22q11.2 Deletion Syndrome

Guidance for primary care clinicians diagnosing and managing children with 22q11.2 deletion syndrome

Individuals with 22q11.2 deletion syndrome have a wide range of clinical presentations, and the manifestations may vary among affected individuals within the same family. Some presentations are obvious and life-threatening (e.g., DiGeorge syndrome), whereas others may be more subtle (palate incompetence and learning problems). Common clinical manifestations include:

  • Characteristic facial features
  • Congenital heart disease (particularly conotruncal malformations)
  • Palatal abnormalities
  • Hypocalcemia related to hypoparathyroidism
  • Feeding problems
  • Gastroesophageal reflux
  • Chronic otitis media
  • Developmental delay/cognitive problems (especially in the areas of expressive language)
  • Behavioral, emotional, and psychiatric issues
  • Immune dysfunction due to small or absent thymus gland

Since all abnormalities associated with the syndrome may occur independently, the cluster of symptoms should trigger suspicion of this diagnosis. Medical home clinicians should be watchful for children with subtle presentations. [Shooner: 2005] Less common features are described in the Presentations section below.

Other Names

Because of the variety of clinical presentations, many different names have been given to syndromes that have turned out to be due to 22q11.2 deletion, including DiGeorge syndrome (DGS), conotruncal anomaly face syndrome, velocardiofacial syndrome (VCFS), and Shprintzen syndrome.

Key Points

When to test for 22q11.2 deletion syndrome
Strongly consider testing for 22q11.2 deletion syndrome in the presence of any of these factors:

  • Velopharyngeal insufficiency
  • Conotruncal cardiac defects
  • Persistent hypocalcemia, even in older individuals [Hiéronimus: 2006]
  • Characteristic facial findings, especially if coupled with learning difficulties

Screening echocardiogram
Obtain a screening echo when 22q11.2 deletion syndrome is diagnosed, as some cardiac anomalies do not have clear clinical features, such as a murmur. Approximately 50% of individuals with 22q11.2 deletion syndrome have congenital heart defects, and they are a major cause of mortality.

Hypocalcemia
There is an increased risk of hypocalcemia in individuals with 22q11.2 deletion syndrome due to hypoparathyroidism. While routine screening may be medically unnecessary, consider checking serum calcium levels (ionized calcium is preferred) in symptomatic individuals or screen during periods of acute physiologic stress, such as severe illness, significant trauma, and surgery.

Bleeding problems
Bleeding problems occur much more frequently in individuals with 22q11.2 deletion than in the general population due to the high frequency of comorbid idiopathic thrombocytopenia purpura (ITP) and Bernard-Soulier syndrome (BSS). Exercise caution prior to surgical procedures and consider hematology consultation and/or lab testing for bleeding disorders prior to surgery.

Immune dysfunction and immunodeficiency
Individuals with 22q11.2 deletion can be more vulnerable to infections (immune dysfunction), but an actual immunodeficiency resulting in an immunocompromised state is rare. In DiGeorge syndrome, impaired thymus gland development and function may result in decreased T-lymphocyte production, but severe immunodeficiency due to an absent thymus is rare. Routine screening is not generally advised; test for immunodeficiencies with T-cell subsets or immunodeficiency panels only when there is increased clinical suspicion based on atypical or severe infections.

Because actual immunodeficiency is rare, most children with 22q11.2 deletion syndrome should follow the same immunization schedule as the rest of the pediatric population. If the individual is immunocompromised, follow recommendations restricting administration of live virus vaccines in immunocompromised individuals. [Perez: 2003]

Considerations with hospital admissions and surgeries

  • Irradiated and cytomegalovirus-seronegative blood components have been recommended for infants who need blood products if immunodeficiency is present or suspected. Standard blood product precautions can be employed in individuals without immunodeficiency.
  • Check ionized calcium in children admitted to the hospital for illness or in conjunction with major surgeries, as hypocalcemia can affect the course. [Jatana: 2007]
  • Affected individuals may have abnormally located carotid arteries, usually closer to the nasopharynx than usual. This needs to be considered by otolaryngologists planning palatal surgeries.

