22q11.2 Deletion Syndrome

Description

Other Names

These include clinical subsets of 22q11.2 deletion syndrome:
  • DiGeorge syndrome (DGS)
  • Velocardiofacial syndrome (VCFS)
  • Shprintzen syndrome

Diagnosis Coding

ICD-10

Q93.81, velo-cardio-facial syndrome

D82.1, DiGeorge syndrome

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

Description

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). 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), velocardiofacial syndrome (VCFS), and Shprintzen syndrome. Common clinical manifestations include:
  • Characteristic facial features
  • Congenital heart disease (particularly conotruncal malformations)
  • Palatal abnormalities
  • Hypocalcemia
  • 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
Since all abnormalities associated with the syndrome may occur independently, it is the cluster of symptoms that 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.

Prevalence

Once thought to be an uncommon diagnosis, prevalence is now estimated at 1 in 4,000. [McDonald-McGinn: 2011]

Genetics

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. Another diagnostic approach gaining popularity is CGH (comparative genomic hybridization). See 22q11.2 Deletion Syndrome (GeneReviews) for more detail.

Prognosis

22q11.2 deletion syndrome is a life-long 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.

Roles Of The Medical Home

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. 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]

Practice Guidelines

There are no published practice guidelines.

Helpful Articles

PubMed search for 22q11.2 deletion syndrome.

Pereira E, Marion R.
Chromosome 22q11.2 deletion syndrome.
Pediatr Rev. 2015;36(6):270-2; discussion 272. PubMed abstract / Full Text

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

Shprintzen RJ.
Velo-cardio-facial syndrome: 30 Years of study.
Dev Disabil Res Rev. 2008;14(1):3-10. PubMed abstract / Full Text

Carotti A, Digilio MC, Piacentini G, Saffirio C, Di Donato RM, Marino B.
Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome.
Dev Disabil Res Rev. 2008;14(1):35-42. PubMed abstract

Schneider M, Debbané M, Bassett AS, Chow EW, Fung WL, van den Bree M, Owen M, Murphy KC, Niarchou M, Kates WR, Antshel KM, Fremont W, McDonald-McGinn DM, Gur RE, Zackai EH, Vorstman J, Duijff SN, Klaassen PW, Swillen A, Gothelf D, Green T, Weizman A, Van Amelsvoort T, Evers L, Boot E, Shashi V, Hooper SR, Bearden CE, Jalbrzikowski M, Armando M, Vicari S, Murphy DG, Ousley O, Campbell LE, Simon TJ, Eliez S.
Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome.
Am J Psychiatry. 2014;171(6):627-39. PubMed abstract / Full Text

Clinical Assessment

Screening

For The Condition

Prenatal diagnosis is possible through fluorescent in situ hybridization (FISH) testing on samples from chorionic villous sampling (CVS) or amniocentesis and, in some cases, by diagnostic ultrasound. FISH or CGH 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]

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. Although dilation by an experienced clinician may be sufficient to rule out the diagnosis, parents should consider being screened for the syndrome, particularly when clinical evaluation is equivocal, or when a diagnosis is suspected.

