22q11.2 deletion syndrome medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ayushi Jain, M.B.B.S[3]

Overview

Although genetic transplantation methods are currently being developed by researchers, there is yet no genetic treatment of this disease.

It is important that the immune problems are identified early as special precautions are required regarding blood transfusion and immunization with live vaccines.

Treatment is largely symptomatic, infections are treated with antibiotics. Hypoparathyroidism causing hypocalcemia is often transient, but may require lifelong vitamin D treatment.

Thymus transplantation can be used to address absence of the thymus in complete DiGeorge syndrome.

Medical Therapy

Although genetic transplantation methods are currently being developed by researchers, there is yet no genetic treatment of this disease.

It is important that the immune problems are identified early as special precautions are required regarding blood transfusion and immunization with live vaccines.

Treatment is largely symptomatic, infections are treated with antibiotics. Hypoparathyroidism causing hypocalcemia is often transient, but may require lifelong vitamin D treatment.

Thymus transplantation can be used to address absence of the thymus in complete DiGeorge syndrome.[1]

  • Fortunately, many patients with DGS have minor immunodeficiency, with preservation of T cell function despite decreased T cell production. Frequent follow-up with an immunologist experienced in treating primary immunodeficiencies is advisable. Immunodeficiency in neonates with complete DGS (cDGS) requires management with isolation, intravenous IgG, antibiotic prophylaxis, and either thymic or hematopoietic cell transplant (HSCT).
  • Immunization, boosters, intravenous immunoglobulin, and antibiotic prophylaxis regimens should revolve around the individual patient's laboratory values. Antibody titer to administered vaccines should be re-evaluated every six to twelve months to determine the necessity of re-vaccination.Controversy exists surrounding the administration of live vaccines, including the MMR, oral polio, and rotavirus vaccines. However, current evidence suggests both safety and efficacy in children older than one year with proven vaccine response, CD8 count greater than 300, and CD4 count greater than 500. Rotavirus vaccination, of note, has been associated with diarrheal illness in patients with SCID and should not be administered to infants with reduced T cell counts.[2] [3]
  • Cardiac anomalies, if not diagnosed during the fetal ultrasound, may present shortly after birth as life-threatening cyanotic heart disease. Pediatric cardiothoracic surgery evaluation may be urgently required. Blood products, if necessary, should be irradiated, CMV negative, and leukocyte reduced to prevent transfusion-associated graft-versus-host disease. These measures also aim to reduce lung injury, particularly in surgical cases requiring cardiopulmonary bypass.
  • Cleft palate cases require evaluation by an otolaryngologist, plastic surgeon, or oral & maxillofacial surgeon with experience in surgical correction of palatal defects. Repair of a cleft palate can improve feeding ability, speech, and reduce the incidence of sinopulmonary infections.
  • Hypocalcemia is manageable with calcium and vitamin D supplementation. Recombinant human PTH is an option in DGS patients refractory to standard therapy.
  • Autoimmune diseases are common in DGS patients, including immune thrombocytopenia (ITP), rheumatoid arthritis, autoimmune hemolytic anemia, Graves disease, and Hashimoto thyroiditis. DGS patients should be evaluated carefully for autoimmune symptoms regularly.
  • Audiologic evaluation is necessary for DGS patients experiencing difficulty with hearing. Children too young to express difficulty with hearing need assessment, particularly with a delay in cognitive and behavioral development.
  • Early intervention services are beneficial for children with impaired cognitive and behavioral development.
  • Speech therapy is necessary for difficulty with language secondary to craniofacial anomalies and/or cognitive impairment.
  • Psychiatric care for DGS patients with depressive and psychotic symptoms is necessary, as diseases like schizophrenia are associated with DGS.[4] [5]
  • Genetic counseling is a reasonable consideration for parents of a child with DGS who desire more children, as well as for patients with DGS who may want to become parents. If a parent has the same mutation as an affected child, there is a 50% chance a new baby will also have DGS.

Advanced approaches for the management of children with complete DiGeorge anomaly

In the cDGS featuring no thymus function and bone marrow stem cells can not develop into T cells, children usually die by age 2 years due to severe infections. In this setting, the proposal is to T cell–replete HSCT. Nevertheless, because of the absence of thymus, this strategy can only obtain engraftment of post thymic T cells.[6] A multicenter survey on the outcome of HSCT showed a survival rate of 33% after matched unrelated donors and 60% in the case of matched sibling transplantations.[7] Recently, the FDA approved the thymus transplantation as standard care. This approach focuses on producing naive T cells with a broad T-cell receptor set. The procedure takes place using general anesthesia, and thymus tissue usually gets transplanted into the recipient subject's quadriceps. Studies indicate up to 75% of long-term survival but have described frequent autoimmune sequelae (e.g., autoimmune hemolysis, thyroiditis, thrombocytopenia, enteropathy, and neutropenia) in survivors.[8]

References

  1. Markert ML, Devlin BH, Alexieff MJ; et al. (2007). "Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants". Blood. 109 (10): 4539–47. doi:10.1182/blood-2006-10-048652. PMID 17284531.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. Al-Sukaiti N, Reid B, Lavi S, Al-Zaharani D, Atkinson A, Roifman CM, Grunebaum E. Safety and efficacy of measles, mumps, and rubella vaccine in patients with DiGeorge syndrome. J. Allergy Clin. Immunol. 2010 Oct;126(4):868-9.
  3. Bakare N, Menschik D, Tiernan R, Hua W, Martin D. Severe combined immunodeficiency (SCID) and rotavirus vaccination: reports to the Vaccine Adverse Events Reporting System (VAERS). Vaccine. 2010 Sep 14;28(40):6609-12.
  4. Sumitomo A, Horike K, Hirai K, Butcher N, Boot E, Sakurai T, Nucifora FC, Bassett AS, Sawa A, Tomoda T. A mouse model of 22q11.2 deletions: Molecular and behavioral signatures of Parkinson's disease and schizophrenia. Sci Adv. 2018 Aug;4(8):eaar6637.
  5. Meechan DW, Maynard TM, Tucker ES, Fernandez A, Karpinski BA, Rothblat LA, LaMantia AS. Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development. Prog. Neurobiol. 2015 Jul;130:1-28.
  6. McGhee SA, Lloret MG, Stiehm ER. Immunologic reconstitution in 22q deletion (DiGeorge) syndrome. Immunol. Res. 2009;45(1):37-45.
  7. Janda A, Sedlacek P, Hönig M, Friedrich W, Champagne M, Matsumoto T, Fischer A, Neven B, Contet A, Bensoussan D, Bordigoni P, Loeb D, Savage W, Jabado N, Bonilla FA, Slatter MA, Davies EG, Gennery AR. Multicenter survey on the outcome of transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly. Blood. 2010 Sep 30;116(13):2229-36.
  8. Davies EG, Cheung M, Gilmour K, Maimaris J, Curry J, Furmanski A, Sebire N, Halliday N, Mengrelis K, Adams S, Bernatoniene J, Bremner R, Browning M, Devlin B, Erichsen HC, Gaspar HB, Hutchison L, Ip W, Ifversen M, Leahy TR, McCarthy E, Moshous D, Neuling K, Pac M, Papadopol A, Parsley KL, Poliani L, Ricciardelli I, Sansom DM, Voor T, Worth A, Crompton T, Markert ML, Thrasher AJ. Thymus transplantation for complete DiGeorge syndrome: European experience. J. Allergy Clin. Immunol. 2017 Dec;140(6):1660-1670.e16.

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