Clinical Description

Clinical Description

Natural History

Findings in 250 individuals (48% male; 52% female) with 22q11.2 deletion syndrome are summarized below [McDonald-McGinn et al 1999b]. In unpublished data on 600 individuals, the percentages for the following findings remain the same [Author, unpublished data 2005].

Thirty-three percent of individuals were five years of age or younger. Marked inter- and intrafamilial variability is observed.

Genotype-Phenotype Correlations

The majority of individuals have the same large deletion of the DGCR. Of note, the size of the deletion remains unchanged with parent-to-child transmission. The great inter- and intrafamilial clinical variability makes genotype-phenotype correlations difficult [Driscoll et al 1995, McDonald-McGinn et al 2001]. Anecdotally, developmental delays appear to be more significant in familial cases; however, this may reflect socioeconomic rather than genetic factors.

Penetrance

Penetrance is complete in individuals with deletion 22q112 detected by FISH; variability is marked.

Anticipation

To date, anticipation has not been observed.

Nomenclature

It is now recognized that the 22q11.2 deletion syndrome encompasses the phenotypes previously called DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS) (Shprintzen syndrome), conotruncal anomaly face syndrome (CTAF) [Matsuoka et al 1994], many cases of the autosomal dominant Opitz G/BBB syndrome [McDonald-McGinn et al 1995, Fryburg et al 1996, LaCassie & Arriaza 1996], and Cayler cardiofacial syndrome (asymmetric crying facies) [Giannotti et al 1994]. The clinical descriptions of DGS, VCFS, and CTAF resulted from an ascertainment bias.

DGS was originally described as a developmental field defect of the third and fourth pharyngeal pouches with a conotruncal cardiac anomaly and aplasia or hypoplasia of the thymus gland and parathyroid glands. Later, congenital heart disease was added. The majority of individuals with DGS were identified in the neonatal period with a major congenital heart defect, hypocalcemia, and immunodeficiency.

VCFS, also called Shprintzen syndrome, was originally described as the combination of velopharyngeal incompetence (VPI), congenital heart disease (usually a ventricular septal defect or tetralogy of Fallot), characteristic facial features, and developmental delay or learning difficulties. Children with VCFS tended to be diagnosed in cleft palate clinics or craniofacial centers when they reached school age and speech and learning difficulties became evident [Wilson et al 1993, Wulfsberg et al 1996, McDonald-McGinn et al 1997b, Thomas & Graham 1997].

Prevalence

Estimates of prevalence vary from one in 4000 [Wilson et al 1994] to one in 6395 [Devriendt et al 1998]. Given the variable expression of the deletion 22q11.2, the incidence is probably much higher than previously estimated. In a population-based study in Sweden, the mean annual incidence was 14.1 per 100,000 live births [Oskarsdottir et al 2004, Oskarsdottir et al 2005a, Oskarsdottir et al 2005b]. A U.S. population-based study conducted by the Centers for Disease Control (CDC) found an overall prevalence of about one in 6000 in whites, blacks, and Asians, and one in 3800 in Hispanics [Botto et al 2003].

Congenital heart defects are present in 74% of affected individuals and are the major cause of mortality (>90% of all deaths) in this diagnosis [McDonald-McGinn et al 2001] (Table 2).

Table 2. Cardiac Findings in 222 Individuals with 22q11.2 Deletion Syndrome

Cardiac Finding % of Affected Individuals
Tetralogy of Fallot (TOF) 22%
Interrupted aortic arch (IAA) 15%
Ventricular septal defect (VSD) 13%
Truncus arteriosus (TA) 7%
Vascular ring 5%
Atrial septal defect 3%
Aortic arch anomaly 3%
VSD; ASD 4%
Other 1 4%
Normal 26%
From McDonald-McGinn et al [1999a]
  1. Hypoplastic left heart syndrome; pulmonary valve stenosis; double outlet right ventricle/interrupted aortic arch; bicuspid aortic valve; heterotaxy/A-V canal/interrupted aortic arch

 

Sixty-nine percent of individuals with deletion 22q11.2 have a palatal abnormality (Table 3). The most common, velopharyngeal incompetence (VPI), may be a structural problem (short palate), a functional problem (hypotonia of the velophayrngeal musculature), or a combination of the two. Often children initially diagnosed with deletion 22q11.2 because of a cardiac defect are subsequently found to have unrecognized but clinically significant VPI [McDonald-McGinn et al 1997a]. About 17% of persons have no palatal involvement.