For Complications

Consider screening for:
  • Cardiac defects - All individuals with 22q11.2 deletion syndrome should have screening echocardiography around the time of their initial diagnosis.
  • Significant renal anomalies upon confirmation of diagnosis
  • Hypocalcemia in the neonatal period, in times of physiologic stress, prior to elective surgery, and when signs and symptoms suggest this complication
  • Thrombocytopenia when a history of easy bruising, prolonged bleeding, recurrent epistaxis, and elective surgery exists
  • Visual and hearing impairments annually - because of chronic middle ear effusions, a low threshold for referral to pediatric otolaryngology should be maintained
  • Dental/enamel weakness and refer to pediatric dentistry after 12 months of age because of relatively high incidence
  • Cervical spine abnormalities - Children with 22q11.2 deletion syndrome are more likely than the general population to have cervical flexion/extension instability. Screening 6-view cervical spine x-rays (AP, lateral, open mouth, flexion, and extension) are recommended at age 4, when the bones ossify, by some investigators. 22q11.2 Deletion Syndrome (GeneReviews)
  • Periodic developmental and neuropsychological screenings should be considered, particularly speech and language assessments. Mental health screening should be routine for adolescents because of increased incidence of schizophrenia, bipolar disorder, anxiety, and depression.
Screening for immunodeficiency is controversial: though feature of the classic DiGeorge phenotype, immunodeficiency is rare even in this condition. Immunodysfunction is more common, but does not require special diagnostic testing, and rarely influences medical management. Testing for immunodeficiency should be considered in cases of lymphocytopenia and a clinical history of atypical or recurrent serious infection. These tests are best ordered and interpreted by immunologist, but because they rarely appropriately alter medical management for most of the population affected by chromosome 22q11.2 deletion syndrome, T cells sub sets and/or immunodeficiency panels should not be routinely used.

Presentations

22q11.2 deletion syndrome has a highly variable phenotype with respect to clinical severity. Infants presenting with major congenital heart defects, hypocalcemia, and immunodeficiency were said to have "DiGeorge syndrome." 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. As some presentations may be subtle and presentations vary widely, it is possible for offspring of mildly affected parents to have life-threatening problems. The following lists general characteristics:

Most common:
  • 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) and 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.
  • 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.
  • 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, but not usually requiring special measures of intervention) due to thymic hypoplasia. Immunodeficiency has also been described, but this especially rare.)
  • Hypocalcemia due to parathyroid dysfunction
  • Mental health problems (commonly mild manifestations of anxiety and maladaptive behaviors) are seen in over 50% of individuals
  • Kidney/genitourinary tract anomalies
  • Dental problems due to enamel deficiency
Less common:
  • Skeletal problems, including polydactyl, extra ribs, hemivertebrae, craniosynostosis
  • Laryngotracheal-esophageal structural defects, such as webs and vascular rings
  • Eye abnormalities, including ptosis, colobomas, cataracts, 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

Though clinical findings were previously used to make diagnosis, it is now based on genetic testing.

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]

If 22q11.2 syndrome is suspected clinically and FISH testing is negative, it is possible that there is a microdeletion not apparent in standard testing or a deletion of another untested region (10p13-p14) nearby. Manifestations of non-specific forms of aneuploidy may also overlap with those of 22q11.2 deletion syndrome. A geneticist may recommend additional testing to be performed in a reference or research laboratory.

Children with Smith-Lemli-Opitz syndrome may share some of the features of 22q11.2 deletion syndrome, but typically have a serum cholesterol <50 and elevated serum concentration of 7-dehydrocholesterol or an elevated 7-dehydrocholesterol:cholesterol ratio.

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 overlap with that of 22q11.2 deletion syndrome.

Comorbid Conditions

Immune deficits: Immune problems in 22q11.2 deletion syndrome range from total absence of the thymus to a typical response to infection. The majority of children will require only monitoring for and early aggressive treatment of infections, although in rare cases other measures may be necessary (IVIG therapy, thymus transplantation). 22q11.2 Deletion Syndrome (GeneReviews) See the Screening section, above.

Cardiac defects: 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 three major defects are tetralogy of Fallot, interrupted aortic arch, and ventricular septal defects, although others are possible. See the Screening section, above.

Cervical spine abnormalities: 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 hyperthyroidism, and celiac disease are more common in individuals with 22q11.2 deletion than in the general population.

Pearls & Alerts

A compilation of important cautions and considerations can be found at Recommended Assessments for 22q11.2 Deletion Syndrome [Bassett: 2011].

Hypocalcemia

Persistent hypocalcemia, even in older individuals, should lead to a consideration of 22q11.2 deletion syndrome. [Hiéronimus: 2006] 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. Maintain a low threshold for testing serum calcium levels (ionized calcium is preferred) when the patient is symptomatic, or initiate screening during periods of acute physiologic stress, such as severe illness, significant trauma, and surgery.

