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Clinical and Cytogenomic Findings in the Oculoauriculovertebral Spectrum (OAVS)

Group IIb including cases 41 and 42 were diagnosed to be due to a teratogenic insult. Case (41) was diagnosed as fetal methotrexate syndrome (methotrexate embryopathy), based on the history of methotrexate injection during the 1st trimester of gestation. The patient had growth retardation and dysmorphic features.

Methotrexate (MTX), a methyl derivate of aminopterin, is a folic acid antagonist widely used as an antineoplastic agent, as well as in the treatment of several dermatological, rheumatologic, gynecological, and obstetric conditions, including the elective medical termination of pregnancy(Lloyd, Carr, McElhatton, Hall, & Hughes, 1999).

The critical period for the teratogenicity of methotrexate is suspected to be between 6 to 8 weeks post-conception(Bawle, Conard, & Weiss, 1998). Prenatal exposure to MTX in the first trimester may lead to fetal death, and surviving children have increased risks for cranial dysostosis, cerebral anomalies, dysmorphic facies, anomalies of the external ears, skeletal malformations, limb defects, and growth retardation, a pattern of defects recognized as fetal MTX syndrome (FMS)(M. P. Adam et al.

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, 2003).

Most of the craniofacial features in the present case were previously observed(M. P. Adam et al., 2003; Usta, Nassar, Yunis, & Abu?Musa, 2007); including broad nasal bridge, shallow supraorbital ridges, prominent eyes, retrognathia, and small malformed ears. The patient had plagiocephaly which may indicate the presence of craniosynostosis. The current case had eyelid coloboma, consistently with previous observations, that MTX may cause abnormalities in first branchial arch derivatives(Koren, 2011).

Cardiac anomalies (VSD, ASD, and pulmonary stenosis) were present in this case. Dawson et al.(Dawson, Riehle?Colarusso, Reefhuis, Arena, & Study, 2014) observed that out of 16 cases, 11 (68.

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8%) had a congenital heart defects; including atrial septal defect, tetralogy of Fallot, valvar pulmonary stenosis, ventricular septal defect, and total anomalous pulmonary venous return.

No limb defects or cerebral anomalies were found in this case, however, they have been previously published(Corona?Rivera et al., 2010; Mesiano, 2019).

Case 42 was provisionally diagnosed as Retinoic acid embryopathy based on the history of the use of Retin A (Tretinoin) for hair renewal and acne treatment in the first trimester of gestation. The patient had severe bilateral microphthalmia with features of OAVS and congenital heart disease.

Isotretinoin is a derivative of Vitamin A, first licensed in the United States in September 1982 with brand name Accutane. Isotretinoin (13-cis-retinoic acid) was initially recognized to be a human teratogen. In 1985, Lammer et al. set forth the spectrum of structural defects of 21 affected infants. Seventeen individuals had defects of the craniofacial area including microtia and preauricular tags, 12 had cardiac defects, 18 had altered morphogenesis of central nervous system (CNS), and 7 had anomalies of thymic development(Jones, Jones, & Del Campo, 2013; Edward J Lammer et al., 1985).

The cause of this disorder is prenatal exposure to isotretinoin (Accutane). A 35% risk for the isotretinoin embryopathy exists in the offspring of women who continue to take isotretinoin beyond the 15th day following conception(Jones et al., 2013). The daily dosage of isotretinoin from 0.5 to 1.5 mg/kg of maternal body weight is thought to be teratogenic. The abnormalities found in infants exposed to isotretinoin are craniofacial, cardiovascular, CNS, thymic, and parathyroid abnormalities(Jones et al., 2013).

The mechanism responsible for producing many of the malformations in infants exposed to retinoic acid is an abnormality of cephalic neural crest cell activity. The mechanisms responsible for producing CNS malformations are poorly understood and probably differ from those affecting neural crest cells (E. J. Lammer et al., 1985). Human embryos are more sensitive to isotretinoin than embryos of other species due to the slow elimination of the drug and continuous isomerization of retinoic acid(Dai, LaBraico, & Stern, 1992).

Isotretinoin increases the risk of spontaneous abortions and stillbirths up to 40% in pregnancies exposed in the first quarter of this medicine(S. M. Lee et al., 2009). Presenting with pregnancy during treatment with isotretinoin is a failure of prevention strategies. Contraception should be used 1 month before the administration of isotretinoin until 1 month after stopping its use. According to the program IPLEDGE and teratology society, the patients should be advised to have a negative pregnancy test before using isotretinoin and repeat every month during treatment to confirm and 1 month after stopping(S. M. Lee et al., 2009).