Table 3. Palatal Findings with 22q11.2 Deletion Syndrome

Palatal Finding % of Affected Individuals
Velopharyngeal incompetence (VPI) 27%
Submucosal cleft palate (SMCP) 16%
Overt cleft palate 11%
Bifid uvula 5%
Cleft lip/cleft lip and palate 1 2%
Infantile VPI 2 8%
Need follow-up 3 14%
Normal 17%

From McDonald-McGinn et al [1999b]

  1. Either unilateral or bilateral
  1. “Infantile VPI” or occult submucosal cleft palate diagnosed by history (nasal regurgitation and frequent otitis media), physical examination, or nasendoscopy (incomplete closure of the velopharyngeal mechanism during crying and swallowing) in children too young to provide an adequate speech sample for definitive diagnosis
  1. No overt abnormality, but children too young to provide an adequate speech sample

About 30% of children have feeding difficulties, often severe dysphagia requiring nasogastric tube feedings and/or gastrostomy tube placement. Feeding difficulties are independent of cardiac defects and palatal anomalies. Further evaluation of such children may reveal a preponderance of nasopharyngeal reflux, prominence of the cricopharyngeal muscle, abnormal cricopharyngeal closure, and/or diverticulum. Thus, the underlying feeding problem in many children appears to be dysmotility in the pharyngoesophageal area, which is derived from the third and fourth pharyngeal pouches [Eicher et al 2000].

Immunodeficiency occurs as a result of thymic hypoplasia. Because the role of the thymus is to support the maturation of functional T cells, impaired T-cell production is the primary defect. T-cell functional defects and antibody defects are less common and are secondary to the T-cell production abnormality [Sullivan 2004].

Compared to control individuals without the deletion, newborns with the 22q11.2 deletion syndrome have significantly fewer cells of thymic lineage; however, improvement in T-cell production occurs over time. In one study, children with the most significant deficiencies in T-cell production improved most in the first year of life [Sullivan et al 1999]. In a study of immune function in 60 affected children over the age of six months, 77% were considered to be immunodeficient regardless of their clinical presentation. Sixty-seven percent had impaired T-cell production, 19% had impaired T-cell function, 23% had humoral defects, and 13% had IgA deficiency [Smith et al 1998, Sullivan et al 1998].

Additional phenotypic features associated with 22q11.2 deletion syndrome such as aspiration pneumonia, palatal dysfunction, and gastroesophageal reflux can all contribute to recurrent infection, especially true in persons with congenital heart disease. Furthermore, dysphagia can lead to poor nutrition which further impairs cellular immunity. Despite these issues, very few school-aged children require active management for their immunodeficiency [Sullivan 2004].

Hypocalcemia is present in 17-60% of persons with deletion 22q11.2 and is typically most serious in the neonatal period. Calcium homeostasis typically normalizes with age, although recurrence of hypocalcemia in later childhood has been reported during illness and/or puberty. In some instances, children receiving ongoing care for infantile hypocalcemia may not be diagnosed with the 22q11.2 deletion syndrome until school age; while at least one otherwise asymptomatic adult came to attention following onset of hypoparathroidism in the fourth decade [M Eagen, personal communication].

Craniofacial findings include auricular abnormalities, nasal abnormalities, “hooded eyelids,” ocular hypertelorism, cleft lip and palate, asymmetric crying facies, and craniosynostosis [McDonald-McGinn et al 2005a]. However, the presence of these features as well as other facial findings, such as a long face and malar flatness, is variable. In fact, some individuals offer no clues to their underlying diagnosis based on their facial features, especially persons of African-American heritage [McDonald-McGinn et al 1996, McDonald-McGinn et al 2005b].

A prospective evaluation for ocular abnormalities in 33 individuals revealed hooding of the upper lids (41%), ptosis (9%), hooding of the lower lids (6%), epicanthal folds (3%), and distichiasis (3%). Other findings included posterior embryotoxon (69%), isolated corneal nerves (3%), sclerocornea (3%), deep iris crypts (10%), tortuous retinal vessels (58%), small optic nerves (7%), and tilted discs (3%). Strabismus was observed in 13% and amblyopia in 6%. While posterior embryotoxon was observed in 12-32% of controls, the incidence in individuals with the 22q11.2 deletion syndrome was almost as high as that seen in Alagille syndrome (89%) [Krantz et al 1997]. The incidence of astigmatism, myopia, and hyperopia was comparable to that in the general population. A small number of persons have cataracts and colobomas.

Ear abnormalities include overfolded or squared off helices; cupped, microtic, and protuberant ears; preauricular pits or tags, and narrow external auditory meati. A prominent nasal root, bulbous nasal tip, hypoplastic alae nasae, and a nasal dimple/bifid nasal tip are common [Gripp et al 1997]. Stridor resulting from vascular ring, laryngomalacia, and laryngeal webs can occur. Chronic otitis media and chronic sinusitis are common. Both sensorineural and conductive hearing loss have been reported.

