DiGeorge Syndrome: Clinical Features and Anesthetic Considerations

Patrick Baker, MD
Pediatric Anesthesiology Fellow
OHSU Doernbecher Children’s Hospital
Portland, Oregon
bakepatr@ohsu.edu

Dean Laochamroonvorapongse, MD, MPH
Assistant Professor of Anesthesiology
OHSU Doernbecher Children’s Hospital
Portland, Oregon
laochamr@ohsu.edu

Introduction
The combination of congenital cardiac defects, hypocalcemia, and immunodeficiency has been mentioned in the literature since 1829. In 1965, Dr. Angelo DiGeorge published the first case series describing a group of infants with a congenital absence of a thymus and parathyroid glands. Today, the classic triad of conotruncal cardiac abnormalities, thymic hypoplasia (leading to cellular mediated immunodeficiency), and hypocalcemia (from absence of parathyroid glands) still carries his name. 

Chromosome 22q11.2 microdeletion syndrome (22qDS) is a multisystem disorder which, depending on the phenotype, has been given a variety of names including the aforementioned DiGeorge Syndrome, velocardiofacial syndrome, and CATCH-22 syndrome.  Indeed, more than 180 different associated physical findings and symptoms have been described1, which result from abnormal development of the third and fourth pharyngeal pouches and fourth branchial arch. Outside of the classic triad, 22qDS patients may present with any combination of the following: seizures, abnormal facies, palatal dysfunction, feeding problems, congenital gut abnormalities, behavioral disturbances, and developmental delay. 

A large proportion of these patients will present for some form of surgery and the clinical phenotype of these patients places them at high risk for anesthetic and surgical complications. Some common clinical problems with anesthetic implications include the high likelihood of congenital heart defects, airway abnormalities, aspiration risk, immunodeficiency, metabolic abnormalities, and neurocognitive delay that can complicate induction. 
This review provides a concise overview of pertinent clinical information to help guide anesthesiologists caring for 22qDS patients. 

Pathophysiology
The diverse phenotypes of these patients lie in the fact that more than 35 different genes are within the commonly deleted region of 22q11.2. The nomenclature of 22qDS can lead to confusion, as some patients with the deletion do not carry the typically associated phenotype and likewise, some patients with the typical phenotypic presentation do not carry the deletion.2 

The deleted region of chromosome 22 is bracketed by low copy number repeats (LCRs), which are inherently unstable. Unequal meiotic exchange of the LCRs typically leads to the deletion.3 Murine studies have indicated deletion of the gene encoding the transcription factor T-box protein 1 (TBX1) is a major determinant of the cardiac, thymic, and parathyroid phenotypes.2 TBX1 is expressed in the pharyngeal mesenchyme and endodermal pouch, which give rise to the face/upper thorax and parathyroid glands/thymus, respectively. Haploinsufficiency for TBX1 leads to decreased proliferation of the endoderm cells in the branchial arches and impaired pharyngeal arch development.3

Furthermore, the gene that codes for catechol-O-methyltransferase (COMT) also is in this region, which is important for regulation of catecholamine levels. Dysregulation of catecholamine breakdown in the central nervous system is postulated to lead to the neurodevelopmental abnormalities seen with these patients.1 Although the inheritance pattern is generally autosomal dominant, over 90% of deletions are de novo.2 

Epidemiology
Heterozygous deletions of the 22q11.2 region are relatively common in the general population, making it the most prevalent microdeletion syndrome.4 Indeed, 22q11.2 deletion syndromes are the second most common of the pediatric genomic syndromes, behind Down syndrome (Trisomy 21). Estimates of incidence range from 1/1000 to 1/6000 live births5,6,7. Males and females are affected equally and 22qDS syndromes may be underdiagnosed, given the relatively mild phenotypic presentations in some patients. 

Clinical features related to anesthetic risk
We highlight the main clinical findings that may increase the risk of perioperative complications. 

Conotruncal Heart Defects
Conotruncal cardiac defects occur in approximately 80% of 22qDS patients2,3,8. Defects in the distal fetal heart early in embryonic development lead to structural deformity of the aortic and pulmonary roots, which develop from the conotruncal region. The most common congenital cardiac defects are: interrupted aortic arch, truncus arteriosus, Tetralogy of Fallot, ASD/VSD, and vascular rings. Hypoplastic left heart syndrome and transposition of the great vessels is also seen. Severity of CHD usually determines survival of patients with 22qDS, with most deaths occurring within the first six months9. Full understanding of an individual patient’s cardiac history, including history of defect repairs and pertinent imaging is critical during preoperative assessment.

Airway and Pulmonary Risks
Dysmorphic facies is associated with 80% of patients presenting with 22qDS, which includes long face, ocular hypertelorism, narrow palpebral fissures, squared nasal root, narrowed nares, low-set ears, small mouth, and retrognathia.9 Furthermore, abnormalities of the palate, pharynx, larynx, and trachea are frequent in patients with 22qDS. Cleft palate is present in 9-11% of 22qDS patients.2 Velopharyngeal insufficiency is present in at least one-third of patients and can be due to structural abnormalities (cleft palate) or neuromuscular cause (hypotonia). This can lead to obstructive sleep apnea and recurrent serous otitis media.  Pierre-Robin sequence is seen in 11-17% of patients with 22qDS. The presence of these abnormalities can make insertion of a laryngeal mask airway and intubation with direct laryngoscopy difficult to impossible. It is extremely important to conduct a thorough airway evaluation to formulate a comprehensive airway management plan.  Back up video laryngoscopy and/or fiberoptic bronchoscopy should always be considered in a 22qDS patient with no documented airway history. Short tracheal anatomy can also be seen, necessitating strict attention to the depth of the endotracheal tube once it is inserted to avoid endobronchial (right mainstem) intubation. GERD and pharyngeal and esophageal dysmotility can lead to an increased risk of aspiration, which has been noted in a case report.10 

Immunodeficiency Risks
T-cell immunodeficiency is typical of the DiGeorge Syndrome, and is the result of thymic hypoplasia. It is present in about 17% of patients with 22qDS. These patients tend to have repeated infections, especially infections of the upper airway.9 T-cell mediated immunity gradually improves with age. Nevertheless, strict aseptic technique should be followed during invasive procedures and blood products should be irradiated to prevent graft-versus-host disease.11

Endocrine Risks
Hypocalcemia develops in the newborn period in up to 60% of patients with 22qDS and can be life threatening.12 This typically presents with jitteriness, tetany, and/or generalized seizures. Low serum calcium, elevated serum phosphorus concentrations, and low serum parathyroid hormone levels are seen. Ionized calcium levels should be checked preoperatively and treatment is calcium and vitamin D supplementation. Hypocalcemia, like T-cell mediated immunity, tends to resolve with age9.

Summary
Beyond the classic triad (cardiac anomalies, cell-mediated immunodeficiency, hypocalcemia), 22qDS patients may present with variety of clinical sequelae that may be challenging for the anesthesiologist to manage. Ideally, a collaborative, multidisciplinary approach should be taken to care for these patients and an anesthetic should be administered by a pediatric anesthesiologist. With their expertise, the pediatric anesthesiologist can help reduce the morbidity of operative intervention and diagnostic/therapeutic procedures in patients with this rare microdeletion syndrome. 

Table 1: Clinical features of Chromosome 22q1DS
Adapted from: Hiroe Yotsui-Tsuchimochi et al. Anesthetic management of a child with chromosome 22q11 deletion syndrome. Pediatric Anesthesia 2006; 16: 454–457

References

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