Practice Guidelines

International clinical practice guidelines for managing children with 22q11.2 deletion syndrome were updated in 2023:

Óskarsdóttir S, Boot E, Crowley TB, Loo JCY, Arganbright JM, Armando M, Baylis AL, Breetvelt EJ, Castelein RM, Chadehumbe M, Cielo CM, de Reuver S, Eliez S, Fiksinski AM, Forbes BJ, Gallagher E, Hopkins SE, Jackson OA, Levitz-Katz L, Klingberg G, Lambert MP, Marino B, Mascarenhas MR, Moldenhauer J, Moss EM, Nowakowska BA, Orchanian-Cheff A, Putotto C, Repetto GM, Schindewolf E, Schneider M, Solot CB, Sullivan KE, Swillen A, Unolt M, Van Batavia JP, Vingerhoets C, et. al.
Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome.
Genet Med. 2023;25(3):100338. PubMed abstract

Diagnosis

Due to the variability of symptoms and phenotypical expression, genetic testing for the diagnosis of 22q11.2 deletion syndrome can be considered at any time during the lifespan, although more severely affected individuals are more likely to be diagnosed early in life. The following section describes these variable presentations, how to make the diagnosis, related labs, imaging, and other studies to obtain, and summaries of prevalence, differential diagnosis, comorbidities, and prognosis so that the primary care clinician can help families during this process.

Presentations

22q11.2 deletion syndrome has a highly variable phenotype with respect to clinical severity, and it is possible for offspring of mildly affected parents to have life-threatening problems. Some clinical signs of 22q11.2 deletion syndrome may be obvious on prenatal ultrasound (e.g., congenital heart disease, Robin anomaly, renal anomalies). Classically, infants presenting with major congenital heart defects, hypocalcemia, and impaired immune function were said to have "DiGeorge syndrome," whereas children presenting as toddlers or preschoolers in cleft palate clinics with developmental delays or with learning and behavior problems were said to have velocardiofacial or Shprintzen syndrome. It is now clear that 22q11.2 deletion syndrome includes a wide range of possible characteristics.
More common characteristics:
  • Palatal abnormalities, especially velopharyngeal insufficiency (due to underdevelopment of the soft tissues of the palate) and/or velopharyngeal incompetence (the tissue is present but does not perform satisfactorily), which is often associated with a nasal voice. Abnormalities may range from submucosal or obvious cleft palate to subtle signs of velopharyngeal insufficiency (VPI) and/or oromotor apraxia. VPI may occur independently in children with this syndrome, or it may follow cleft palate repair.
  • Congenital heart disease, especially conotruncal malformations, is seen in roughly 50% of affected individuals and is responsible for most of the mortality associated with this syndrome. Malformations include tetralogy of Fallot, interrupted aortic arch type B, ventricular septal defect, truncus arteriosus, and others.
  • Learning problems, developmental delay, and/or IQ scores in the low average, borderline, or mildly/moderately intellectually disabled range. Many children will have an unusual pattern with higher verbal than performance scores. Autism spectrum disorders are present in about 14%.
  • Feeding and swallowing difficulties, present in about 30% of children with 22q11.2 deletion syndrome, may lead to nasogastric or gastrostomy tube placement.
  • Affected individuals are likely to be smaller than their gender-matched siblings, although they typically are within the normal range on standard growth curves. Actual growth hormone deficiency is rare.
  • Characteristic facial features may be variable but include hooding of the eyes, short palpebral fissures, a broad nasal root, a bulbous nasal tip, midface hypoplasia, a small chin (although prognathism is commonly found in adults), abnormal development of the perioral region giving rise to an asymmetric smile or grimace, and dysplasia of the auricles. See Pictures of Typical Facial Appearance [Shprintzen: 2008] for examples.
  • Immune dysfunction - more vulnerable to infection due to thymic hypoplasia, but not usually requiring special measures of intervention. Immunodeficiency from thymus aplasia has also been described, but this is rare.
  • Hypocalcemia due to parathyroid dysfunction
  • Mental health problems (commonly mild manifestations of anxiety and maladaptive behaviors) - seen in over 50% of individuals
  • Kidney/genitourinary tract anomalies
  • Dental problems due to enamel deficiency
Less common characteristics:
  • Skeletal problems can include polydactyly, extra ribs, hemivertebrae, or craniosynostosis (Cranial Deformation and Craniosynostosis)
  • Laryngotracheal-esophageal structural defects, such as webs and vascular rings
  • Eye abnormalities, including ptosis, colobomas, cataracts, and strabismus
  • CNS abnormalities are many and varied
  • Gastrointestinal malformations
  • Hearing loss, both conductive and sensorineural
  • Various autoimmune diseases, including juvenile idiopathic arthritis, Graves' disease, Hashimoto thyroiditis, vitiligo, thrombocytopenia
  • Growth hormone deficiency