Although the majority of individuals with the 22q11.2 deletion syndrome have a history of hypotonia in infancy and learning disabilities [Moss et al 1995], specific neurologic manifestations are uncommon. Seizures are seen in some individuals and are most often, but not always, associated with hypocalcemia. In one study, 7% (27/383) of persons with deletion 22q11.2 had unprovoked seizures [Kao et al 2004].

Several individuals have asymmetric crying facies [Cayler 1969, Levin et al 1982, Silengo et al 1986, Sanklecha et al 1992, Giannotti et al 1994].

Rarely, ataxia and atrophy of the cerebellum are observed [Lynch et al 1995].

Additional CNS abnormalities include multicystic white matter lesions of unknown significance and perisylvian dysplasia [Bingham et al 1997], hypoplastic pituitary gland, and polymicrogyria (see Polymicrogyria Overview).

Recent investigations utilizing functional MRI scans revealed significantly reduced posterior brain volumes relative to age- and sex-matched controls with more significant white matter loss in the left occipital and left parietal regions than in the frontal lobes [Barnea-Goraly et al 2003, Bearden et al 2004, Bish et al 2004, Kates et al 2004]. Many of these changes in brain structure can be postulated to relate to the specific cognitive deficits exhibited in the area of working memory, executive function, visuospatial skill, language, and math performance.Overall, the pattern of CNS abnormalities is broad and overlaps with that seen in some cases of Opitz G/BBB syndrome [Neri et al 1987, Guion-Almeida & Richieri-Costa 1992, MacDonald et al 1993].

Overall, the pattern of CNS abnormalities is broad and overlaps with that seen in some cases of Opitz G/BBB syndrome [Neri et al 1987, Guion-Almeida & Richieri-Costa 1992, MacDonald et al 1993].

In general, young children with the 22q11.2 deletion syndrome have delays in motor milestones (mean age at walking of 18 months), delay in emergence of language (many are nonverbal at age 2-3 years), and autism/autistic spectrum disorders in approximately 20% [Fine et al 2005].

Specifically, in a study of 28 toddlers assessed with standardized tests, mental development was average in 21%, mildly delayed in 32%, and significantly delayed in 46%; in motor development, 8% were average, 13% were mildly delayed, and 79% were significantly delayed.

In a group of 12 preschoolers assessed using the WPPSI-R, the full-scale IQ was 78±11, the mean performance IQ was 78±14, and the mean verbal IQ was 82±15. In total language, 16% were average, 44% were mildly delayed, and 40% were significantly delayed [Solot et al 1998].

Older individuals with 22q11.2 deletion syndrome generally have an atypical neuropsychologic profile across multiple domains, the most striking aspect of which is a significantly higher verbal IQ score than performance IQ score. Moss et al [1995] observed a mean split between the verbal IQ and performance IQ in 66% of 80 school-age children consistent with a nonverbal learning disability that is rare in the general population [Wang et al 1998]. Because the full-scale IQ score alone does not accurately represent the abilities of many individuals with 22q11.2 deletion syndrome, verbal and performance IQ scores need to be considered separately. In addition, affected individuals exhibit relative strengths in the areas of rote verbal learning and memory, reading decoding, and spelling. Deficits are found in the areas of nonverbal processing, visual-spatial skills, complex verbal memory, attention, working memory, visual-spatial memory, and mathematics. This evidence of stronger verbal than visual memory skills and stronger reading than math skills also supports the presence of a nonverbal learning disorder that requires specific cognitive remediation, behavior management, and parental counseling.

In a group of 80 school-aged children assessed with the age-appropriate Weschler IQ test, the mean IQ score was 76, whereas, 18% attained full-scale IQ scores in the average range, 20% in the low-average range, 32% in the borderline range, and 30% in the retarded range.

Behavior and temperament observed in some individuals with the 22q11.2 deletion syndrome include disinhibition and impulsiveness on the one hand and shyness and withdrawal on the other [Swillen et al 1999]. Attention deficit, anxiety, perseveration, and difficulty with social interactions are also common, along with autism and autistic spectrum disorders [Swillen et al 1999; Niklasson et al 2001; Vorstman, personal communication].

The incidence of psychiatric disorders, including schizophrenia, bipolar disorder, anxiety, and depression, is increased. The prevalence and exact nature of these psychiatric disorders are still being investigated [Shprintzen et al 1992, Chow et al 1994, Bassett et al 1998, Yan et al 1998, Murphy et al 1999, Baker & Skuse 2005, Bassett et al 2005, Oskarsdottir et al 2005]

Most adults with the 22q11.2 deletion syndrome are of normal stature; however, in 95 children between the ages of one and 15 years, 41% were below the fifth centile in height. Of these, four were significantly below the fifth centile; all had low levels of growth factors IGF1 and IGFBP3. Three had evidence of growth hormone deficiency; three had a small pituitary gland on MRI; and two responded to human growth hormone therapy [Weinzimer et al 1998].

