22q11.2 Deletion Syndrome

By Brian C. Kellogg, MD, Chief of Plastic and Craniofacial Surgery, Nemours Children’s Health

Q: WHAT IS 22Q11.2 DELETION SYNDROME?

A: 22q11.2 deletion syndrome (22qDS) is a common microdeletion disorder of variable expressivity that results in multi-organ system dysfunction. Patients may present with heterogenous combinations of cardiac anomalies, genitourinary anomalies, endocrinopathies, immunodeficiencies, overt or submucous cleft palate, velopharyngeal dysfunction (hypernasal speech), hematologic problems, gastrointestinal problems, developmental delays, neuropsychiatric illness and characteristic facial features. Several previously described disorders, including DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, Opitz G/BBB syndrome and Cayler cardiofacial syndrome, are now recognized as different manifestations of 22qDS. The incidence of 22qDS is estimated to be around 1 in 4,000. It is the second most common cause (behind Down syndrome) of congenital heart disease and developmental delays, and it is the most common genetic cause of structural anomalies of the palate.

Q: WHAT CAUSES 22QDS?

A: 22qDS is caused by a microdeletion on the long (q) arm of the 22nd chromosome. It has an autosomal dominant inheritance pattern with variable expressivity, but 90-95% of cases are believed to result from de novo mutations. 22qDS has not been linked to any extrinsic or environmental factors during fetal development.

Q: WHAT ARE THE SIGNS AND SYMPTOMS OF 22QDS?

A: Congenital heart anomalies are often the earliest sign that a patient may have 22qDS. Further investigation into other organsystems and genetic testing can confirm the diagnosis. Other patients may escape diagnosis in the neonatal period only to present to a specialist later in life with very specific complaints, such as hypernasal speech. Specific signs and symptoms affecting different organ-systems that may be present include:

General: 22q facies (short forehead, hooded eyelids, upslanting palpebral fissures, prominent ears, malar flatness, bulbous nasal tip, small nasal alae, generalized hypotonia, multiple congenital anomalies, polyhydramnios, learning disabilities

Cardiac: Any congenital heart anomaly, especially conotruncal (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, transposition of the great vessels, etc.)

Endocrine: Hypoparathyroidism, hypocalcemia, growth hormone deficiency, hypothyroidism

Palate: Submucous cleft palate, overt cleft palate, high-pitched cry, nasal regurgitation, recurrent otitis media, hearing loss, hypernasal speech (velopharyngeal dysfunction)

Hematologic: Intrinsic platelet dysfunction, thrombocytopenia, easy bleeding, splenomegaly

Immunologic: Humoral and cell-mediated immunodeficiencies, may manifest as recurrent infections

GI: GERD, dysmotility/dysphagia, cholelithiasis, imperforate anus, malrotation, Hirschprung’s disease

Genitourinary: Any structural GU anomaly, unilateral renal agenesis, multicystic dysplastic kidneys

Skeletal: Scoliosis, C-spine anomalies

Development: Failure to thrive, short stature, expressive and receptive language delays, gross motor delays, learning disabilities

Neuropsych: Attention deficit or autism spectrum in young children, anxiety or depression, schizophrenia or other psychotic disorders in teens/adults

Q: HOW IS 22QDS DIAGNOSED?

A: Genetic testing is required to confirm the diagnosis. Fluorescent in situ hybridization (FISH) or chromosomal microarray are two commonly employed modalities.

Q: HOW IS 22QDS TREATED?

A: Patients require a multitude of tests at the time of diagnosis. Per care guidelines, many of these assessments must be repeated at regular intervals. For example, children with 22qDS only require an immunologic evaluation at the time of diagnosis and once again in preschool years (unless specific concerns arise). However, guidelines recommend thyroid studies annually.

Due to the multi-system nature of 22qDS, these patients are most effectively managed in the setting of an interdisciplinary team experienced in treating patients with 22qDS and wellversed in the care guidelines. Care coordination is crucial when working with children with 22qDS because of the large number of specialists who are involved and the complexity of the child’s care. Studies have shown that interdisciplinary team care leads to significantly improved adherence to care guidelines.

Q: WHAT ARE THE OUTCOMES FOR CHILDREN WITH 22QDS?

A: Outcomes for children with 22qDS are highly variable based on the systems involved and the degree to which they are affected. 22qDS can affect any system of the body, which is why early detection and treatment is so important. While there is no cure for 22qDS, therapies and medical interventions can help address its associated symptoms.

There is still very little information available for this population. Most 22qDS clinics are housed in pediatric institutions, so a transition to adult care should be carefully planned as these patients near adulthood.

Brian C. Kellogg, MD, serves as the chief of plastic and craniofacial surgery as well as the director of the Cleft Lip and Palate Program at Nemours Children’s Health. He completed a fellowship in pediatric plastic and craniofacial surgery at Nationwide Children’s Hospital after an integrated residency in plasticsurgeryatUniversityofSouthFlorida.Dr.Kelloggearnedhis medical degree at University of Cincinnati College of Medicine. 