Approach Considerations
A multidisciplinary team best cares for individuals with 22q11.2DS; however, one physician (usually the primary physician) must take the lead and provide a medical home for the patient. The primary physician also must monitor growth and development. A system-by-system approach results in the best outcome.
Management of 22q11.2DS includes the following:
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Calcium supplementation: For hypoparathyroidism-associated hypocalcemia; vitamin D supplementation may also be needed
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Surgery: Cardiovascular surgery, cleft palate repair, and, for congenital anterior glottic webs, tracheotomy or surgical reconstruction
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Immunodeficiency: Therapies include thymus transplantation (allogeneic processed thymus tissue [Rethymic]) and adoptive transfer of mature T cells (ATMTC) for individuals with complete DiGeorge syndrome and appropriate prophylaxis measures and monitoring autoimmune complications for incomplete or partial DiGeorge syndrome.
Helpful clinical guideline summaries include those from the Joint Council of Allergy, Asthma and Immunology (Practice parameter for the diagnosis and management of primary immunodeficiency [57] ) and the British Committee for Standards in Haematology ([1] Transfusion guidelines for neonates and older children; [2] amendments and corrections to the transfusion guidelines for neonates and older children [58] ).
Contraception
For patients with chromosome 22q11.2 deletion syndrome, gynecologic evaluation and contraceptive education should be instituted at age 12-18 years and after age 18 years.
Follow-up
Consensus guidelines for follow-up finalized in 2010 at the International 22q11.2 Deletion Syndrome Meeting [59] for use by the international community are an excellent resource. Practical guidelines for managing problems in adults with 22q11.2 DS were published in 2015 and are very useful as well. [60] A good source for professionals is the 22q11.2 society (22qsociety.org), which consists of a group of researchers and physcians who specialize in this syndrome.
Transfusion and Immunization in Immunodeficient Patients
The utmost care must be taken to avoid the use of nonirradiated blood products in patients with 22q11.2DS. In the presence of significant T-cell defects, transfusions with nonirradiated blood may prove fatal secondary to a graft versus host response initiated by donor lymphocytes contaminated in blood products. If a blood transfusion is necessary in infancy, use only cytomegalovirus-negative, irradiated blood products.
Do a complete blood count (CBC) at diagnosis and again at age 1-5 years. If absolute lymphopenia is present, consult an immunologist. Follow the immunologist's recommendations regarding follow-up for future immunologic issues and for immunizations.
Live vaccines are typically contraindicated in patients with 22q11.2DS and in household members of such patients because of the risk of shedding of live organisms. Adverse events and fatal reactions have been well documented after severely immunocompromised patients with 22q11.2DS have received live vaccines [61] ; however, a few studies have shown that live viral vaccines (LVVs) may be safe in select populations affected by the syndrome.
Azzari et al evaluated the safety and immunogenicity of measles-mumps-rubella (MMR) vaccine in children with DGS and found no severe adverse reactions in the 14 patients studied. [62] Patients and control subjects experienced the same frequency of seroconversion for measles and rubella. The mean titers of anti-measles or anti-rubella antibodies were the same in patients and controls, and no decrease in CD4 cells was detected after immunization.
In a study of 53 patients at Texas Children’s Hospital with partial 22q11.2DS, no significant adverse events were recorded in the 25 who received an LVV. [63]
Similarly, a retrospective analysis by Perez et al of 59 patients with 22q11.2DS who received LVV for varicella (32 patients) and MMR (52 patients) found that the incidence of adverse effects was comparable to that reported in the general population. All of the side effects were mild. [64]
Management of Hypoparathyroidism and Hypocalcemia
Obtain a serum calcium level at diagnosis and repeat at ages 1-5, 6-11, 12-18, and over 18 years. If the patient is found to be hypocalcemic, begin calcium supplementation after proper tests (simultaneous serum calcium and serum parathyroid hormone [PTH] levels) are performed. Vitamin D supplementation may become necessary.