Autism spectrum disorders (ASD)

In a study by [Fine: 2005], 14% of children with 22q11.2 deletion syndrome qualified for diagnosis of ASD.

Bleeding problems

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 four 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.

History & Examination

Assessment of individuals with 22q11.2 deletion syndrome varies with the severity of the clinical features, as well as with the age of the individual. Recommended Assessments for 22q11.2 Deletion Syndrome [Bassett: 2011] presents a chart of assessment recommendations by age.

Family History

The majority of 22q11.2 deletion syndrome occurs sporadically, but ask about other family members with similar facial features, heart defects, a nasal voice, palate anomalies, and learning problems.

Pregnancy Or Perinatal History

Some clinical signs of 22q11.2 deletion syndrome may be obvious on prenatal ultrasound (e.g., congenital heart disease, Robin anomaly, renal anomalies). Perinatal period may be complicated by hypocalcemia and congenital heart disease.

Current & Past Medical History

Ask about the child's history of infections, constipation, feeding problems, and pneumonia. Feeding problems are common, including reflux and difficulty with sucking/swallowing, especially with liquids. Frequent episodes of otitis or sinusitis may be due to regurgitation of food into the nasal cavity due to velopharyngeal insufficiency. Ask about voice quality.

Developmental & Educational Progress

Developmental delay, impaired cognitive abilities, psychiatric problems, and features of anxiety disorder, ADHD, and autistic spectrum disorders are relatively common. Children with intellectual disability may develop behavior problems.

Social & Family Functioning

Assess family functioning and resources for caring for a child with health problems or disabilities. 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.

Physical Exam

General

Relevant facial features include: auricular dysplasia, hypertelorism, a bulbous nose tip, broad nasal root, the classic configuration of the mouth, etc. The facial features of some individuals may be completely unhelpful in the diagnosis. Listen to vocalizations and speech for stridor and nasality. Evaluate general interaction for cognitive abilities, mood, and behavior.

Growth Parameters

Ht | Wt | BMI 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 may impact weight gain and BMI. 22q11.2 Deletion Syndrome (GeneReviews) A great number of affected individuals have low weight for height in the first 10 years of life, whereas young adults are frequently overweight. Look for poor weight gain or height below the 5th percentile.

HEENT

Check for presence of ear infection, palatal abnormalities, and abnormal or irregular dentition. Look for palatal abnormalities and listen to quality of speech.

Heart

Congenital heart defects are present in up to 50% of individuals with this syndrome and are a major cause for mortality. Although most are obvious, some will present with subtle signs and symptoms. Evaluation is specific to likely known cardiac abnormalities.

Extremities/Musculoskeletal

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.

Neurologic Exam

Neurologic features are non-specific and the exam is usually normal except for hypotonia and oromotor apraxia in young children. CNS abnormalities are possible and a screening neurologic exam should include balance, coordination, cranial nerves, reflexes, and tone.

Testing

Sensory Testing

Following diagnosis, sensory testing should include evaluation for hearing loss and vision abnormalities. Evaluation of hearing may be indicated if there have been frequent or persistent ear infections, especially if speech development is delayed.

Laboratory Testing

If clinically indicated, test for hypocalcemia (serum ionized calcium concentration) and immune function (absolute lymphocyte count, with T- and B-cell subsets if low). Although hypocalcemia usually presents in infancy, it may occur in older individuals, particularly during puberty and during illnesses. 22q11.2 Deletion Syndrome (GeneReviews)

Thyroid dysregulation should be suspected if the individual is symptomatic. [Choi: 2005] Although no clear guideline exists, periodic screening for thyroid dysregulation should be performed (T4, TSH). In children with height below the 2nd centile, consider checking levels of growth factors IGF1 and IGF-BP3.