Diagnostic Criteria & Classifications

Though the aforementioned clinical findings were previously used to make the diagnosis, it is now based on genetic testing for 22q11.2 deletion.

Screening & Diagnostic Testing

To make the diagnosis, genetic testing for 22q11.2 deletion syndrome should be obtained, as well as a genetics consultation. Previously, fluorescent in situ hybridization (FISH) was used to make the diagnosis. In recent years, chromosomal microarray (CMA) became the preferred test as it identifies genome-wide copy number variants (CNVs), including 22q11.2 deletions and any other relevant CNVs, if present. Parental testing with CMA or with targeted analysis (FISH) should also be obtained, with appropriate genetic counseling provided if the results are positive.
Prenatal diagnosis of 22q11.2 deletion syndrome is possible with CMA testing on samples from chorionic villus sampling (CVS) or amniocentesis and, in some cases, by diagnostic ultrasound. CMA testing in low-risk pregnancies (those with no family history) should also be considered if prenatal ultrasound demonstrates Robin anomaly and/or congenital heart disease. Prenatal diagnosis, even if performed late in pregnancy, may help with expectant management of the newborn. [Driscoll: 2001] Fetuses with 22q11.2 deletion should be considered high-risk pregnancies, given the elevated prevalence of late preterm births and intrauterine growth restriction, which may impact delivery method and location.

Laboratory Testing

Current guidelines recommend testing multiple specific labs at initial diagnosis, including an endocrinologic assessment, an immunologic assessment, and a CBC with differential.

  • Endocrinologic assessment: PTH, calcium, magnesium, creatinine, TSH, and free T4. A serum ionized calcium level should be obtained in newborns.
  • Immunoglobulin levels should only be checked in children >6 months of age. They include IgG, IgA, IgM, and IgE levels. [Óskarsdóttir: 2023]

Otherwise, test if there is clinical suspicion for any of the following:

  • Thrombocytopenia – when there is a history of easy bruising, prolonged bleeding, recurrent epistaxis, and elective surgery exists
  • Growth hormone deficiency – test growth factors IGF1 and IGF-BP3 in children with height below the 2nd percentile.

Imaging

  • All individuals newly diagnosed with 22q11.2 deletion syndrome should have an EKG, echocardiogram, and/or a chest MRI. 22q11.2 Deletion Syndrome (GeneReviews)Arch sidedness should be evaluated at initial diagnosis.
  • A renal and bladder ultrasound should also be obtained; renal anomalies may be found in as many as 30% of individuals.
  • A one-time brain MRI may identify CNS abnormalities. Although no large population studies have been performed, a study found minor cerebellar abnormalities in up to 1/3 of affected children. [Robin: 2006] Polymicrogyria, enlarged ventricles, heterotopias, and other abnormalities have also been described. [Gerkes: 2010]
  • Seizures, usually associated with hypocalcemia, occur in a small percentage of individuals. Consider an EEG if there is a medical history consistent with seizure, especially in the absence of documented hypocalcemia.
  • Consider X-rays (spine/chest) for vertebral anomalies. Six-view cervical spine X-rays (AP, lateral, open mouth, flexion, and extension) are recommended by some experts at age 4, when the bones ossify, to look for cervical instability. [McDonald-McGinn: 2020]
  • Referral to cleft-palate team is recommended at initial diagnosis to assess for overt cleft, submucous cleft palate, and velopharyngeal dysfunction with nasoendoscopy/videofluoroscopy as needed. [Óskarsdóttir: 2023]
  • A swallow study may be helpful if there are symptoms of nasal regurgitation of food, coughing or choking when drinking, or other signs of swallowing problems.

