Abnormalities in pharyngeal arch-derived structures in SATB2-associated syndrome.

SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that Satb2 is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches. Satb2-/- mutant mice exhibit microglossia, a shortened lower jaw, smaller trigeminal ganglia, and larger thyroids. We correlate these findings with the detailed clinical phenotype of four individuals with SAS and remarkable craniofacial phenotypes with one requiring mandibular distraction in childhood. We conclude that the mouse and patient data presented support less well-described phenotypic aspects of SAS including mandibular morphology and thyroid anatomical/functional issues.

Sonographic Findings of Cervical Chondrocutaneous Branchial Remnants-A Comparison With Dermal Lesions/Cysts and a Literature Review: A Pilot Study.

OBJECTIVES: Cervical chondrocutaneous branchial remnants (CCBRs) and dermal lesions, such as epidermoid cysts or brachial anomalies, including lateral cervical cysts/sinuses or dermal sinuses of anterior chest lesions, are usually located at the lower neck at the anterior or posterior border of the sternocleidomastoid muscle (SCM). We aimed to demonstrate the usefulness of ultrasonography in the differential diagnosis and evaluation of CCBRs. METHODS: We evaluated 22 lesions of 20 pediatric patients, classified into CCBR and dermal lesion groups. We used Fisher's exact test to evaluate differences between these groups in terms of lesion shape (low-echoic mass- or tubular-like), whether the lesion was adjacent to/in contact with the SCM or not, and the presence or absence of a concave SCM caused by the lesion. RESULTS: Of the 22 lesions, 8 were CCBRs, and 14 were dermal lesions. We found a significant difference in the presence/absence of adjacency to or contact with the SCM (presence/absence of adjacency to or contact with the SCM in CCBRs vs that in dermal lesions: 6/2 vs 1/13, P = .002) and presence/absence of lesion-induced concavity of the SCM (presence/absence of lesion-induced concavity of the SCM in CCBRs vs that in dermal lesions: 3/5 vs 0/14, P = .036). The lesion shape (low-echoic mass-like/tubular-like lesions) did not significantly differ between the two study groups (low-echoic mass-like/tubular-like lesions in CCBRs vs that in dermal lesions: 5/3 vs 11/6, P = .624). CONCLUSIONS: CCBRs have a strong association with the SCM. These sonographic findings may be useful in the differential diagnosis of dermal cervical lesions.

Branchiogenic cyst ‒ a rare finding in vascular surgery.

Branchiogenic cysts are benign lesions caused by anomalous development of the branchial cleft. They are typically detected in individuals aged between their twenties and forties. Ultrasonography is the first-line imaging method of choice. Surgical excision is the sole treatment modality (Tab. 1, Fig. 6, Ref. 25). Keywords: branchiogenic cyst, extirpation, ultrasonography, computed tomography.

HRAS-related epidermal nevus syndromes: Expansion of the spectrum with first branchial arch defects.

Epidermal nevus syndrome (ENS) comprises a heterogeneous group of neurocutaneous syndromes associated with the presence of epidermal nevi and variable extracutaneous manifestations. Postzygotic activating HRAS pathogenic variants were previously identified in nevus sebaceous (NS), keratinocytic epidermal nevus (KEN), and different ENS, including Schimmelpenning-Feuerstein-Mims and cutaneous-skeletal-hypophosphatasia syndrome (CSHS). Skeletal involvement in HRAS-related ENS ranges from localized bone dysplasia in association with KEN to fractures and limb deformities in CSHS. We describe the first association of HRAS-related ENS and auricular atresia, thereby expanding the disease spectrum with first branchial arch defects if affected by the mosaic variant. In addition, this report illustrates the first concurrent presence of verrucous EN, NS, and nevus comedonicus (NC), indicating the possibility of mosaic HRAS variation as an underlying cause of NC. Overall, this report extends the pleiotropy of conditions associated with mosaic pathogenic variants in HRAS affecting ectodermal and mesodermal progenitor cells.

Branchial cleft cyst and branchial cleft cyst carcinoma, or cystic lymph node and cystic nodal metastasis?

