DESCRIPTION

22q11.2 deletion syndrome is the most common cause of DiGeorge syndrome and etiologically associated with other previously described clinical conditions including velocardiofacial, conotruncal anomaly face, Cayler cardiofacial, and Opitz G/BBB syndromes. The 22q11.2 deletion syndrome is a multisystem disorder with variable severity. Commonly associated features include congenital anomalies such as palatal differences (especially velopharyngeal insufficiency) and congenital heart disease, developmental and language delay, feeding and swallowing issues, hypoparathyroidism with hypocalcemia, immunodeficiency, and psychiatric illness.

• Intellectual disability is rarely severe.
• Treatable psychiatric illness is common.
• Rarely (≤1%), neonates have a severe T-cell immunodeficiency.

EPIDEMIOLOGY

Estimated prevalence is 1 in 2,148 live births.

RISK FACTORS

PATHOPHYSIOLOGY

Developmental defect of 3rd and 4th pharyngeal arches is thought to be part of complex mechanisms that may affect every organ system from conception onward.

HISTORY

• The condition is underrecognized at all ages; thus, an index of suspicion is needed for any person at any age with multisystem features.
• Most commonly, no family members are affected.
• No association with advanced maternal age
• Congenital anomalies of any organ system
• Cardiac defects in up to 50%, including septal defects, tetralogy of Fallot ± pulmonary atresia, interrupted aortic arch type B, truncus arteriosus, vascular ring
• Developmental delays, motor and most often speech
• Failure to thrive, feeding and swallowing difficulties
• Neonatal and later-onset hypocalcemia secondary to hypoparathyroidism (in up to 60%)
• Recurrent infection
• Anxiety, attention-deficit disorder, obsessive-compulsive disorder (OCD), schizophrenia
• Dysphagia/gastroesophageal reflux disease (GERD)
• Autoimmune disease, including hypothyroidism; hyperthyroidism
• Occasional growth hormone deficiency
• Thrombocytopenia, rarely immune thrombocytopenia (ITP)/Bernard-Soulier
• Skeletal differences including scoliosis and club foot
• Idiopathic and provoked seizures

PHYSICAL EXAM

• Developmental delay, any but particularly speech
• Learning and neurobehavioral disorders
• Nasal regurgitation, hypernasality, articulation errors
• Chronic otitis media; auricular anomalies, hearing loss
• Heart murmur
• Renal/urogenital abnormalities
• Splenomegaly
• Scoliosis, usually typical adolescent onset
• Club foot, other skeletal abnormalities
• Juvenile rheumatoid arthritis
• Enamel hypoplasia; chronic caries
• Subtle dysmorphic craniofacial features (e.g., malar flatness, hooded eyelids, small malformed ears, bulbous nasal tip/nasal dimple, small mouth, micrognathia), often not recognizable, especially in non–European Americans

DIAGNOSTIC TESTS & INTERPRETATION

GENERAL MEASURES

• Standard treatments are generally effective for each associated feature.
• Vitamin D supplements (if hypoparathyroid will need 1,25 vitamin D replacement and calcium supplements)
• Depending on features that manifest over time, consultation and/or ongoing follow-up are required:
  • Infant stimulation; educational consultant
  • Intervention for speech and language delays
  • Palate team, otolaryngology
  • Cardiology
  • Endocrinology
  • Gastroenterology/feeding team
  • Dentistry
  • Immunology; severe immunodeficiency requires specialist management.
  • Orthopedics
  • Neurology
  • Psychiatry
• Special consideration at surgery/obstetrics/injury
  • Risk of hypocalcemia with biologic stress
• Special consideration for infants
  • Initially withhold live vaccines; assess CD4+ count.
  • Live viral vaccines are safe for most patients with CD4+ cell counts >500 cells/mm³.
  • Cytomegalovirus (CMV)-negative irradiated blood products
  • Respiratory syncytial virus prophylaxis
  • For rare severe T-cell dysfunction, consider immunoglobulin replacement therapy, varicella immunoglobulin, IV acyclovir if varicella develops; avoid live viral vaccines
• COVID-19, influenza vaccinations recommended
• Special consideration around transition to adult care
  • Sexual health, reproductive/genetic counseling
  • Neuropsychiatric issues and functioning

FOLLOW-UP RECOMMENDATIONS

PROGNOSIS

• Most patients survive childhood. Exceptions include those with very severe associated conditions (e.g., cardiac anomalies, immunodeficiency, airway issue).
• Life expectancy of adults is reduced and more so with serious congenital cardiac disease.
• Associated conditions continue to arise through adulthood, including risk for treatable psychiatric illness (e.g., about 1 in 4 develop schizophrenia), autoimmune, neurologic, endocrinologic, metabolic and other disorders.
• Adult functioning generally is correlated with intellectual deficit and severe psychotic illness.

COMPLICATIONS

• Newborns and infants may have hypocalcemic tetany/seizures. Use of sodium phosphate enemas may exacerbate hypocalcemia.
• Feeding and swallowing issues are rarely associated with cardiac disease.
• Complications of any associated feature, including cardiac and other anomalies, recurrent infections
• Complications of speech and other developmental delays, developmental, and neurobehavioral issues, including some decline/“growing into deficit” from age 11 years, and nonverbal (> verbal) learning disability requiring targeted intervention
• Risk is higher for surgical complications of all types.
• Risk is higher for developing multiple later-onset common conditions, including autoimmune diseases, scoliosis, obesity and cardiometabolic diseases, idiopathic seizures, movement disorders including Parkinson disease, mood and psychotic disorders, and other treatable neuropsychiatric illnesses.

ICD 10

• Q93.81 Velo-cardio-facial syndrome
• D82.1 Di George’s syndrome