Other Testing

Following diagnosis of 22q11.2 deletion syndrome, sensory testing should include evaluation for hearing loss and vision abnormalities and be repeated annually.
  • Periodic developmental and neuropsychological screenings, particularly speech and language assessments, should be considered. Speech and language assessment can be helpful in the diagnosis of velopharyngeal insufficiency and oromotor apraxia.
  • Ophthalmic evaluation/vision assessment is recommended at diagnosis to assess for refractive errors, strabismus, exotropia, sclereocornea, coloboma, and ptosis.
  • Mental health screening should be routine for adolescents because of the increased incidence of schizophrenia, bipolar disorder, anxiety, and depression.

Testing of Family Members

Most children with 22q11.2 deletion syndrome have de novo mutations, yet 5-10% will have inherited the syndrome from a parent. A review of parental features and physical exam and/or referral to Medical Genetics is probably sufficient to determine if parental testing is advisable. Ask about other family members with similar facial features, heart defects, a nasal voice, palate anomalies, and learning problems.

Genetics & Inheritance

22q11.2 deletion syndrome is inherited in an autosomal dominant fashion, although approximately 90% of cases are not inherited and occur secondary to a spontaneous chromosome deletion. This region is estimated to contain about 30 to 40 genes. The genes COMT and TBX1 are of particular interest as they may contribute significantly to the phenotype. See 22q11.2 Deletion Syndrome (GeneReviews) for more detail.

Prevalence

Once thought to be an uncommon diagnosis, the prevalence of 22q11.2 deletion syndrome is now estimated at 1:2148 live births and 1:992 pregnancies. [Donna: 2022]

Differential Diagnosis

22q11.2 deletion syndrome is the most common syndrome associated with velopharyngeal insufficiency. The syndrome is also highly associated with conotruncal cardiac defects and should be tested for in children with these defects. [Goldmuntz: 2005]
Other genetic conditions can present similarly to 22q11.2 syndrome, for which CMA microarray testing is the preferred initial test that could identify other microdeletions or aneuploidy. A geneticist may recommend additional testing in a reference or research laboratory.
Children with Smith-Lemli-Opitz syndrome may share some of the features of 22q11.2 deletion syndrome, but they typically have an elevated serum concentration of 7-dehydrocholesterol.
Children with VATER association and Goldenhar syndromes may clinically resemble those with 22q11.2 deletion syndrome - unfortunately, no diagnostic testing is yet available to confirm those diagnoses.
The phenotypes of fetal alcohol syndrome, CHARGE syndrome, and isotretinoin embryopathy may also overlap with that of 22q11.2 deletion syndrome.

Comorbid Conditions

Immune problems in 22q11.2 deletion syndrome range from total absence of the thymus to a typical response to infection. For infections, most children will only require monitoring and quick, aggressive treatment. In rare cases, other measures may be necessary (IVIG therapy, thymus transplantation). [McDonald-McGinn: 2020] See the Screening section above. Immune screening is now recommended in infancy as it is important to determine whether the T-cell deficiency is so severe as to require a thymus transplant, and/or if blood transfusions need to be irradiated. T-cell evaluations are also warranted to determine whether and when there are sufficient T cells to safely allow the administration of live viral vaccines. [Urschel: 2022]
More than half of the individuals with 22q11.2 deletion syndrome are estimated to have some abnormality of their cardiac system. Cardiac abnormalities account for the majority of early deaths in children with this syndrome. The most common major defects include conotruncal defects, tetralogy of Fallot, interrupted aortic arch type B, and truncus arteriosis; others are possible. See the Screening section above. Infants with conotruncal defects typically require surgical intervention in infancy, with reintervention later in life. This necessitates the need for multidisciplinary preoperative planning with multiple specialty teams.
Children with 22q11.2 deletion syndrome are more likely than the general population to have cervical flexion/extension instability. See the Screening section above.
Although rare, autoimmune disorders such as juvenile idiopathic arthritis, hypo- and hyper-thyroidism, and celiac disease are more common in individuals with 22q11.2 deletion than in the general population.

