Clinical Description (V体育官网)

This section summarizes findings based on publications of individuals with 22q11.2 deletion syndrome (22q11.2DS).

Heart. A recent record review of 1,421 individuals with 22q11.2DS revealed congenital heart defects (CHD) in 64% of individuals [Campbell et al 2018]. The most frequent anomalies are conotruncal defects of the outflow tract (see Table 2). Ventricular septal defects were the most common abnormality identified on echocardiography. CHD are the major cause of mortality (~87% of all deaths) in children with 22q11.2DS [McDonald-McGinn et al 2015]. In addition, adults with 22q11.2DS die prematurely, with sudden death and heart failure being the most common causes of death, even in individuals without CHD [Bassett et al 2009]. A subset of affected individuals are found to have dilated aortic root [John et al 2009]. The natural history of aortic root dilatation is unknown.

Palate. In a review of 1,048 individuals with 22q11.2DS, 67% of individuals had a palatal abnormality (Table 3) [Jackson et al 2019] – a finding consistent with previous studies. The most common abnormality, velopharyngeal incompetence (VPI), may be a structural problem (short palate), a functional problem (hypotonia of the velopharyngeal musculature), or a combination of the two. Submucosal cleft palate and/or a bifid uvula are also fairly prevalent, whereas overt cleft palate and cleft lip/palate are less frequently observed. Often children initially diagnosed with 22q11.2DS because of a cardiac defect are subsequently found to have unrecognized but clinically significant VPI [McDonald-McGinn et al 1997]. It is important to note that the reported incidence of palatal abnormalities varies widely, depending on numerous factors including the reporting technique, the diligence with which the diagnosis is sought, the age at which the individual is evaluated, and the inherent ascertainment bias of any single center. About 26.6% of persons have no palatal involvement.

Feeding. About 36% of children have significant feeding difficulties, often severe dysphagia requiring nasogastric tube feedings and/or gastrostomy tube placement. Feeding difficulties have been reported in individuals without cardiac defects or palatal anomalies. Further evaluation of such children often reveals 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. Aspiration should be considered a possible cause for respiratory compromise or recurrent pulmonary infections and reactive airway disease [Eicher et al 2000].

Constipation is a chronic feature in the majority of individuals. In addition, structural anomalies such as imperforate anus, intestinal malrotation, intestinal non-rotation, congenital diaphragmatic hernia, esophageal atresia, tracheoesophageal fistula, Hirschsprung disease, and feeding difficulties secondary to a vascular ring have all been reported and can contribute to significant feeding and swallowing problems and in some instances to constipation [Digilio et al 1999, Kilic et al 2003, Jyonouchi et al 2009, Campbell et al 2018].

Immune function. Immunodeficiency occurs as a result of thymic hypoplasia and subsequent impaired T-cell production. Newborns with 22q11.2DS have significantly fewer cells of thymic lineage. In previous studies, 67% of individuals had impaired T-cell production and 19% had impaired T-cell function [Smith et al 1998, Sullivan et al 1999, Sullivan 2019]. In a study of 1,421 individuals with 22q11.2DS, 50% had abnormal T-cell populations [Campbell et al 2018]. Improvement in T-cell production occurs over time and children with the most significant deficiencies in T-cell production improved most in the first year of life [Sullivan et al 1999]. Individuals with slight decreases in T-cell numbers typically had normal defenses against pathogens [Sullivan 2019].

CD4+ lymphopenia is associated with TBX1 deletions. In a study of 52 infants approximately age one year, CD3 and CD4 counts were significantly lower in infants with a TBX1 deletion (proximal deletions; A-B, A-C, A-D) than in those who did not have a TBX1 deletion (nested and distal deletions; B-D, C-D, D-E, D-F) [Crowley et al 2018].

Abnormalities of humoral immunity were observed in 17% of individuals [Campbell et al 2018]. IgA deficiency was reported in 13% and appears to be particularly common in those with autoimmune problems including juvenile rheumatoid arthritis (JRA) [Sullivan 2019]. Hypogammaglobulinemia present in the first year of life usually resolves and hypergammaglobulinemia may occur after age five. Although the majority of affected individuals have normal antibody function and antibody avidity, some have functional antibody defects. Those with recurrent sinopulmonary infections frequently have immunoglobulin abnormalities, in particular impaired antibody responses to pneumococcal polysaccharide vaccine [Gennery et al 2002, Sullivan 2019].

Palatal dysfunction, gastroesophageal reflux, and aspiration pneumonia can all contribute to recurrent infection, especially in persons with congenital heart disease. Furthermore, dysphagia can lead to poor nutrition, which further impairs cellular immunity. Thus, older children and adults continue to have infections, including 25%-33% with recurrent sinusitis or otitis media and 4%-7% with recurrent lower respiratory infections [Jawad et al 2001]. However, despite these issues, very few school-aged children require active management for their immunodeficiency [Sullivan 2019].

