22q11.2 Deletion Syndrome

Introduction

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans with an estimated prevalence between 1:2000 and 1:6000 births. As a comparison, Down syndrome occurs in 1:1200 births globally, making 22q11.2DS the second most common cause of developmental delay and congenital heart defects (CHDs). Other common manifestations of 22q11.2DS include facial dysmorphisms, immune deficiencies, cleft palate, and psychiatric conditions. Historically, its heterogeneous presentations were described by various names, including velocardiofacial, DiGeorge, conotruncal anomaly face, Shprintzen, and CATCH 22 syndromes. ^, However, after the identification of the underlying casual microdeletion in 1981, 22q11.2DS has become the preferred nomenclature. Nonetheless, the large phenotypic variance among affected patients requires complex medical management between multiple subspecialist providers. With a multiplicity of head and neck manifestations, otolaryngologists play an essential role in the coordinated care of these patients.

Genetics

The frequency of 22q11.2DS is related to the genetic architecture of the involved chromosome. The 22q11.2 region includes at least eight low copy repeats (LCRs) consisting of palindromic AT-rich sequences. The similar genetic structure in these repeats results in a high rate of recombination events during which DNA can be duplicated or deleted. In 22q11.2DS, over 85% of patients have a hemizygous deletion in this region resulting in a 1.5- to 3-Mb (megabase) loss. Approximately 90% of cases occur de novo within the population. Because of the inherent susceptibility of the 22q11.2 region to deletions, 22q11.2DS is 10 times more common than the next most common deletion syndrome. ^,

Within the 22q11.2 region, the T-box transcription factor gene ( TBX1 ) is thought to be a major contributor to the clinical manifestations of this syndrome. Expressed in the embryologic endodermal, mesodermal, and ectodermal germ layers of the pharyngeal arches, TBX1 is linked to neural crest cell function and the development of various anatomic regions, including the aortic arches, branchiomeric muscles, and palate. ^, TBX1 knockout mice demonstrate a similar range of cardiovascular, skeletal muscle, palatal, thymic, and parathyroid defects as seen in 22q11.2DS patients. In addition, multiple other genes and environmental factors are proposed to play a role in the manifestations of 22q11.2DS, either directly or indirectly through upstream or downstream effects on TBX1. ^, However, specific genotype-phenotype correlations have not been established, suggesting further research is needed before the clinical manifestations of the syndrome can be predicted by the size or location of the deletion for any one patient. ^,

Testing

Because of the clinical overlap of 22q11.2DS with CHARGE, Kabuki, Smith Lemli Opitz, 10p13-p14 deletion, and Goldenhar syndromes, it is important to use genetic testing to definitively obtain a molecular diagnosis. Diagnostic confirmation aids both in the medical management and counseling of affected individuals and their families. However, there currently are no accepted guidelines for when to test a patient with suspected 22q11.2DS. The variability of the phenotypic features makes it difficult to identify the exact situations in which testing is indicated. Various algorithms have been developed to determine when testing is clinically warranted, with most focusing on a subset of the symptoms that often present simultaneously. Diagnostic strategies generally rely on identification of two or more classic features of the syndrome. These include conotruncal cardiac abnormalities, palatal defects/hypernasal speech, developmental delays/learning disabilities, and characteristic facial dysmorphisms, with psychiatric illness, hypocalcemia, and immunodeficiency included less frequently, ^, However, for patients without two classic symptoms or variability in presentation, even this proposed strategy leaves the decision up to providers, leading to possible diagnostic delay. Notably, although there is no ethnic variation in the incidence of 22q11.2DS, the visible manifestations can vary widely among different ethnic groups, potentially compounding diagnostic uncertainty for clinicians working with diverse patient populations. ^, This testing ambiguity means that providers must maintain a high index of suspicion regarding 22q11.2DS.