Prognosis

22q11.2 deletion syndrome is a lifelong condition. Life expectancy may be affected, particularly if a severe heart defect exists. The degree of intellectual disability will determine the individual's ability to function independently as an adult.

Treatment & Management

Clinical management of individuals with 22q11.2 deletion syndrome varies with the severity of the clinical features and the age of the child. Early in life, the focus tends to be on acute medical problems, including heart disease, frequent infections, feeding problems, and those associated with palatal dysfunction. Delays in the achievement of developmental milestones deserve identification and attention. After the child reaches school age, the focus shifts to cognitive and behavioral problems. Multisystem Features of 22q11.2 Deletion Syndrome [Bassett: 2011] presents a chart of common features and management considerations by age.

The medical home is particularly important in the management of children with genetic syndromes. Regularly scheduled care management visits should be considered to allow adequate time to discuss syndrome-associated developmental and medical issues. These include screening for associated complications, referring to appropriate subspecialists when needed, providing a comprehensive medical history in case of emergency, providing immunizations, monitoring developmental and educational progress and interventions, and providing routine anticipatory guidance and advocacy for the child. Pediatric Guidelines and Assessment Checklist (International 22q11.2 Foundation) lists the various labs and evaluations to be performed at different ages. Due to the wide variability of clinical presentations, it is important that genetic counseling be a part of ongoing management. [Shooner: 2005] [McDonald-McGinn: 2001]]

Cardiovascular

Approximately 50% of individuals with 22q11.2 deletion syndrome have congenital heart defects. Heart defects may be small and physiologically insignificant or severe, such as a conotruncal defect, tetralogy of Fallot, and interrupted aortic arch type B. Although most are obvious, some will present with subtle signs and symptoms. Heart defects account for greater than 90% of all deaths associated with 22q11.2 deletion syndrome. [McDonald-McGinn: 2001] Management may include observation, medical interventions, and a combination of medical and surgical management that will vary with the heart defect and associated problems (e.g., hypocalcemia, immune deficiency). Even without known CHD, people with 22q11.2 deletion should undergo periodic screening for arrythmias, EKG abnormalities, and dilated aortic root.

Endocrine/Metabolism

Individuals may have multiple endocrine abnormalities, including hypocalcemia, hypoparathyroidism, thyroid dysregulation, and growth problems.
Although hypocalcemia is more likely to occur during infancy, especially in the setting of cardiac problems, it also may occur as an isolated finding in children and older individuals. Consider checking serum calcium levels (ionized calcium is preferred) in symptomatic individuals or screening during periods of acute physiologic stress, such as severe illness, significant trauma, and surgery. Mild hypocalcemia may manifest as muscle cramping, shortness of breath secondary to bronchospasm, distal extremity numbness, tingling sensations, cataracts, dry skin, coarse hair, brittle nails, psoriasis, chronic pruritus, and poor dentition. Acute hypocalcemia may result in tetany, syncope, seizures, and cardiovascular compromise. [Hiéronimus: 2006] In general, parathyroid hormone (PTH) levels do not need routine monitoring.
Thyroid problems are also fairly common in individuals with 22q11.2 deletion syndrome and may be due to autoimmune-related thyroid diseases, such as Graves' disease and Hashimoto thyroiditis.
Most individuals with 22q11.2 deletion syndrome will have normal growth parameters; however, up to 41% may be around the 5th percentile. A small percentage may have growth hormone deficiency and feeding difficulties that may impact weight gain and BMI. [McDonald-McGinn: 2020] A number of affected individuals have low weight for height in the first 10 years of life, whereas adolescents and young adults who suffer from decreased physical activity and are more likely to be overweight or obese. Individuals with this syndrome whose height is low for age, especially if below the 2nd percentile, should be evaluated for growth hormone deficiency and treated as necessary. [Choi: 2005] Provide counseling to parents to help navigate growth issues.

