A unique phenotype in a patient with a rare triplication of the 22q11.2 region and new clinical insights of the 22q11.2 microduplication syndrome: a report of two cases

Abstract

BackgroundThe rearrangements of the 22q11.2 chromosomal region, most frequently deletions and duplications, have been known to be responsible for multiple congenital anomaly disorders. These rearrangements are implicated in syndromes that have some phenotypic resemblances. While the 22q11.2 deletion, also known as DiGeorge/Velocardiofacial syndrome, has common features that include cardiac abnormalities, thymic hypoplasia, characteristic face, hypocalcemia, cognitive delay, palatal defects, velopharyngeal insufficiency, and other malformations, the microduplication syndrome is largely undetected. This is mainly because phenotypic appearance is variable, milder, less characteristic and unpredictable. In this paper, we report the clinical evaluation and follow-up of two patients affected by 22q11.2 rearrangements, emphasizing new phenotypic features associated with duplication and triplication of this genomic region.Case PresentationPatient 1 is a 24 year-old female with 22q11.2 duplication who has a heart defect (ostium secundum atrial septal defect) and supernumerary teeth (hyperdontia), a feature previously not reported in patients with 22q11.2 microduplication syndrome. Her monozygotic twin sister, who died at the age of one month, had a different heart defect (truncus arteriousus). Patient 2 is a 20 year-old female with a 22q11.2 triplication who had a father with 22q11.2 duplication. In comparison to the first case reported in the literature, she has an aggravated phenotype characterized by heart defects (restrictive VSD and membranous subaortic stenosis), and presented other facial dysmorphisms and urogenital malformations (ovarian cyst). Additionally, she has a hemangioma planum on the right side of her face, a feature of Sturge-Weber syndrome.ConclusionsIn this report, we described hyperdontia as a new feature of 22q11.2 microdeletion syndrome. Moreover, this syndrome was diagnosed in a patient who had a deceased monozygotic twin affected with a different heart defect, which corresponds to a phenotypic discordance never reported in the literature. Case 2 is the second clinical report of 22q11.2 triplication and presents an aggravated phenotype in contrast to the patient previously reported.

Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis

“…Duplication, triplication and hemizygous deletion of a few hundred kb to a few Mb, collectively termed copy number variants, confer the most robust risk factors, to date, for developmental delays in cognitive function and developmental neuropsychiatric disorders. 20 , 21 , 22 Carriers of a 1.5 Mb to 3 Mb duplication or triplication at human chromosome 22q11.2 exhibit high rates of developmental delays in cognitive capacities 23 , 24 , 25 and ASD and ID. 26 Duplication of this chromosomal locus is also enriched in individuals with ASD and ID.…”

Importance and usage of chromosomal microarray analysis in diagnosing intellectual disability, global developmental delay, and autism; and discovering new loci for these disorders

“…In case 23, parents’ diagnoses support the duplication of region 22q11.2 in both alleles, which can be described as homozygous duplication. Case 23 is the fifth patient diagnosed with 22q11.2 tetrasomy in the literature [ 4 , 10 , 11 ] and the third patient diagnosed with 22q11.2 homozygote duplication (Table 2 ). In other published 22q11.2 tetrasomy cases, three copies of an allele were reported.…”

22q11.2 microduplication syndrome with associated esophageal atresia/tracheo‐esophageal fistula and vascular ring

“…As more case reports describe unique and newfound features associated with the duplication, such as hyperdontia , pachygyria , thyroid hemiagenesis , amyoplasia , polymicrogyria, and callosal agenesis , it becomes apparent that characterizing a phenotypic gestalt to the microduplication is not only challenging, but also exemplary of the difficulty in predicting phenotypic consequences in situations of a prenatal diagnosis and discussion about prognosis. The etiology of the phenotypic variability is not known, but proposed explanations include nonpenetrance, epigenetic factors, modifier genes, and environmental factors .…”