinib. There is a paucity of these cases in the literature and to the best of our knowledge this is the first-ever diagnosed case of Reticular dysgenesis that has survived two years after a successful haploidentical stem cell transplant.\u003c/p\u003e \u003cp\u003eMany children with reticular dysgenesis develop fulminant sepsis and succumb to death without being diagnosed due to limitations of resources and the unavailability of genetic testing like whole genome sequencing and next-generation sequencing. Therefore, any sick neonate or infant with a combination of neutropenia and lymphopenia should have a high clinical suspicion of reticular dysgenesis. Every possible effort should be made to exclude the diagnosis. We require a longer follow-up to document the complete recovery of the disease.\u003c/p\u003e"},{"header":"PATIENTS PERSPECTIVE","content":"\u003cp\u003eSince our patient is a little child, his parents and grandparents are very grateful and ever thankful for well management of the challenging bone marrow transplant of this rare disease. They had lots of reservations and apprehensions in the beginning. But as the transplant progressed, all his events were managed pre-emptively and in a skillful manner. Undoubtedly it was an overwhelming and everlasting learning experience for the entire team.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConsent for publication:\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003eInformed written consent was obtained from the parent of the child to publish the information and image in an online open-access publication.\u003cbr\u003e\u003cbr\u003e\u0026nbsp;Ethical Approval\u003cbr\u003e\u003cbr\u003eOur Institution doesn\u0026rsquo;t require IRB for Case reports:\u003cbr\u003e\u003cbr\u003eCompeting interests\u003cbr\u003e\u003cbr\u003eNo conflict of interest.\u003cbr\u003e\u003cbr\u003eAuthors\u0026apos; contributions\u003cbr\u003e\u003cbr\u003eZAINAB GHIAS\u003c/p\u003e\n\u003cp\u003eChief contributor and final compilation of case report according to CARE checklist.\u003c/p\u003e\n\u003cp\u003eRABAB JAFRI\u003c/p\u003e\n\u003cp\u003eTabulation, images and formatting of al laboratory workup\u003c/p\u003e\n\u003cp\u003eSHAFAQ SAMAD\u003c/p\u003e\n\u003cp\u003eManagement of the hematopoietic stem cell transplantation and post-transplant care\u003c/p\u003e\n\u003cp\u003eSAIMA MUNZIR\u003c/p\u003e\n\u003cp\u003eGenetic workup (NGS) panel of Primary Immunodeficiency disease\u003c/p\u003e\n\u003cp\u003eTASNEEM FARZANA\u003c/p\u003e\n\u003cp\u003eManagement of the hematopoietic stem cell transplantation and post-transplant care\u003c/p\u003e\n\u003cp\u003eUZMA ZAIDI\u003c/p\u003e\n\u003cp\u003eManagement of the hematopoietic stem cell transplantation and post-transplant care\u003c/p\u003e\n\u003cp\u003eFunding\u003cbr\u003e\u003cbr\u003eNo funding was accessed for this article.\u003cbr\u003e\u003cbr\u003eAvailability of data and materials:\u003cbr\u003e\u003cbr\u003eThe data of the current study available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHoenig M, Lagresle-Peyrou C, Pannicke U, Notarangelo LD, Porta F, Gennery AR, Slatter M, Cowan MJ, Stepensky P, Al-Mousa H, Al-Zahrani D. Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome. Blood, The Journal of the American Society of Hematology. 2017 May 25;129(21):2928-38.\u003c/li\u003e\n \u003cli\u003eSmall TN, Wall DA, Kurtzberg J, Cowan MJ, O\u0026rsquo;Reilly RJ, Friedrich W. Association of reticular dysgenesis (thymic alymphoplasia and congenital aleukocytosis) with bilateral sensorineural deafness. The Journal of pediatrics. 1999 Sep 1;135(3):387-9.\u003c/li\u003e\n \u003cli\u003eDe Santes KB, Lai SS, Cowan MJ. Haploidentical bone marrow transplants for two patients with reticular dysgenesis. Bone marrow transplantation. 1996 Jun 1;17(6):1171-3.\u003c/li\u003e\n \u003cli\u003eFriedrich W, Goldmann SF, Ebell W, Bl\u0026uuml;tters-Sawatzki R, Gaedicke G, Raghavachar A, Peter HH, Belohradsky B, Kreth W, Kubanek B, Kleihauer E. Severe combined immunodeficiency: treatment by bone marrow transplantation in 15 infants using HLA-haploidentical donors. European journal of pediatrics. 1985 Jul;144:125-30.\u003c/li\u003e\n \u003cli\u003eLevinsky R, Tiedeman K. Successful bone-marrow transplantation for reticular dysgenesis. The Lancet. 1983 Mar 26;321(8326):671-3.