Polyarticular juvenile rheumatoid arthritis (JRA) occurs in children with the 22q11.2 deletion syndrome at a frequency 20 times that of the general population rate. The age of onset of JRA ranges from 17 months to five years. HLA types permissive for the development of JRA are observed [Sullivan et al 1997, Keenan et al 1997]. Other autoimmune disorders associated with 22q11.2 deletion syndrome include: idiopathic thrombocytopenia purpura (ITP), hyperthyroidism (Grave’s disease), hypothyroidism, vitiligo, hemolytic anemia, autoimmune neutropenia, aplastic anemia, and celiac disease. ITP is seen 200 times more frequently in individuals with deletion 22q11.2 than in the general population [Sullivan et al 1997, Jawad et al 2001, Kawame et al 2001].

Of 108 individuals evaluated for skeletal abnormalities, 6% had upper-extremity anomalies, including pre- and postaxial polydactyly, and 15% had lower-extremity anomalies including postaxial polydactyly, club foot, overfolded toes, and syndactyly of toes 2 and 3 [Ming et al 1997].

Of 63 individuals on whom chest films were examined, 19% had vertebral anomalies including butterfly vertebrae, hemivertebrae, and coronal clefts; 19% had rib anomalies, most commonly supernumerary or absent ribs. Hypoplastic scapulae were seen in 1.5% [Ming et al 1997]. Significant cervical spine abnormalities observed in 50% of 79 persons studied prospectively included posterior block vertebrae of C2-C3 without block vertebrae in 21%, hypoplastic/anomalous C1 in 75%, dysmorphic C2 in 59%, and posterior element fusion with block vertebrae of C2-C3 in 13% [Ricchetti et al 2004]. In addition, 56% of persons with cervical spine anomalies had instability on flexion and extension radiographs; 33% had increased motion at more than one vertebral level; of these, four children had abnormalities including increased C2-C3 segmental motion with anterior and posterior narrowing of the spinal canal on further examination with cervical CT scan and/or MRI. Two of the four had surgical stabilization; one of the two required an emergency procedure following onset of symptoms of spinal cord compression.

A prospective evaluation using renal ultrasonography in 80 individuals with the 22q11.2 deletion syndrome who had no prior history of uropathy revealed renal or other GU abnormalities in 31% [Wu et al 2002]. These included single kidney, echogenic kidney, multicystic dysplastic kidney/small kidneys, calculi, bladder wall thickening, horseshoe kidney, duplicated collecting system, renal tubular acidosis, and hydronephrosis (5%), and enuresis. The high incidence of renal abnormalities is similar to that reported by Devriendt et al [1996]. In addition, hypospadias, undescended testes [McDonald-McGinn et al 1995] and absent uterus have also been observed [Huff, personal communication].

Other findings observed in individuals with the 22q11.2 deletion syndrome include: abnormal lung lobation, significant constipation, imperforate anus, intestinal malrotation/nonrotation, Hirshsprung disease, diaphragmatic hernia (including late presentation), umbilical and inguinal hernia, leg pain, and craniosynostosis [McDonald-McGinn et al 1995, McDonald-McGinn et al 1999a, McDonald-McGinn et al 2004, McDonald-McGinn et al 2005a].

Bernard-Soulier syndrome (BSS) [Budarf et al 1995], an autosomal recessive disorder of thrombocytopenia and giant platelets, is caused by a mutation in one of four genes, one of which (GP1BB) maps to 22q11.2. BSS is associated with the 22q11.2 deletion syndrome in persons whose non-deleted chromosome 22 has a mutation in GP1BB. Individuals with both 22q11.2 deletion syndrome and BSS are particularly susceptible to bleeding secondary to surgical procedures.

Despite recent reports of neoplasia in individuals with deletion 22q11.2, it is unclear if deletion 22q11.2 predisposes to cancer. Malignancies reported include: hepatoblastoma [Patrone et al 1990; Scattone et al 2003; Adam, personal communication 2004]; renal cell carcinoma [Scattone et al 2003]; Wilms tumor [Wallgren-Pettersson, personal communication]; and neuroblastoma [Chatten et al 1991]. Based on these reports a causal relationship between 22q11.2 deletion syndrome and hepatoblastoma seems likely as the population incidence of hepatoblastoma is 1:1,000,000.

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