Some investigators also recommend testing for immune system deficiencies. 22q11.2 Deletion Syndrome (GeneReviews)

Imaging

All individuals newly diagnosed with 22q11.2 deletion syndrome should have a CXR, EKG, and echocardiogram and/or chest MRI. 22q11.2 Deletion Syndrome (GeneReviews)

A renal ultrasound should also be considered – renal anomalies may be found in as many as 30% of individuals.

A one-time brain MRI may identify CNS abnormalities, which occur in some children with 22q11.2 syndrome. 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 occur in a small percentage of individuals, usually associated with hypocalcemia. 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.6 -view cervical spine x-rays are recommended at age 4, when the bones ossify, by some experts, to look for cervical instability. 22q11.2 Deletion Syndrome (GeneReviews)

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.

Genetic Testing

FISH testing for 22q11.2 deletion syndrome should be obtained, as well as a genetics consultation. Depending on the reference lab or clinical presentation, CGH may also be used.

Other Testing

Speech and language assessment can be helpful in the diagnosis of velopharyngeal insufficiency and oromotor apraxia.

Subspecialist Collaborations & Other Resources

Pediatric Genetics (see Services below for relevant providers)

Consultation is appropriate for diagnostic testing, counseling, education, and expectant management.

Pediatric Otolaryngology (see Services below for relevant providers)

Referral may be appropriate to evaluate for palate abnormalities, chronic middle ear effusions, and recurrent otitis.

Pediatric Cardiology (see Services below for relevant providers)

Referral may be appropriate to evaluate for cardiac abnormalities.

Pediatric Ophthalmology (see Services below for relevant providers)

Evaluation can be helpful for various eye abnormalities or vision deficits.

Pediatric Endocrinology (see Services below for relevant providers)

Consultation for those with hypocalcemia or for those who are below the 2nd percentile for height.

Pediatric Immunology/Rheumatology (see Services below for relevant providers)

Consider consultation for children with frequent infections consistent with impaired T-cell function, and for those showing signs and symptoms of autoimmune disease or juvenile idiopathic arthritis.

Pediatric Orthopedics (see Services below for relevant providers)

Consider consultation for those with musculoskeletal abnormalities.

Developmental Pediatrics (see Services below for relevant providers)

Consultation may be helpful for those with developmental delays.

Psychologist, Child-18 (see Services below for relevant providers)

Consider referral for IQ and achievement testing and evaluation of autistic features.

Speech/Language Therapy (see Services below for relevant providers)

Consider a speech therapy evaluation for oromotor apraxia and hypernasality.

Psychiatrist, Child-18 (see Services below for relevant providers)

Consider evaluation for concerns regarding maladaptive behaviors or mental illness.

Neuropsychology (see Services below for relevant providers)

Consider referral for in-depth testing, including IQ and achievement testing, evaluation of possible autistic features, and evaluation for a nonverbal learning disability.

Treatment & Management

Overview

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, by age, and management considerations.

How should common problems be managed differently in children with 22q11.2 Deletion Syndrome?

Growth Or Weight Gain

Provide counseling to parents to help navigate issues related to growth. Maintain vigilance in screening for pathologic etiologies of poor growth. Adolescents and young adults typical suffer for decreased physical activity compared to peers and are more likely to be overweight or obese.

Development (cognitive, motor, language, social-emotional)

Plan for delays, especially in language development. 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.

Pearls & Alerts

Caution with live virus vaccines

Caution should guide the use of live virus vaccines in individuals who manifest immunocompromise. Do not confuse immunodysfunction with immunocompromised/immunodeficiency. Otherwise, children with 22q11.2 deletion syndrome should follow the same immunization schedule as the rest of the pediatric population. [Perez: 2003]

Considerations with hospital admissions

The use of irradiated and cytomegalovirus-seronegative blood components has been recommended for infants who need blood products since immunodeficiency may be present. Standard precautions can be employed in individuals without immunodeficiency. Check ionized calcium in children who are admitted to the hospital for illness, or in conjunction with major surgeries. [Jatana: 2007]

Abnormal carotid artery locations

Affected individuals may have abnormally located carotid arteries, generally closer to the nasopharynx than usual. This needs to be considered by otolaryngologists planning palatal surgeries.