Immunology/Infectious Disease

Individuals with 22q11.2 deletion can be more vulnerable to infections (immune dysfunction), but an actual immunodeficiency resulting in an immunocompromised state is rare. Even in DiGeorge syndrome, impaired thymus gland development and function may result in decreased T-lymphocyte production, but severe immunodeficiency due to an absent thymus is quite uncommon. Immunology assessment with B and T cell phenotyping is now recommended at diagnosis and should be repeated in the early childhood and teenage years. Immunologic assessment with IgG, IgA, IgM, and IgE levels should also be assessed during these periods, but not prior to 6 months old. Collaboration with an immunologist is appropriate for children with impaired immunity as measured by a decreased absolute lymphocyte count with measurement of T- and B-cell subsets.
Children with impaired lymphocytic function should be treated aggressively for infection. In a small percentage of children, prophylactic antibiotics, IVIG therapy, and thymic transplantation have been necessary.
While most children with 22q11.2 deletion syndrome should follow the same immunization schedule as the rest of the pediatric population, children with significant thymic dysfunction should not receive live vaccines (e.g., MMR, varicella) unless cleared by immunologists familiar with the disorder. Consider immunologic studies to ensure that children have mounted adequate immune responses to vaccinations.

Nose/Throat/Mouth/Swallowing/Dental

Relevant facial features of 22q11.2 deletion syndrome include auricular dysplasia, hypertelorism, a bulbous nose tip, broad nasal root, the classic configuration of the mouth, etc. Look for palatal abnormalities and listen to quality of vocalizations and speech for stridor and nasality.
Children with 22q11.2 deletion syndrome will often have velopharyngeal insufficiency and/or velopharyngeal incompetence (VPI) even without a history of cleft palate. VPI occurs when there is insufficient closure of the nasal cavities during phonation and, sometimes, during swallowing. Children with VPI may need evaluation and management by speech therapists, otolaryngologists, and/or oral surgeons. Otolaryngologists may recommend fiberoptic nasoendoscopy and/or video fluoroscopy to evaluate palatal function. Treatment may include speech therapy, oral devices, and/or surgery.
Feeding problems are common, including reflux and difficulty with sucking/swallowing, especially with liquids. Children with difficulty swallowing, especially if they are not gaining weight well, may benefit from nasogastric or gastrostomy tube feedings. See Feeding Tubes & Gastrostomies in Children. A swallow study may be helpful if there are symptoms of nasal regurgitation of food, coughing or choking when drinking, or other signs of swallowing problems. Consider early referral to a multidisciplinary feeding clinic in this patient population.
Check for abnormal or irregular dentition. Refer to pediatric dentistry after 12 months of age because of the relatively high incidence of dental problems and enamel weakness.

Ears/Hearing

Check for presence of ear infection. Frequent episodes of otitis or sinusitis may be due to regurgitation of food into the nasal cavity due to velopharyngeal insufficiency.
Evaluation of hearing may be indicated if there have been frequent or persistent ear infections, especially if speech development is delayed. A low threshold for referral to pediatric otolaryngology should be maintained. Sensory testing should include an annual evaluation for hearing loss.

Eyes/Vision

Annual vision exams are recommended.

Gastro-Intestinal & Bowel Function

Children may also have feeding difficulties related to Gastroesophageal Reflux Disease or intestinal problems and Constipation (e.g., malrotation, Hirschsprung disease).

Hematology/Oncology

Idiopathic thrombocytopenia purpura (ITP) occurs 200 times more frequently in individuals with 22q11.2 deletion than in the general population.
Individuals with 22q11.2 deletion syndrome may also have Bernard-Soulier syndrome (BSS), which is an autosomal recessive disorder that results in giant platelets and thrombocytopenia. Children with BSS often have difficulty with excessive bleeding during surgical procedures. The clinical syndrome of BSS may result from a mutation in any of 4 genes; one lies in the region that is commonly deleted in 22q11.2 deletion syndrome (GP1BB). In an individual with 22q11.2 deletion syndrome, one of these genes is absent. If the other allele carries a mutation, there will be no functional copy of BSS and a bleeding diathesis would exist.
Exercise caution prior to surgical procedures and consider hematology consultation and/or lab testing for bleeding disorders prior to surgery.