A study by Matarazzo et al indicated that in children with syndromic hypoparathyroidism, subcutaneous recombinant human PTH (rhPTH) therapy used in place of calcium and vitamin D supplementation can effectively treat hypocalcemia while sparing patients the side effects of calcium and vitamin D. In this 2.5-year, self-controlled trial, involving 6 pediatric patients (including 2 with DiGeorge syndrome), rhPTH therapy enabled 2 patients to end treatment with calcium and vitamin D, 3 patients to stop calcium therapy, and 2 patients to reduce vitamin D treatment. In 4 of the patients, fewer tetanic episodes occurred during rhPTH treatment than during conventional therapy. [65]
Immunologic Therapy
The FDA approved the first therapy, allogeneic processed thymus tissue (Rethymic), to reconstitute immunity in children with congenital athymia in October 2021.
Several therapies have been used to treat immunodeficiency associated with 22q11.2DS. Cases of immune reconstitution have been reported following transplantation of human leukocyte antigen (HLA) ̶ identical bone marrow, peripheral blood mononuclear cells, and fetal thymus. However, some of the patients treated may have had partial DGS, which can improve on its own, so results in certain cases may have been coincidental.
Thymus transplantation
Allogeneic processed thymus tissue (Rethymic) is implanted surgically in the quadriceps muscle of the recipient. Approval of allogeneic processed thymus tissue was based on 10 prospective single-arm, open-label studies that included 105 patients from 1993 to 2020. Survival rates were analyzed with the longest follow-up period of 25.5 years. In the EAS, Kaplan-Meier estimated survival rates (95% CI) were 77% (0.670–0.841) at 1 year and 76% (0.658–0.832) at 2 years. For patients who were alive at 1 year post implantation, the estimated long-term survival rate was 94% at a median follow-up time of 10.7 years. For the patients in the clinical trials, naïve T-cell levels were measured using flow cytometry at 6, 12, and 24 months after implantation. Patients in the clinical trials started out with very few naïve T cells, but naïve CD4 and CD8 T cells began to reconstitute over the first year, with a durable increase through the second year. Reductions in the number of infections over time during the first 2 years after treatment were statistically significant (p < 0.001). [66]
Early thymus transplantation (ie, before the onset of infectious complications) may promote successful immune reconstitution. (Goldsobel et al reported disappointing results for thymus transplantation, but a significant number of patients in their study were lost to follow-up. [67] ) Because T-cell function may improve in patients with partial 22q11.2DS, thymus transplantation is indicated only for patients with complete 22q11.2 DS, phenotypically similar to SCID. [36, 68, 69, 70, 71]
In a study by Markert et al of 5 patients with complete 22q11.2DS who were treated with allogeneic, cultured, postnatal thymus tissue, 4 patients displayed immune reconstitution with T-cell proliferative responses to mitogens. [72]
In a follow-up study, Markert and colleagues reviewed 54 patients with complete 22q11.2DS who were enrolled in protocols for thymus transplantation and found that 1 year after transplantation, 25 of 25 subjects tested had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Additionally, transplantation was fairly well tolerated; the most common adverse events were hypothyroidism and enteritis. [68]
At the time of the study’s publication, at which point posttransplant follow-up had been as long as 13 years, 33 of the 44 subjects who received a transplant were alive (75%). All deaths were reported to have occurred within 12 months of thymic transplantation.
Bone marrow transplantation
Adoptive transfer of mature T cells (ATMTC) through bone marrow transplantation has emerged as a successful therapy for complete 22q11.2DS, providing a potential alternative to thymic transplantation. Compared with thymic transplant, ATMTC is thought to be an easier procedure to accomplish and is available at more centers; however, there are differences in the nature of the T-cell reconstitution that results. Predictably, more naïve T cells and recent thymic emigrants are present in patients treated with thymus transplant. [73]
There are no significant differences in mortality between the 2 procedures, but the number of patients is too limited to conclude that the techniques are equally effective. Adoptive transfer will likely be pursued as a reasonable treatment for patients with 22q11.2DS who require immune reconstitution when thymus transplant is not available. [69]
Growth and Development
Physical growth
Monitor growth in patients with 22q11.2DS. Feeding difficulties and failure to thrive are common in these patients, especially in those with a significant cleft palate. Occasionally, placement of a nasogastric or gastrostomy tube is necessary for feeding during the first 6-12 months of life. The tube provides adequate nutrition to prevent serious growth failure. Later, monitor the patient for growth hormone deficiency, which may manifest as significant short stature or deceleration of rate of growth in height. 22q11.2 DS–specific growth charts are available for Caucasian children. [74] In 2017, increased prevalence obesity was noted in adults with this syndrome, and prevention of obesity would be the ideal. [75]
Psychomotor development
Also monitor the child’s development. If there is a developmental delay, refer the patient for physical therapy, occupational therapy, and speech therapy evaluations. The patient should also be referred to a psychologist in order to be screened for learning and behavioral problems, starting at age 4 years and then again at ages 6-11, 12-18, and over 18 years.