Systems

Cardiology

Heart defects may be small and physiologically insignificant or severe, such as in tetralogy of Fallot and interrupted aortic arch type B. Heart defects account for greater than 90% of all deaths associated with 22q11.2 deletion syndrome. [McDonald-McGinn: 2001] Because of the frequency of heart defects, consider a cardiac evaluation for those without symptoms or specific clinical findings. Management may include observation, medical interventions, and a combination of medical and surgical management, and will vary with the heart defect and associated problems (e.g., hypocalcemia, immune deficiency).

Subspecialist Collaborations & Other Resources

Pediatric Cardiology (see Services below for relevant providers)

Children with structural abnormalities need periodic and potentially life-long follow-up (especially in females planning on becoming pregnant and during pregnancy).

Development (general)

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. Before 3 years of age refer to Early Intervention programs and to educational programs after 3.

Subspecialist Collaborations & Other Resources

Developmental Pediatrics (see Services below for relevant providers)

Consider referral for the child with developmental delays.

Early Intervention Programs (see Services below for relevant providers)

Refer children ages 0-35 months who are at risk for, or are demonstrating, developmental delays. Services may include visits by therapists (physical, occupational, speech, vision, etc.) and specific programming for a disability.

Preschool/Early Childhood Education (see Services below for relevant providers)

Refer children with developmental delays who over the age of 3 to a developmental preschool. Contact the local school district for more information.

Head Start/Early Head Start (see Services below for relevant providers)

Refer children ages 0-5 from low-income families for this federally funded school readiness program. Head Start can accommodate delays that are not severe, such as speech articulation, or a need to develop play skills, decrease aggression, etc.

Endocrine/Metabolism

Individuals may have multiple endocrine abnormalities, including hypocalcemia and hypoparathyroidism, thyroid dysregulation, and growth problems. Although hypocalcemia is more likely to occur during infancy, especially in the setting of cardiac problems, it may occur as an isolated finding in children and older individuals and is especially likely to occur during times of increased growth and acute illness. Thyroid problems are also fairly common in individuals with 22q11.2 deletion syndrome, and may at times be due to autoimmune-related thyroid disease such as Graves' disease and Hashimoto thyroiditis. 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 if necessary. [Choi: 2005]

Subspecialist Collaborations & Other Resources

Pediatric Endocrinology (see Services below for relevant providers)

Considered referral for evaluation and management of associated endocrine or growth problems.

Immunology/Infectious Disease

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. 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. 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. Immunology referral and immunology screening in the absence of a suspicious clinical history and/or low absolute lymphocyte count is not recommended.

Subspecialist Collaborations & Other Resources

Pediatric Immunology/Rheumatology (see Services below for relevant providers)

Collaboration is indicated for those with evidence of immunodeficiency.

Nose/Throat/Mouth/Swallowing

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 and/or otolaryngologists. In addition to speech and language evaluation, otolaryngologists may recommend fiberoptic nasoendoscopy and/or video fluoroscopy to evaluate palatal function. Treatment may include speech therapy, oral devices, and/or surgery.

Children may also have feeding difficulties related to gastroesophageal reflux or intestinal problems and constipation (e.g., malrotation, Hirschsprung disease). Children with difficulty swallowing, especially if they are not gaining weight well, may benefit from nasogastric or gastrostomy tube feedings.

Subspecialist Collaborations & Other Resources

Pediatric Plastic Surgery (see Services below for relevant providers)

A cleft palate or craniofacial clinic may be very helpful in the comprehensive management of palatal abnormalities or dysfunction.