Bone/Orthopedics

Relevant findings may include arthropathy (tender, enlarged, or swollen joints), pre- and post-axial polydactyly in the upper extremities and post-axial polydactyly, clubfeet, and syndactyly of toes 2 and 3 in the lower extremities. Consider X-rays (spine/chest) for vertebral anomalies. Six-view cervical spine X-rays (AP, lateral, open mouth, flexion, and extension) are recommended by some experts at age 4, when the bones ossify, to look for cervical instability. [McDonald-McGinn: 2020]

Development

Plan for delays, especially in language development. Periodic developmental and neuropsychological screenings should be considered, particularly speech and language assessments. Speech and language assessment can be helpful in the diagnosis of velopharyngeal insufficiency and oromotor apraxia.
Hypotonia may delay gross motor milestones, yet improvement usually occurs before the children are eligible for services.
Learning disabilities are common and should be anticipated; individualized education programs (IEPs) and learning and testing aides can help.
Encourage families to indoctrinate socialization strategies early since affected individuals can be marginalized by peers and develop poor self-esteem.

Mental Health/Behavior

Psychiatric problems, features of Anxiety Disorders, Attention-Deficit/Hyperactivity Disorder (ADHD), and Autism Spectrum Disorder are relatively common. Children with intellectual disability may develop behavior problems. Mental Health Screening for Children & Teens should be routine for adolescents because of an increased incidence of schizophrenia, bipolar disorder, anxiety, and depression. Consider referral to behavioral health and/or treatment with medications as indicated.
In a study by [Fine: 2005], 14% of children with 22q11.2 deletion syndrome qualified for a diagnosis of autism spectrum disorder (ASD). Consider referral to neuropsychiatric testing, early intervention, and specialized therapies as indicated.

Neurology

The neurologic exam is usually normal except for hypotonia and oromotor apraxia in young children. Central nervous system abnormalities are possible; a neurologic screening should include examination of balance, coordination, cranial nerves, reflexes, and tone. Although no large population studies have been performed, a study found minor cerebellar abnormalities in up to 1/3 of affected children. [Robin: 2006] Polymicrogyria, enlarged ventricles, heterotopias, and other abnormalities have also been described. [Gerkes: 2010] An MRI of the brain may be obtained if there are concerns.
Seizures, usually associated with hypocalcemia, occur in a small percentage of individuals. Consider an EEG if there is a medical history consistent with seizure, especially in the absence of documented hypocalcemia. Check ionized calcium level in a neonate who presents with seizure.

Family

Assess family functioning and resources. Family functioning may be increasingly challenged by the child's intellectual and/or behavioral difficulties. This dynamic is significantly more challenged in families when a parent is personally affected by chromosome 22q11.2 syndrome. Care coordination in the Medical Home can be a supportive measure and improve outcomes for the child and family. Consider a social work referral to assess resources and make safety plans when appropriate.

Transition

Evolving concerns for individuals with 22q11.2 deletion syndrome are expected during adolescence. Individuals are at greater risk for psychiatric illness compared to the general population and may need psychiatric help. [Shprintzen: 2008] (See Anxiety Disorders and Depression.) Offspring of individuals with the syndrome have a 50% chance of inheriting the deletion, and the clinical presentation of the offspring may vary greatly from that of their parent, including the presence of severe cardiac abnormalities. Individuals with this syndrome during childbearing years should consult with genetics if they have not had regular visits. Families can find services, resources, and support systems in the Transition Issues section of the Portal.

Services & Referrals

Pediatric Endocrinology (see RI providers [12])
Consider referral for evaluation and management of associated endocrine or growth problems.

Pediatric Immunology (see RI providers [6])
Consider consultation for children with frequent infections consistent with impaired T-cell function and signs and symptoms of autoimmune disease or juvenile idiopathic arthritis.

Pediatric Cardiology (see RI providers [17])
Children with structural abnormalities need periodic and potentially lifelong follow-up (especially in females planning on becoming pregnant and during pregnancy).

Medical Genetics (see RI providers [4])
Consultation is appropriate for diagnostic testing, counseling, education, and expectant management. Consultation in adolescence is recommended to guide thinking about self-concept and reproduction.