Cleft Palate and Airway Correction
Cleft palate can be repaired with surgical modalities. [2] As patients with 22q11.2DS grow older, correction of hypernasal speech becomes important; this can be performed initially with speech therapy, but surgery may be required. [76, 77] Consult a reconstructive surgeon experienced in treating velopharyngeal incompetence (VPI). Avoid adenoidectomy, as it may worsen the VPI. For the severely affected patients with hyper-nasal speech, the surgical results are not as good as in those who are moderately affected. [78]
In order to establish a more competent airway in patients with 22q11.2DS, congenital anterior glottic webs can be managed with surgical reconstruction or tracheotomy. [3]
Consultations
Coordinated, multidisciplinary follow-up care is necessary to ensure that patients with 22q11.2DS receive optimal medical care; the following consultations should be obtained initially and during follow up [59] :
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Geneticist: For initial evaluation and genetic counseling, which will also include the choice of testing the parents of a child with 22q11.2; ongoing periodic follow-up consultations are recommended to apprise the family of new developments, to reinforce the counseling and recurrence risk assessment, and to direct the family to resources in the community [52]
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Pediatric cardiologist: For evaluation and management of cardiac disease
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Pediatric cardiothoracic surgeon: For help in the evaluation and correction of cardiac and great vessel defects
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Craniofacial specialist: For treatment of patients with cleft palate and feeding difficulties
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Otolaryngologist: When recurrent otitis media occurs and may be needed to manage structural abnormalities in the airway
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Audiologist: For hearing assessment
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Immunologist: For evaluation of immune function and for other immunologic disorders
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Infectious disease specialist: May assist in the management of recurrent infections
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Ophthalmologist: For assessment of ocular malformations
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Pediatric endocrinologist: For evaluation and management of hypocalcemia or for signs of thyroid or growth hormone deficiency
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Psychologist and psychiatrist: Starting at preschool age; psychiatric disorders are common in all patients with developmental delay; however, the association is stronger in patients with chromosome 22q11.2 deletion. Adults may develop schizophrenia and antipsychotic medications may need to be prescribed. One has to be cautious in using antipsychotics that can cause seizures.
Other specialists, such as an orthopedist, a neurologist for signs of Parkinson disease or seizures, or a nephrologist, may be needed based on the patient's signs and symptoms.
Genetic Counseling and Screening
Approximately 8% of the patients with 22q11.2DS or velocardiofacial syndrome (VCFS) studied by Driscoll et al showed familial transmission of the 22q11.2 deletion. [79]
Because persons with 22q11.2 deletion have a 50% risk of transmitting it to each child, they should be offered genetic counseling, as well as fluorescent in situ hybridization (FISH) testing (by chorionic villus sampling) for prenatal detection as early as weeks 10-12 of gestation.
Studies have shown that 22q11 deletions occur in 20-30% of newborns with isolated conotruncal cardiac malformations. Therefore, screen all patients with conotruncal anomalies for 22q11 deletions, identify other family members at risk, and assess the risk in future pregnancies.
Complications
Autoimmune complications are commonly seen in 22q11.2DS patients with lower T-cell numbers at initial presentation increasing the risk of autoimmune complications. Thus monitoring parameters for autoimmune hemolytic anemia, ITP, rheumatolid arthritis, autoimmune thyroiditis, etc. is required.
Neuropsychiatric complications such as learning disabilities are also common and are expected to become more apparent with age. Late neuropsychiatric complications may include schizophrenia and other neuropsychiatric conditions and these complications are implicated with deletion of the DGCR8 gene that controls miRNA production.
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Mother and children with 22q11.2 deletion syndrome.
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An African American girl with 22q11.2 deletion syndrome.
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The same child as in the previous image, showing an asymmetrical crying face.