Pediatric Otolaryngology (see Services below for relevant providers)

Consider referral when velopharyngeal insufficiency is present.

Speech/Language Therapy (see Services below for relevant providers)

Evaluation and treatment may be helpful for issues related to VPI.

Pediatric Gastroenterology (see Services below for relevant providers)

If weight gain is less than expected, consider referral for evaluation and management.

Transitions

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 [Shprintzen: 2008] and may need psychiatric help. 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 been having regular visits. See also the Transition to Adulthood section of the Portal for information about services, resources, and support systems.

Subspecialist Collaborations & Other Resources

Psychiatrist, Child-18 (see Services below for relevant providers)

Consider collaboration for individuals who exhibit symptoms of mood disorders, including bipolar disorder and schizophrenia.

Pediatric Genetics (see Services below for relevant providers)

Consultation in adolescence is recommended to guide thinking about self-concept and reproduction.

Genetics, Prenatal (see Services below for relevant providers)

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.

Frequently Asked Questions

I have a daughter with 22q11.2 deletion syndrome who has significant learning problems. She recently told me that she was pregnant. Will she have children with similar problems?

Details should be discussed with a geneticist or genetic counselor. In general, offspring of an individual with this syndrome have a 50/50 chance of having the syndrome themselves. Cardiovascular physiology changes significantly with pregnancy and women with 22q11.2 deletion syndrome may benefit from prenatal or early intrapartum consultation by cardiology. Prenatal testing can determine if the child has the syndrome. If testing is positive, your daughter should be followed during her pregnancy by a perinatologist and a prenatal geneticist to enable health care providers to anticipate any problems that may arise. Your daughter's child might be born with a serious cardiac problem that could be anticipated with adequate prenatal ultrasound.

Issues Related to 22q11.2 Deletion Syndrome

Funding & Access to Care

Writing Letters of Medical Necessity

Gastro-Intestinal & Bowel Function

Gastroesophageal Reflux

Resources

Information for Clinicians

22q11.2 Deletion Syndrome (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; sponsored by the U.S. National Center for Biotechnology Information, U.S. National Library of Medicine.

Velocardiofacial Syndrome (OMIM)
Extensive review of 22q11.2 deletion syndrome with detailed information about the genetics of the condition; Online Mendelian Inheritance in Man.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. Includes health supervision guidelines and other useful resources; a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

Helpful Articles

PubMed search for 22q11.2 deletion syndrome.

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

Carotti A, Digilio MC, Piacentini G, Saffirio C, Di Donato RM, Marino B.
Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome.
Dev Disabil Res Rev. 2008;14(1):35-42. PubMed abstract

Pereira E, Marion R.
Chromosome 22q11.2 deletion syndrome.
Pediatr Rev. 2015;36(6):270-2; discussion 272. PubMed abstract / Full Text

Schneider M, Debbané M, Bassett AS, Chow EW, Fung WL, van den Bree M, Owen M, Murphy KC, Niarchou M, Kates WR, Antshel KM, Fremont W, McDonald-McGinn DM, Gur RE, Zackai EH, Vorstman J, Duijff SN, Klaassen PW, Swillen A, Gothelf D, Green T, Weizman A, Van Amelsvoort T, Evers L, Boot E, Shashi V, Hooper SR, Bearden CE, Jalbrzikowski M, Armando M, Vicari S, Murphy DG, Ousley O, Campbell LE, Simon TJ, Eliez S.
Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome.
Am J Psychiatry. 2014;171(6):627-39. PubMed abstract / Full Text

Shprintzen RJ.
Velo-cardio-facial syndrome: 30 Years of study.
Dev Disabil Res Rev. 2008;14(1):3-10. PubMed abstract / Full Text

Clinical Tools

Toolkits

Healthcare for Adults with Intellectual & Developmental Disabilities - Toolkit for Primary Care Providers (Vanderbilt)
Online compilation of knowledge resources, checklists, "Health Watch Tables" for autism, Down syndrome, fragile X, Prader-Willi, Williams syndrome, and 22q11.2 deletion syndrome, and other resources to support the adult primary care (and transition thereto) of individuals with developmental and intellectual disabilities; from the Vanderbilt Kennedy Center for Excellence in Developmental Disabilities.