Autoimmune disease. Secondary consequences related to T-cell lymphopenia include an increased risk of atopy and autoimmune disease. JRA occurs in children with 22q11.2DS at a frequency 20 times that in the general population. The age of onset of JRA ranges from 17 months to five years. JRA is often polyarticular and may be difficult to manage. HLA types permissive for the development of JRA are observed [Sullivan et al 1997]. Other autoimmune disorders associated with 22q11.2DS include: idiopathic thrombocytopenia purpura (ITP), hyperthyroidism (Graves disease), hypothyroidism, vitiligo, hemolytic anemia, autoimmune neutropenia, aplastic anemia, and celiac disease. ITP is seen 200 times more frequently in individuals with 22q11.2DS than in the general population [Jawad et al 2001, Kawame et al 2001, Sullivan 2019].

Parathyroid function. Hypoparathyroidism and subsequent hypocalcemia is present in 17%-60% of persons with 22q11.2DS and is typically most serious in the neonatal period. Calcium homeostasis often normalizes with age, although recurrence of hypocalcemia in later childhood and adulthood has been reported during illness, puberty, and pregnancy. Cheung et al [2014] reported that 80% of adults with 22q11.2DS experienced hypocalcemia sometime during their lifetime, and that hypoparathyroidism, hypothyroidism, and hypomagnesemia may contribute to hypocalcemia.

Growth. Most adults with 22q11.2DS are of normal stature; however, in 95 children between age one and 15 years, 41% were below the fifth percentile in height. Of these, four were significantly below the fifth percentile; all four individuals had low concentrations of 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]. Growth charts specific to 22q11.2DS have been developed [Habel et al 2012]. Obesity has been reported in up to 35% of adults with 22q11.2DS [Bassett et al 2005].

Eyes. A prospective evaluation for ocular abnormalities in 90 individuals revealed hooding lids (20%), ptosis (4%), and distichiasis (abnormal growth of lashes from the orifices of the meibomian glands) (2%). Other findings included posterior embryotoxon (49%), prominent corneal nerves (3%), prominent iris crypts (2%), tortuous retinal vessels (34%), and tilted optic nerves (1%). Strabismus was observed in 18% and amblyopia in 4%. A small number of persons have cataracts and colobomas [Forbes et al 2007]. While posterior embryotoxon was observed in 12%-32% of controls, the incidence in individuals with 22q11.2DS 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. Anophthalmia has been observed in a very small subset of individuals [Author, unpublished data].

Other craniofacial features. In addition to palate and ocular anomalies craniofacial findings can include ear anomalies, nasal anomalies, asymmetric crying facies, micrognathia, and craniosynostosis [McDonald-McGinn et al 2015]. Ear abnormalities include overfolded or squared off helices; cupped, microtic, and protuberant ears; preauricular pits or tags; and narrow external auditory meati. Sensorineural and conductive hearing loss have both been reported. A prominent nasal bridge, bulbous nose, hypoplastic alae nasi, and nasal dimple / bifid nasal tip are common [Campbell et al 2018]. Stridor resulting from vascular ring, laryngomalacia, and laryngeal web, laryngeal atresia, and subglottic stenosis can occur. Facial features are variable and may not be present especially in persons of African American descent [Kruszka et al 2017].

Central nervous system. The majority of individuals with 22q11.2DS have a history of hypotonia in infancy [Swillen & McDonald-McGinn 2015]. Studies report asymmetric crying facies in 8%-14% of individuals [McDonald-McGinn et al 1997, Campbell et al 2018]. Microcephaly has been reported in 24%-50% of affected individuals [McDonald-McGinn & Sullivan 2011, Campbell et al 2018]. Seizures are most often associated with hypocalcemia. However, approximately 15% of persons with 22q11.2DS had unprovoked seizures [Fung et al 2015].

A study of 24 individuals with 22q11.2DS and MRI/ MRA showed more than half (13/24) had significant radiographic findings, including persistent cavum septi pellucidi and/or cavum vergae (8/24), polymicrogyria or cortical dysplasia (4/24), and hypoplastic cerebellum (1/24) [Bohm et al 2017]. 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 [Bearden et al 2004, Bish et al 2004, Kates et al 2004]. A large multi-site study using diffusion tensor imaging indicated widespread reductions in mean, axial, and radial diffusivities in individuals with 22q11.2DS especially in major cortico-cortical connections [Villalón-Reina et al 2020].