Multiple ear and eye anomalies are evident in our case. There has been numerous reviews about retinoid-induced ear malformation. In in vivo and in vitro studies, isotretinoin interferes directly with the development of cranial neural crest cells. Earlier exposure in utero produces microtia, auricular duplication, anotia, temporal bone abnormalities, and ossicular malformation. However, an exposure at later developmental stage results in facial tags with less severely affected ears(Webster, Johnston, Lammer, & Sulik, 1986).

OAVS has been associated with both environmental factors such as retinoic acid (RA) exposure (Sven Fischer et al., 2006). Both visceral and skeletal anomalies have been observed in various species and notably, RA administration at E9.5 led to hypoplasia of the branchial arches (79%), as well as auricular (47%) and eye (12.5%) anomalies including microphthalmia and eyelid colobomas in mice(Glineur et al., 1999).

In addition, previous studies (M. Berenguer et al., 2017; Estelle Lopez et al., 2016) have highlighted that MYT1; the unique OAVS gene identified so far, was linked to the RA signaling pathway.

Owing to a similar phenotype of OAVS reported after gestational RA exposures in humans and animals, a recent study aimed to explore the link between genetic and environmental factors through exploring RA targets in a craniofacial developmental context to reveal new candidate genes for these related disorders. Using a proteomics approach, (Marie Berenguer et al., 2018) detected 553 dysregulated proteins in the head region of mouse embryos following their exposure to prenatal RA treatment. This novel proteomic approach implicates changes in proteins that are critical for cell survival/apoptosis and cellular metabolism which could ultimately lead to the observed phenotype. They also identified potential molecular links between three major environmental factors known to contribute to craniofacial defects including maternal diabetes, prenatal hypoxia and RA exposure. Understanding these links could help reveal common key pathogenic mechanisms leading to craniofacial disorders. Using both in vitro and in vivo approaches, that work identified two new RA targets, Gnai3 and Eftud2, proteins known to be involved in craniofacial disorders, highlighting the power of this proteomic approach to uncover new genes whose dysregulation leads to craniofacial defects(Marie Berenguer et al., 2018).

Molecular study:

Patients with OAVS phenotype with irrelevant teratogenic or numerical chromosomal etiology and who fulfill the minimal selection criteria were included in the molecular study (32 from the total of 36 cases with OAVS).

Array Comparative Genomic Hybridization:

Conventional cytogenetic analysis has been the gold standard for detecting chromosomal abnormalities in prenatal diagnosis. It enables the examination of genome-wide numerical and structural abnormalities at the microscopic level and can achieve a resolution of 5-10 Mb (Kirchhoff, Rose, & Lundsteen, 2001). However, the method is labor exhaustive, with a turn-around time of 14 to 21 days. Various molecular cytogenetic techniques, such as Quantitative Fluorescent Polymerase Chain Reaction (QF-PCR) and Fluorescent In Situ Hybridization (FISH) technology, could complement the detection of chromosomal abnormalities and offer faster turn-around times(Hills et al., 2010; Mann & Ogilvie, 2012).

However, these methods are targeted to detect specific chromosomal anomalies and are dependent on the chromosomal probes used. In contrast, whole-genome array comparative hybridization (aCGH) not only provides high-resolution detection of genomic alterations but also allows refinement of breakpoints on chromosome rearrangements(Kan et al., 2014).

In this study, array Comparative Genomic Hybridization (CGH) for detection of Copy number variants (CNVs) included Twenty-six patients and their available parents and revealed many chromosomal aberrations after thorough data analysis using different tools and software previously mentioned.

Array CGH will not identify balanced rearrangements or ploidy abnormalities such as triploidy. Furthermore, low-level mosaicism may not be detected. However, array CGH has a higher resolution for CNV detection than G-banding chromosome analysis which has replaced in many cytogenetics laboratories. It is, therefore, the current gold standard for CNVs detection. It may be replaced by next-generation sequencing technologies in the future but currently, their cost and the technical complexities associated with using short reads for CNV detection mean that this is not yet a good fit for clinical use(Joo Wook Ahn, Coldwell, Bint, & Ogilvie, 2015).