Information & Support for Families

Family Diagnosis Page

Information on the Web

22q11.2 Deletion Syndrome (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; U.S. National Library of Medicine.

Velocardiofacial syndrome (Genome.gov)
Medical information, educational materials, and a link to the genetic and rare disease information center; National Human Genome Research Institute.

22q11.2 Deletion Syndrome Educational Videos (MIND)
Three videos about 22q11.2 deletion syndrome that cover early childhood and adolescence; University of California at Davis Medical Investigation of Neurodevelopmental Disorders Institute.

22q11.2 Deletion Syndrome (GARD)
Links to informational resources, scientific conferences, clinical trials, etc. A "Have Questions" link allows users to submit questions to scientific experts; Genetic and Rare Diseases Information Center.

Chromosome 22q11.2 Deletion Syndrome (NORD)
Overview of the syndrome and its symptoms, causes, and related disorders, along with a list of related organizations; National Organization for Rare Disorders.

22q11.2 Resources - Birth to 5 Years (International 22q11.2 Foundation)
Includes information for families about typical developmental skills, early intervention, expectations at school, coordinating care, and associated behaviors.

Support National & Local

22q11.2 Deletion Syndrome Foundation
Research, resources, and information for families with children who have 22q11.2 deletion syndrome.

Velo-Cardio-Facial Syndrome Education Foundation
An international, not-for-profit organization providing support and information to individuals who are affected by Velo-Cardio-Facial syndrome, their families, physicians, and other practitioners.

Services for Patients & Families

Developmental Pediatrics

See all Developmental Pediatrics services providers (5) in our database.

Early Intervention Programs

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Genetics, Prenatal

See all Genetics, Prenatal services providers (4) in our database.

Head Start/Early Head Start

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Neuropsychology

See all Neuropsychology services providers (33) in our database.

Pediatric Cardiology

See all Pediatric Cardiology services providers (3) in our database.

Pediatric Endocrinology

See all Pediatric Endocrinology services providers (2) in our database.

Pediatric Gastroenterology

See all Pediatric Gastroenterology services providers (3) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (5) in our database.

Pediatric Immunology/Rheumatology

See all Pediatric Immunology/Rheumatology services providers (5) in our database.

Pediatric Ophthalmology

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Pediatric Orthopedics

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Pediatric Otolaryngology

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Pediatric Plastic Surgery

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Preschool/Early Childhood Education

See all Preschool/Early Childhood Education services providers (80) in our database.

Psychiatrist, Child-18

See all Psychiatrist, Child-18 services providers (28) in our database.

Psychologist, Child-18

See all Psychologist, Child-18 services providers (151) in our database.

School Districts

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Speech/Language Therapy

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For other services related to this condition, browse our Services categories or search our database.

Authors

Authors: Alan F. Rope, MD - 5/2009
Lynne M Kerr, MD, PhD - 5/2009
Reviewing Author: Alan F. Rope, MD - 12/2014
Content Last Updated: 1/2015

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

Carotti A, Digilio MC, Piacentini G, Saffirio C, Di Donato RM, Marino B.
Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome.
Dev Disabil Res Rev. 2008;14(1):35-42. PubMed abstract

Choi JH, Shin YL, Kim GH, Seo EJ, Kim Y, Park IS, Yoo HW.
Endocrine manifestations of chromosome 22q11.2 microdeletion syndrome.
Horm Res. 2005;63(6):294-9. PubMed abstract

Driscoll DA.
Prenatal diagnosis of the 22q11.2 deletion syndrome.
Genet Med. 2001;3(1):14-8. PubMed abstract