BACKGROUND: Lateral cervical cysts are usually considered as of branchial cleft origin, despite many studies showing that branchial cysts do not arise from the remnants of the branchial apparatus. In the same way, some authors still consider that a true clinicopathological entity such as 'branchial cleft cyst carcinoma' could exist, at least in theory. Despite insufficient evidence in support of the branchial theory, a number of publications continue to emphasise this concept. METHODS: A literature review of articles in Medline and PubMed databases was carried out to retrieve papers relevant to the topic. RESULTS AND CONCLUSION: The evidence from lateral cervical cyst studies and knowledge about cystic metastasis of Waldeyer's ring could be applicable for both diagnoses. Terms such as 'branchial cleft cyst' and 'branchial cleft cyst carcinoma' are confusing and misleading, and it is questionable as to whether their usage is still tenable.

Nasopharyngeal Presentation of a Pharyngeal Cleft Cyst in a Dog.

A 2 yr old castrated male shih tzu was presented for assessment of worsening chronic snoring since first detected at 3 mo of age. An upper respiratory endoscopic examination and a computed tomographic scan showed a well-circumscribed, fluid-filled nasopharyngeal mass located in the median plane on the nasal side of the soft palate. This lesion was removed using a ventral approach to the nasopharynx by blunt-sharp dissection from the submucosal tissues of the soft palate. Histopathology revealed a cystic lesion lined by a single layer of a pseudostratified columnar ciliated epithelium, characteristic of a pharyngeal cyst. Follow-up 5 mo after surgery revealed complete resolution of the clinical signs with no evidence of local recurrence. Pharyngeal cysts are developmental abnormalities of the branchial apparatus. Most derive from the second branchial arch and cause cysts, sinuses, and fistulae to develop in the neck region. In our case, the lesion was located in the nasopharynx, leading to snoring and exercise intolerance. This condition should be included in the differential diagnosis of suspected nasopharyngeal obstruction.

First branchial arch cyst in an elderly patient: diagnostic dilemma and subsequent management.

The branchial system plays a significant role in the embryological development of the many internal and external human body structures. Failure of normal development of these systems may result in branchial system anomalies. Anomalies of the first branchial cleft are rare and account for 1-8% of all branchial anomalies. They have an incidence of 1 per 1 million births, most of which are diagnosed in early childhood. We present an unusual case of a first branchial arch cyst in an elderly gentleman: a 65-year-old man who presented with a persistent swelling in the left pre-auricular region with no associated sinus, fistulae or lymphadenopathy and with an intact facial nerve. Investigations including fine needle aspiration, ultrasound and magnetic resonance imaging led to the diagnosis of a lesion of salivary origin and an extracapsular dissection was undertaken. The histological appearance on excision was, however, in keeping with a first arch branchial cyst. In conclusion, the nonspecific clinical and radiological presentation of first branchial arch anomalies may lead to difficulty and often delay in the diagnosis of these lesions, particularly in elderly patients as it is more often associated with childhood and adolescence. A high level of suspicion is mandatory to prevent inappropriate management in the form of incision and drainage, which further increases the risk of recurrence and facial nerve injury at the time of formal excision due to scarring.

Patho-Anatomic Spectrum of Branchial Cleft Anomalies: Proposal of Novel Classification System.

PURPOSE: Histogenesis, nomenclature, and classification of branchial cleft anomalies (BCAs) have been subjects of controversy for decades. The purpose of this study was to investigate the accuracy of current developmental theories (congenital, lymph node, and hybrid branchial inclusion theories) in defining the anatomic and histopathological characteristics of BCAs. METHODS: Ninety consecutive patients with BCAs who underwent surgical excision were enrolled in this 2-center retrospective cohort study. RESULTS: The present study included 90 patients: 46 (51.11%) women and 44 (48.89%) men (P > .05). The mean age at presentation was 31.89±17.31 years. Altogether, 92 BCAs were identified within the study population including 49 (53.26%) on the left side and 43 (46.74%) on the right side (P > .05). The BCAs included 79 (85.87%) branchial cleft cysts, 11 (11.96%) branchial cleft sinuses, and 2 (2.17%) branchial cleft fistulae. Three (3.26%) BCAs were distributed in the head regions, 88 (95.65%) in the neck regions, and 1 (1.09%) in the thoracic cavity. Following surgery, lymphoepithelial tissue was detected in the histopathological examination in 83 (90.22%) BCAs. The hybrid branchial inclusion theory exhibited significantly higher accuracy in defining patho-anatomic characteristics of BCAs than the branchial apparatus, precervical sinus, thymopharyngeal, and inclusion theories (90.22, 9.78, 2.17, 0.00, and 0.00%; respectively) (P < .05). CONCLUSION: The novel branchial node (BN) classification system based on the hybrid branchial inclusion theory appears to be superior to other classification systems in determining the patho-anatomy of BCAs.