Additional identification of chromosomal anomalies in patients with phenotypic characteristics of this spectrum was reported (summarised in (A. Beleza-Meireles et al., 2014)). Some of these abnormalities are recurrent. The 5p15 deletion has been observed in several patients with OAVS features; (M. Descartes, 2006; Josifova et al., 2004; Ladekarl, 1968). The region was further narrowed down to 5p15.33-per by Ala-Mello, et al. (Ala-Mello et al., 2008). Deletions of the 12p13.33 region, involving the WNT5B gene, were observed in some patients with OAVS features (Abdelmoity et al., 2011; C. Rooryck et al., 2009). Partially overlapping microduplications on 14q23.1 were identified in two families with autosomal dominant OAVS; (Ballesta-Martinez et al., 2013; Z. Ou et al., 2008)one of these families included two first-degree relatives with clinical features of OAVS and Branchio-to-renal syndrome; hence, the region 14q23.1 might harbor candidate genes for OAVS and additional first and second arch disorders.

Anomalies in 22q have been frequently documented in patients with OAVS (Digilio et al., 2009; G. E. Herman et al., 1988; Quintero-Rivera & Martinez-Agosto, 2013). Chromosomal mosaicism for trisomy 22 has also been described (T. J. de Ravel et al., 2001), making this region a good candidate for some cases of OAVS.

Other candidate single gene loci for OAVS have also been suggested. Kelberman et al,(D. Kelberman et al., 2001) reported linkage to a region of approximately 10.7 cM on chromosome 14q32 (D14S987 and D14S65) containing the GSC (GOOSECOID) gene in an OAVS family with apparent autosomal dominant inheritance. Additionally, Gimelli et al. (Gimelli et al., 2013)reported an interstitial 14q31.1q31.3 deletion, a region neighboring to GSC, transmitted from a mother to her daughter, both with features of hemifacial microsomia. Although GSC could be regarded as a candidate gene, no mutation has been found in OAV spectrum cases with normal karyotypes (A. Beleza-Meireles et al., 2014).

In another family with five OAVS patients, potential linkage was suggested at 15q26.2-q26.3 (X. S. Huang et al., 2010). Moreover, numerous genomic rearrangements ranging from 2.7 kb to 2.3 Mb, were found by Rooryck et al. (C. Rooryck et al., 2010) by high-density oligonucleotide array comparative genomic hybridization (aCGH) analysis. These included a de novo 12q13.33 deletion, which has previously been associated with OAVS (Abdelmoity et al., 2011; C. Rooryck et al., 2009); a 2q11 deletion, which was present in a proband and his affected maternal aunt; and trisomy X in a girl OAVS.

In our studied cohort, we identified by oligonucleotide array-CGH dosage anomalies in 14 patients (6 of which have variants of unknown significance (VUS) /probably pathogenic and pathogenic variants) in 26 OAVS patients (23%). This percentage is higher than the range of the overall detection rate of genomic imbalances by array-CGH (oligonucleotide and BAC arrays) in patients with multiple congenital anomalies and/or developmental delay (10-15%)(C. Rooryck et al., 2010; Stankiewicz & Beaudet, 2007).

Compared to numerous published cases of aneuploidies in OAVS, the relatively greater number of gross chromosomal anomalies found in our study could be due to large number of patients who possess a severe phenotype, OAFNS or Goldenhar syndrome.

Indeed, 4 patients out of 26 (11.1%) presented the spectrum or Goldenhar syndrome, characterized by the association of ear anomalies, hemifacial microsomia and dermoids with vertebral anomalies.

This proportion is consistent with the results reported by Rooryck et al. (Caroline Rooryck, Noui Souakri, et al., 2010) in which only 10% of patients had Goldenhar phenotype, and also more than that observed in the cohort described by Tasse et al. (Tasse et al., 2007) in which only 7.5% of patients had a complete Goldenhar phenotype.

Among the anomalies found in the14 patients, the inheritance status was assessed whenever there were available samples for the parents. All the anomalies tested in trios were de novo, except for the unbalanced translocation found in patient 45. Hence, we recommend investigating more first and second-degree family members of the probands, as this may reveal subtle clinical symptoms and more inherited variants with low penetrance and/or variable expressivity in these families, as already described in this disorder (S. Vendramini-Pittoli & N. M. Kokitsu-Nakata, 2009).

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Clinical and Cytogenomic Findings in the Oculoauriculovertebral Spectrum (OAVS). (2019, Nov 30). Retrieved from

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