Pediatric Otolaryngology (ENT) (see RI providers [7])
Referral may be appropriate to evaluate for palate abnormalities, velopharyngeal insufficiency, chronic middle ear effusions, and recurrent otitis.

Speech - Language Pathologists (see RI providers [33])
Consider a speech therapy evaluation for oromotor apraxia and hypernasality

Pediatric Hematology/Oncology (see RI providers [10])
Consider consultation for those with bleeding disorders such as ITP or BSS.

Pediatric Orthopedics (see RI providers [16])
Consider consultation for those with musculoskeletal abnormalities.

Pediatric Ophthalmology (see RI providers [8])
Evaluation can be helpful for various eye abnormalities or vision deficits.

Pediatric Plastic Surgery (see RI providers [4])
A cleft palate or craniofacial clinic may be very helpful in the comprehensive management of palatal abnormalities or dysfunction.

Pediatric Gastroenterology (see RI providers [18])
If weight gain is less than expected, consider referral for evaluation and management.

Genetic Testing and Counseling (see RI providers [8])
Individuals who desire pregnancy, or if a pregnancy is in progress, should be referred to prenatal genetics. Pre-implantation diagnosis is available for those planning a pregnancy.

Developmental - Behavioral Pediatrics (see RI providers [12])
Because children with 22q11.2 deletion syndrome are at high risk for motor, language, speech, and cognitive delays, they should be closely followed to ensure that all relevant resources are in place.

Early Intervention for Children with Disabilities/Delays (see RI providers [13])
Refer children ages 0-35 months who are at risk for or demonstrating developmental delays. Services may include visits by therapists (physical, occupational, speech, vision, etc.) and specific programming for a disability.

ICD-10 Coding

D82.1, DiGeorge syndrome, DiGeorges syndrome, DiGeorge sequence; the code can be applied to pharyngeal pouch syndrome, thymic alymphoplasia, thymic aplasia, or hypoplasia with immunodeficiency

Q93.81, Velo-cardio-facial syndrome, plus the code can be used for 22q deletion, DiGeorge syndrome, Shprintzen syndrome

Q89.7, Multiple congenital anomalies (when diagnosis is suspected but not yet confirmed by genetic testing)

Resources

Information & Support

Related Portal Content
The Medical Home Portal provides related general diagnosis and management information, including:

Answers to questions that families may frequently ask can be found at: The Care Notebook may also be helpful for tracking medical history, test results, and records.

For Professionals

22q11.2 Deletion Syndrome (GeneReviews)
Clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Velocardiofacial Syndrome (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Pediatric Guidelines and Assessment Checklist (International 22q11.2 Foundation)
From time to time, it is important to have health checks, as these may reveal conditions that need attention. Here are the recommended checks for children with 22q11.2 deletion syndrome.

DiGeorge or 22q11.2 Deletion Syndrome (Immune Deficiency Foundation)
Explains primary immunodeficiency that occurs in DiGeorge and related 22q11.2 deletions

For Parents and Patients

International 22q11.2 Foundation
Extensive resources and support services for families and clinicians caring for those with 22q11.2 deletion syndrome.

Services for Patients & Families in Rhode Island (RI)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Studies

Clinical Trials Related to 22q11.2 Deletion Syndrome (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Authors & Reviewers

Initial publication: December 2013; last update/revision: December 2023
Current Authors and Reviewers:
Author: Reilly F Philliben, DO
Reviewer: Nicola Longo, MD, Ph.D.
Authoring history
2023: update: Reilly F Philliben, DOA
2019: update: Alan F. Rope, MDA
2014: update: Alan F. Rope, MDA
2009: first version: Alan F. Rope, MDA; Lynne M. Kerr, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Bassett AS, McDonald-McGinn DM, Devriendt K, Digilio MC, Goldenberg P, Habel A, Marino B, Oskarsdottir S, Philip N, Sullivan K, Swillen A, Vorstman J.
Practical guidelines for managing patients with 22q11.2 deletion syndrome.
J Pediatr. 2011;159(2):332-9.e1. PubMed abstract / Full Text

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