Generation of a new six1-null line in Xenopus tropicalis for study of development and congenital disease.

The vertebrate Six (Sine oculis homeobox) family of homeodomain transcription factors plays critical roles in the development of several organs. Six1 plays a central role in cranial placode development, including the precursor tissues of the inner ear, as well as other cranial sensory organs and the kidney. In humans, mutations in SIX1 underlie some cases of Branchio-oto-renal (BOR) syndrome, which is characterized by moderate-to-severe hearing loss. We utilized CRISPR/Cas9 technology to establish a six1 mutant line in Xenopus tropicalis that is available to the research community. We demonstrate that at larval stages, the six1-null animals show severe disruptions in gene expression of putative Six1 target genes in the otic vesicle, cranial ganglia, branchial arch, and neural tube. At tadpole stages, six1-null animals display dysmorphic Meckel's, ceratohyal, and otic capsule cartilage morphology. This mutant line will be of value for the study of the development of several organs as well as congenital syndromes that involve these tissues.

Novel MYT1 variants expose the complexity of oculo-auriculo-vertebral spectrum genetic mechanisms.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by anomalies mainly involving the structures derived from the first and second pharyngeal arches. The spectrum presents with heterogeneous clinical features and complex etiology with genetic factors not yet completely understood. To date, MYT1 is the most important gene unambiguously associated with the spectrum and with functional data confirmation. In this work, we aimed to identify new single nucleotide variants (SNVs) affecting MYT1 in a cohort of 73 Brazilian patients diagnosed with OAVS. In addition, we investigated copy number variations (CNVs) encompassing this gene or its cis-regulatory elements and compared the frequency of these events in patients versus a cohort of 455 Brazilian control individuals. A new SNV, predicted as likely deleterious, was identified in five unrelated patients with OAVS. All five patients presented hearing impairment and orbital asymmetry suggesting an association with the variant. CNVs near MYT1, located in its neighboring topologically associating domain (TAD), were found to be enriched in patients when compared to controls, indicating a possible involvement of this region with OAVS pathogenicity. Our findings highlight the genetic complexity of the spectrum that seems to involve more than one variant type and inheritance patterns.

Cervical chondrocutaneous branchial remnants: A report of 29 cases and review of the literature.

OBJECTIVE: Cervical chondrocutaneous branchial remnants (CCBRs) are rare masses located in the anterior region of the neck. Though the basic characteristics of these rare masses were first described by Atlan in 1997, a critical amount of information about these masses remains unknown. This study aimed to further clarify the characteristics of these rare masses. METHODS: We retrospectively reviewed the clinical records of patients with CCBRs in our facility during a 32-year period ranging from 1988 to 2019. We then compared our clinical records with other case reports. RESULTS: There were 29 patients with CCBRs in our facility, including 19 males and ten females, Three patients were involved bilaterally (among patients involved unilaterally, the right side included 11 patients, and the left side was 15 patients), eight patients also had associated abnormalities. We submitted CCBRs from 18 patients to pathology, and all of them contained elastic cartilages. Among all the surgical data could be confirmed, cartilages did not reach beyond the musculature of the neck. We could confirm a similar tendency with Atlan regarding sex, the location of CCBRs (involvement side, localization in the neck), and the depth of CCBRs. Among the cases contained in this study, there was a disparity in the rate of associated abnormalities and pathology of contained cartilages. CONCLUSION: Some critical characteristics of CCBRs included, a male predominance, scarcity of bilateral cases and common left side involvement among unilateral involved cases, a common location of CCBRs in the inferior third of the neck and anterior to the sternocleidomastoid muscle, and an involvement of cartilage in CCBRs which has no connections to deep underlying structure of the neck. Further investigations are required to determine the origin of CCBRs and the precise incidence of the associated abnormalities. Systemic examination in patients with CCBRs is recommended because many associated abnormalities have been reported.