\u003c/li\u003e\n \u003cli\u003eStephan JL, Vlekova V, Le Deist F, Blanche S, Donadieu J, De Saint-Basile G, Durandy A, Griscelli C, Fischer A. Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. The Journal of pediatrics. 1993 Oct 1;123(4):564-72.\u003c/li\u003e\n \u003cli\u003eKwan A, Puck JM. History and current status of newborn screening for severe combined immunodeficiency. InSeminars in perinatology 2015 Apr 1 (Vol. 39, No. 3, pp. 194-205). WB Saunders.\u003c/li\u003e\n \u003cli\u003eRissone A, Weinacht KG, la Marca G, Bishop K, Giocaliere E, Jagadeesh J, Felgentreff K, Dobbs K, Al-Herz W, Jones M, Chandrasekharappa S. Reticular dysgenesis\u0026ndash;associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress. Journal of Experimental Medicine. 2015 Jul 27;212(8):1185-202.\u003c/li\u003e\n \u003cli\u003eSix E, Lagresle-Peyrou C, Susini S, De Chappedelaine C, Sigrist N, Sadek H, Chouteau M, Cagnard N, Fontenay M, Hermine O, Chomienne C. AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages. Cell Death \u0026amp; Disease. 2015 Aug;6(8):e1856-.\u003c/li\u003e\n \u003cli\u003eLagresle-Peyrou C, Six EM, Picard C, Rieux-Laucat F, Michel V, Ditadi A, Chappedelaine CD, Morillon E, Valensi F, Simon-Stoos KL, Mullikin JC. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nature genetics. 2009 Jan;41(1):106-11.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Reticular dysgenesis, haploidentical transplant, post-transplant cyclophosphamide, case report","lastPublishedDoi":"10.21203/rs.3.rs-3323241/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3323241/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eReticular dysgenesis is the most severe and rarest form of primary immunodeficiency disorder. Children with severe combined immunodeficiency mainly have lymphopenia. But this rare variant has an additional feature of neutropenia not responding to growth factor. There should be a high index of suspicion for this disease if any infant is presenting with recurrent infections with persistently low myeloid and lymphoid cell lines. A late preterm and low birth weight baby was found to have bi cytopenia incidentally. Presumed sepsis was treated but there was persistent lymphopenia and neutropenia. He had recurrent infections that raised the suspicion of immunodeficiency. He was a product of consanguineous marriage. He was diagnosed with reticular dysgenesis on whole exome sequencing homozygous mutation in mitochondrial AK2 gene variant c.94-2A\u0026thinsp;\u0026gt;\u0026thinsp;G. At 3.5 months of age, he underwent a haploidentical bone marrow transplant using myeloablative conditioning. He had neutrophil and platelet engraftment on post-transplant day\u0026thinsp;+\u0026thinsp;14 and day\u0026thinsp;+\u0026thinsp;16 respectively. He maintained full donor chimerism (\u0026gt;\u0026thinsp;90%) at post-transplant D\u0026thinsp;+\u0026thinsp;30, +\u0026thinsp;60 and +\u0026thinsp;120. Nine months after the transplant his blood counts dropped and he developed severe neutropenia not responding to GCSF. He was given a CD34 booster dose (6.6 x 10^6 cells per kg/recipient body weight). Then eventually his blood count recovered. After, twenty months of transplant, he presented with grade 3 chronic GVHD of nails. At post-transplant 2.5 years both T and B cell immune reconstitution have been achieved with full donor chimerism. Any child with repeated infections and combination of lymphopenia and neutropenia should have high index of suspicion for reticular dysgenesis.\u003c/p\u003e","manuscriptTitle":"Successful haploidentical stem cell transplantation in a 3-month-old child with reticular dysgenesis using post-transplant cyclophosphamide: A case report \u0026amp; literature review from Pakistan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-06 21:06:48","doi":"10.21203/rs.3.rs-3323241/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"406b1015-09d4-4244-8b84-f0785347f651","owner":[],"postedDate":"October 6th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-12T17:08:31+00:00","versionOfRecord":[],"versionCreatedAt":"2023-10-06 21:06:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3323241","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3323241","identity":"rs-3323241","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}