Historically, karyotype analysis was the only means to test for 22q11.2DS, but the resolution of this technique was inadequate to detect submicroscopic deletions often associated with the syndrome. Since 1992, fluorescence in situ hybridization (FISH) with DNA probes targeting the chromosome region 22q11.2 has been commonly used. However, FISH is limited by cost and testing time, and although it identifies the majority of deletions, it misses atypical mutations that fall outside of the region of the probe. ^{, ,} Newer options for testing include multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH), and oligonucleotide-targeted chromosomal microarrays (CMAs). ^, Although costs may vary, these methods have the benefit of analyzing more of the genome in less time, missing fewer of the atypical 22q11.2DS deletions and helping to identify other genetic mutations when the diagnosis is uncertain. Thus CMA and MLPA are now frequently chosen as first-line tests for 22q11.2DS and may replace FISH in some laboratories. ^{, , , ,}

Although most instances of 22q11.2DS result from sporadic mutations, an increasing number of cases involve inherited mutations. Death in childhood from 22q11.2DS is now uncommon and most often a result of cardiac disease. The vast majority of 22q11.2DS patients survive into adulthood. As the prevalence of affected adults continues to increase, it is important to note that patients with milder phenotypes are more likely to reproduce, supporting the recommendation to pursue genetic testing for the parents of diagnosed children. ^, If positive, genetic counseling should be offered regarding late-onset symptoms and education on the 50% recurrence risk for future children.

Although there is uncertainty regarding who to test, there is agreement that earlier identification of 22q11.2DS is beneficial. ^, Prenatal testing is becoming increasingly common, mainly after ultrasound identification of fetal heart defects. However, a significant proportion of patients with 22q11.2DS will present to the otolaryngologist prior to the molecular diagnosis. By developing the clinical acumen to recognize the head and neck manifestations of the syndrome, the otolaryngologist will be able to appropriately refer for testing and provide access to interventions and multidisciplinary teams, optimizing care for these complex patients.

Otolaryngologic Manifestations of Disease

Facial Dysmorphisms

The presence of facial dysmorphisms is common, yet variable among 22q11.2DS patients ( Table 11.1 and Fig. 11.1 ). For many patients, the abnormalities are subtle and may not be noticed until after the syndrome is diagnosed. Differences related to ethnicity and age may lead to variations in facial appearance and contribute to inconsistent identification. ^{, ,} Because of the degree of clinical experience needed to associate the various dysmorphisms with 22q11.2DS, facial analysis technology is now being used in an attempt to aid early detection.

TABLE 11.1

A Summary of Ophthalmologic, Craniofacial, Nasal, and Otologic Features Seen in 22q11.2DS

Facial Dysmorphisms in 22q11.2 Deletion Syndrome
Ophthalmic	Nasal
Narrow palpebral fissures	Broad nose
Epicanthal folds	Bulbous nasal tip
Hooded eyelids	Thickened nasal bridge
Ptosis	Prominent nasal root
Hypertelorism	Elongated nose
Slanting eyes (up or down)	Narrow nares/alar base
Superior eyebrow displacement	Nasal dimpling/bifid tip appearance
Strabismus
Coloboma	External Auricular
	Low set ears
Craniofacial	Attached lobules
Retrognathia	Rotated ears (posteriorly)
Elongated face	Helical anomaly
Lower facial hypoplasia	Overfolded helix
Thin lips	Thickened helix
Small mouth	Adherent helix
Microcephaly	Squared off helix
Facial asymmetry/hemifacial microsomia	Small ears/microtiaCupped earsProtuberant ears
Asymmetric crying facies
Craniosynostosis

The most commonly noted craniofacial features are a broad nose, malar flattening, and retrognathia. Although once thought to be independent findings, it has been postulated that these features are all a consequence of an enlarged cranial base angle known as platybasia. The resultant posterior rotation of the glenoid fossa and temporomandibular joint leads to retrognathia. A retruded mandible gives an appearance of vertical maxillary excess and flat malar eminences because of its more posterior position. An alternate theory posits that TBX1 mutations cause altered mandibular formation from the first pharyngeal arches in these patients. Other commonly described craniofacial features include lower face hypoplasia, hemifacial microsomia, and asymmetric crying facies.

The effect of 22q11.2DS on the pharyngeal development of the branchiomeric muscles, external ear, and other facial structures dictates a number of other facial dysmorphisms. Common nasal manifestations include a narrow alar base, along with a bulbous or bifid nasal tip. ^, Eyelid hooding, hypertelorism, and slanting palpebral fissures are the most frequently reported ocular manifestations. ^, Last, patients with 22q11.2DS have a number of auricular anomalies. Although low set, rotated, or protuberant pinna are common, microtia and preauricular pits have also been noted in this patient population. ^{, , ,} Aside from external anomalies, children with 22q11.2DS often have narrow external auditory canals, which may limit the ability to perform otoscopic examinations.