Fine SE, Weissman A, Gerdes M, Pinto-Martin J, Zackai EH, McDonald-McGinn DM, Emanuel BS.
Autism spectrum disorders and symptoms in children with molecularly confirmed 22q11.2 deletion syndrome.
J Autism Dev Disord. 2005;35(4):461-70. PubMed abstract / Full Text

Gerkes EH, Hordijk R, Dijkhuizen T, Sival DA, Meiners LC, Sikkema-Raddatz B, van Ravenswaaij-Arts CM.
Bilateral polymicrogyria as the indicative feature in a child with a 22q11.2 deletion.
Eur J Med Genet. 2010;53(5):344-6. PubMed abstract

Goldmuntz E.
DiGeorge syndrome: new insights.
Clin Perinatol. 2005;32(4):963-78, ix-x. PubMed abstract

Hiéronimus S, Bec-Roche M, Pedeutour F, Lambert JC, Wagner-Malher K, Mas JC, Sadoul JL, Fénichel P.
The spectrum of parathyroid gland dysfunction associated with the microdeletion 22q11.
Eur J Endocrinol. 2006;155(1):47-52. PubMed abstract / Full Text

Jatana V, Gillis J, Webster BH, Adès LC.
Deletion 22q11.2 syndrome--implications for the intensive care physician.
Pediatr Crit Care Med. 2007;8(5):459-63; quiz 464. PubMed abstract

McDonald-McGinn DM, Sullivan KE.
Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).
Medicine (Baltimore). 2011;90(1):1-18. PubMed abstract

McDonald-McGinn DM, Tonnesen MK, Laufer-Cahana A, Finucane B, Driscoll DA, Emanuel BS, Zackai EH.
Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net!.
Genet Med. 2001;3(1):23-9. PubMed abstract

Pereira E, Marion R.
Chromosome 22q11.2 deletion syndrome.
Pediatr Rev. 2015;36(6):270-2; discussion 272. PubMed abstract / Full Text

Perez EE, Bokszczanin A, McDonald-McGinn D, Zackai EH, Sullivan KE.
Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).
Pediatrics. 2003;112(4):e325. PubMed abstract / Full Text
Live virus vaccination is likely safe in children with 22q11.2 deletion, though caution is warranted, especially in those with severe immuno-compromise.

Robin NH, Taylor CJ, McDonald-McGinn DM, Zackai EH, Bingham P, Collins KJ, Earl D, Gill D, Granata T, Guerrini R, Katz N, Kimonis V, Lin JP, Lynch DR, Mohammed SN, Massey RF, McDonald M, Rogers RC, Splitt M, Stevens CA, Tischkowitz MD, Stoodley N, Leventer RJ, Pilz DT, Dobyns WB.
Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation.
Am J Med Genet A. 2006;140(22):2416-25. PubMed abstract

Schneider M, Debbané M, Bassett AS, Chow EW, Fung WL, van den Bree M, Owen M, Murphy KC, Niarchou M, Kates WR, Antshel KM, Fremont W, McDonald-McGinn DM, Gur RE, Zackai EH, Vorstman J, Duijff SN, Klaassen PW, Swillen A, Gothelf D, Green T, Weizman A, Van Amelsvoort T, Evers L, Boot E, Shashi V, Hooper SR, Bearden CE, Jalbrzikowski M, Armando M, Vicari S, Murphy DG, Ousley O, Campbell LE, Simon TJ, Eliez S.
Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome.
Am J Psychiatry. 2014;171(6):627-39. PubMed abstract / Full Text

Shooner KA, Rope AF, Hopkin RJ, Andelfinger GU, Benson DW.
Genetic analyses in two extended families with deletion 22q11 syndrome: importance of extracardiac manifestations.
J Pediatr. 2005;146(3):382-7. PubMed abstract

Shprintzen RJ.
Velo-cardio-facial syndrome: 30 Years of study.
Dev Disabil Res Rev. 2008;14(1):3-10. PubMed abstract / Full Text