Craniofacial Microsomia (CFM) also known as Oculo-auriculo-vertebral Spectrum (OAVS) or Goldenhar Syndrome, presents wide phenotypic and etiological heterogeneity. It affects mainly the structures originated from the first and second pharyngeal arches. In addition, other major anomalies may also be found, including congenital heart diseases. In this study, we report a patient with distal deletion in the 22q11.2 region and a phenotype which resembles CFM. The proband is a girl, who presented bilateral preauricular tags, left auditory canal stenosis, malar hypoplasia, cleft lip and palate, mild asymmetry of soft tissue in face, congenital heart disease, intestinal atresia, annular pancreas and hydronephrosis. The genomic imbalances investigation by Multiplex Ligation-dependent Probe Amplification (MLPA) and Chromosomal Microarray Analysis (CMA) revealed a distal deletion of 1,048 kb at 22q11.2 encompassing the region from Low Copy Repeats (LCRs) D to E. We did review of the literature and genotype-phenotype correlation. This is the sixth case of distal 22q11.2 deletion resembling CFM and the second encompassing the region between LCRs D to E. All cases share some phenotypic signs, such as preauricular tags, facial asymmetry, cleft lip and palate, and congenital heart diseases. Candidate genes in this region have been studied by having an important role in pharyngeal arches developmental and in congenital heart diseases, such as HIC2, YPEL1and MAPK1/ERK2. This case corroborates the phenotypic similarity between 22q11.2 distal deletion and CFM/OAVS. It also contributes to genotype-phenotype correlation and reinforces that candidate genes for CFM, in the 22q11.2 region, might be located between LCRs D and E.

The aim of this study was to perform 22q11.2 deletion screening and chromosomal microarray analysis (CMA) in individuals clinically diagnosed with craniofacial microsomia (CFM) and review previously published cases of CFM with genomic imbalances. It included 54 individuals who were evaluated by a clinical geneticist. Copy number variants (CNVs) in the 22q11.2 region were investigated by multiplex ligation-dependent probe amplification (MLPA) for all individuals. The CMA was performed only for individuals with additional major features. MLPA revealed pathogenic CNVs at the 22q11 region in 3/54 (5.6%) individuals. CMA revealed pathogenic CNVs in 4/17 (23.5%) individuals, including the three CNVs at the 22q11 region also detected by MLPA, and CNVs classified as variants of unknown significance (VOUS) in 4/17 (23.5%) individuals. Pathogenic alterations were found at the 2p12, 5p15, 13q13, and 22q11 regions. VOUS were found at 3q29, 5q22.2, 5q22.1, and 9p22 regions. All individuals with pathogenic alterations presented additional major features, including congenital heart disease (CHD). The literature review revealed pathogenic CNVs in 17/193 (8.8%) individuals and most of them also presented additional major features, such as CHD, renal anomalies, or developmental delay. In conclusion, CNVs should be investigated in patients with CFM and additional major features.

Insertions are rare balanced chromosomal rearrangements with an increased risk of imbalances for the offspring. Moreover, balanced rearrangements in individuals with abnormal phenotypes may be associated to the phenotype by different mechanisms. This study describes a three-generation family with a rare chromosomal insertion. G-banded karyotype, chromosomal microarray analysis (CMA), whole-exome sequencing (WES), and low-pass whole-genome sequencing (WGS) were performed. Six individuals had the balanced insertion [ins(9;15)(q33;q21.1q22.31)] and three individuals had the derivative chromosome 9 [der(9)ins(9;15)(q33;q21.1q22.31)]. The three subjects with unbalanced rearrangement showed similar clinical features, including intellectual disability, short stature, and facial dysmorphisms. CMA of these individuals revealed a duplication of 19.3 Mb at 15q21.1q22.31. A subject with balanced rearrangement presented with microcephaly, severe intellectual disability, absent speech, motor stereotypy, and ataxia. CMA of this patient did not reveal pathogenic copy number variations and low-pass WGS showed a disruption of the RABGAP1 gene at the 9q33 breakpoint. This gene has been recently associated with a recessive disorder, which is not compatible with the mode of inheritance in this patient. WES revealed an 88 bp deletion in the MECP2 gene, consistent with Rett syndrome. This study describes the clinical features associated with the rare 15q21.1–q22.31 duplication and reinforces that searching for other genetic causes is warranted for individuals with inherited balanced chromosomal rearrangements and abnormal phenotypes.

This study aims to discuss diagnostic criteria and severity assessment for craniofacial microsomia (CFM). A series of 61 patients with diverse CFM phenotypes had their clinical data collected by experienced dysmorphologists using a single protocol.Genetic abnormalities were searched through karyotype and chromosomal microarray analysis. Sex ratio, prenatal risk factors, and recurrence rate corroborated the literature. Despite the wide variability of clinical findings, ear disruption was universal.Eight patients were assigned as syndromic, four of whom had demonstrable genetic alterations. The majority of patients (67.2%) fulfilled four known diagnostic criteria, while 9.8% fulfilled one of them. Data strengthened disruptions of the ear and deafness as a semiotically valuable sign in CFM. Facial impairment should consider asymmetry as a mild expression of microsomia. Spinal and cardiac anomalies, microcephaly, and developmental delay were prevalent among extra craniofacial features and should be screened before planning treatment and follow up. The severity index was able to recognize the less and the most affected patients. However, it was not useful to support therapeutic decisions and prognosis in the clinical scenario due to syndromic and non-syndromic phenotypes overlapping. These issues make contemporary the debate on diagnostic methods and disease severity assessment for CFM.They also impact care and etiopathogenetic studies.congenital microtia, craniofacial microsomia, oculoauriculovertebral spectrum, severity of illness index | INTRODUCTIONCraniofacial microsomia (CFM), also known as the oculo-auriculovertebral spectrum, is a term employed to group phenotypes that affect predominantly facial bones, ears, eyes, and spine. It is usual to find it described as otomandibular dysostosis, lateral facial dysplasia, hemifacial microsomia, and Goldenhar, facioauriculovertebral and first and second branchial arch syndromes. [1][2][3][4] The prevalence of CFM is estimated by 3.8 per 100 000 births according to the largest population study on the subject. 5 It has been considered the second most common craniofacial defect, behind oral clefts. 1,3,4,6 Understanding the etiology and pathogenesis of CFM remains a challenge. Most cases are sporadic and probably result from genetic susceptibility acting along with non-genetic factors. Among familial cases, it is not always possible to

This study reports three patients with Cat-eye Syndrome (CES), two of which present a previous clinical diagnosis of Craniofacial microsomia (CFM). Chromosomal microarray analysis (CMA) revealed a tetrasomy of 1,7 Mb at the 22q11.2q11.21 region, which is the typical region triplicated in the CES, in all patients. The most frequent craniofacial features found in individuals with CFM and CES are preauricular tags and/or pits and mandibular hypoplasia. We reinforce that the candidate genes for CFM features, particularly ear malformation, preauricular tags/pits, and facial asymmetry, can be in the proximal region of the 22q11.2 region.

No abstract