Psychosocial development and cognitive function. In general, young children with 22q11.2DS have delays in motor milestones with a mean age at walking of 18 months, and delay in emergence of language (many are nonverbal at age 2-3 years).

In 55 toddlers assessed with Bayley Scales, mental development was average in 22%, mildly delayed in 20%, and significantly delayed in 58%. The mean mental developmental index was 67±15, which falls in the significantly delayed range, and the mean psychomotor developmental index was 61±13. Speech and language delays were present in all children assessed. In the same study, in a group of 24 preschoolers assessed using the WPPSI-R, the full-scale IQ was 78±12, the mean performance IQ was 78±12, and the mean verbal IQ was 81±13. In total language, 20% were average, 46% were mildly delayed, and 34% were significantly delayed with receptive language scores higher than expressive [Gerdes et al 2001].

In a group of 80 school-aged children assessed with the age-appropriate Weschler IQ test, the mean IQ score was 76.8±13.0; 39% attained full-scale IQ scores in the average range, 31% in the low-average range, and 31% in the borderline range [Niarchou et al 2014].

Older individuals with 22q11.2DS 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 [Swillen et al 2018]. Because the full-scale IQ score alone does not accurately represent the abilities of many individuals with 22q11.2DS, 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.

Psychiatric illness. Behavior and temperament observed in some individuals with 22q11.2DS include disinhibition and impulsiveness on the one hand and shyness and withdrawal on the other. Attention deficit, anxiety, perseveration, and difficulty with social interactions are also common. Autism / autism-spectrum disorders are reported in approximately 20% of individuals [Swillen & McDonald-McGinn 2015].

It has been suggested that 60% of adults have a psychiatric disorder. Most notably, schizophrenia is identified in approximately 25% of individuals; however, anxiety and depressive disorders are also quite common [Bassett et al 2011]. Behavioral differences may begin at a young age; screening children with 22q11.2DS for psychiatric issues before age ten years may provide an opportunity for early intervention [Swillen & McDonald-McGinn 2015].

Early-onset Parkinson disease. 22q11.2DS is associated with an increased risk of early-onset Parkinson disease with a reported prevalence of 5.9% [Fung et al 2015]. To date, there are few studies of other neurodegenerative disorders in 22q11.2DS.

Musculoskeletal system. A review of the musculoskeletal manifestations in 22q11.2DS revealed strong evidence that 90.5%-100% of individuals with occiput and cervical imaging (10 studies including 408 individuals) had at least one occipital-cervical anomaly [Homans et al 2018]. Common features included flattening of the skull, dysmorphic shape or an open arch at the first cervical vertebra, and dysmorphic dens with upswept lamina and posterior elements at the second vertebra. A frequently reported anomaly on flexion-extension radiographs is increased segmental motion (56%). Scoliosis was described in 14 studies (2,264 individuals), with a prevalence of 0.6%-60%. Rib anomalies were noted in two studies with a prevalence of 2%-19% and vertebral differences were observed in 1.1%-11%.

The most common extremity manifestation is pes equinovarus (clubfoot) which was described in 15 studies (2,115 individuals), with a prevalence of 1.1%-13.3%. Patellar dislocation was observed in three studies with a prevalence of 10%-20%, though this evidence was weaker. Other anomalies reported included polydactyly, shoulder deformities, and overfolded toes.

Genitourinary. Renal anomalies were identified in 16% of individuals with 22q11.2DS; the most common anomalies included unilateral hydronephrosis, renal agenesis, and multicystic dysplastic kidney [Campbell et al 2018]. Although hydronephrosis was the most common upper tract finding, the majority (63%) had isolated upper tract dilatation. Boys were significantly more likely to be diagnosed with a genitourinary abnormality than girls (8% vs 0.5%). Among males, 4% had cryptorchidism and 4% had hypospadias. Additional anomalies in females included vaginal agenesis in two individuals and uterine agenesis in one individual. Other reported abnormalities included umbilical hernia, inguinal hernia, chordee, phimosis, and undescended testes.

Other. Other findings observed in individuals with 22q11.2DS:

• Abnormal lung lobation [McDonald-McGinn et al 1995]
• Dental carries
• Malignancies including hepatoblastoma, renal cell carcinoma, thyroid carcinoma, melanoma, leukemia, Wilms tumor, and neuroblastoma [Campbell et al 2018, Lambert et al 2018]; overall prevalence approximately 6%
• Autosomal recessive disorders (reported in individuals with 22q11.2DS and a "V体育安卓版" pathogenic variant of the second allele) including Bernard-Soulier syndrome (caused by a "V体育安卓版" pathogenic variant in GP1BB) and CEDNIK syndrome (caused by a "V体育安卓版" pathogenic variant in SNAP29) [Campbell et al 2018].