Description of a family with X-linked oculo-auriculo-vertebral spectrum associated with polyalanine tract expansion in ZIC3.

Oculo-auriculo-vertebral spectrum (OAVS) [MIM:164210], or Goldenhar syndrome, is a developmental disorder associating defects of structures derived from the first and second branchial arches. The genetic origin of OAVS is supported by the description of rare deleterious variants in a few causative genes, and several chromosomal copy number variations. We describe here a large family with eight male members affected by a mild form of the spectrum, mostly auricular defects, harboring a hemizygous ZIC3 variant detected by familial exome sequencing: c.159_161dup p.(Ala55dup), resulting in an expansion of the normal 10 consecutive alanine residues to 11 alanines. Segregation analysis shows its presence in all the affected individuals, with a recessive X-linked transmission. Whole-genome sequencing performed in another affected male allowed to exclude linkage disequilibrium between this ZIC3 variant and another potential pathogenic variant in this family. Furthermore, by screening of a cohort of 274 OAVS patients, we found 1 male patient carrying an expansion of 10 to 12 alanines, a variant previously reported in patient presenting with VACTERL. Loss-of-function variants of ZIC3 are causing heterotaxy or cardiac malformations. These alanine expansion variants could have a different impact on the protein and thereby resulting in a different phenotype within the OAVS/VACTERL.

The utilization of selective neck dissection in the treatment of recurrent branchial cleft anomalies.

To investigate the characteristics of recurrent branchial cleft anomalies (BCAs) and to evaluate the surgical technique and outcomes of patients undergoing reoperation.From January 2005 to August 2018, the clinical data of 216 patients with recurrent second, third, and fourth BCAs were retrospectively analyzed. According to the embryological and anatomical features of the cleft palate and recurrence site, selective neck dissection techniques were used for surgical treatment.Among all 216 patients, 203 healed by primary healing. Twelve patients with local infections and 1 patient with a pharyngeal fistula healed after dressing changes. Eleven patients experienced transient hoarseness and recovered after a few months. Three patients developed permanent hoarseness, and 5 patients developed coughing after eating and drinking. Three patients underwent internal jugular vein ligation. Only 4 recurrences occurred during a follow-up period of more than 1 year. The total cure rate was 98.15%.Selective neck dissection is an effective and safe surgical treatment for recurrent second, third, and fourth branchial cleft anomalies.

Biallelic disruption of PKDCC is associated with a skeletal disorder characterised by rhizomelic shortening of extremities and dysmorphic features.

BACKGROUND: During mouse embryonic development the protein kinase domain containing, cytoplasmic (Pkdcc) gene, also known as Vlk, is expressed in several tissues including the ventral midbrain, with particularly strong expression in branchial arches and limb buds. Homozygous Pkdcc knockout mice have dysmorphic features and shortened long bones as the most obvious morphological abnormalities. The human PKDCC gene has currently not been associated with any disorders. OBJECTIVE: To use clinical diagnostic exome sequencing (DES) for providing genetic diagnoses to two apparently unrelated patients with similar skeletal abnormalities comprising rhizomelic shortening of limbs and dysmorphic features. METHODS: Patient-parents trio DES was carried out and the identified candidate variants were confirmed by Sanger sequencing. RESULTS: Each patient had a homozygous gene disrupting variant in PKDCC considered to explain the skeletal phenotypes shared by both. The first patient was homozygous for the nonsense variant p.(Tyr217*) (NM_1 38 370 c.651C>A) expected to result in nonsense-mediated decay of the mutant transcripts, whereas the second patient was homozygous for the splice donor variant c.639+1G>T predicted to abolish the donor splice site by three in silico splice prediction algorithms. CONCLUSIONS: Biallelic gene disrupting variants in PKDCC in humans, just like in mice, cause dysmorphic features and rhizomelic shortening of limbs.

Citrobacter freundii impairs the phosphoryl transfer network in the gills of Rhamdia quelen: Impairment of bioenergetics homeostasis.

The precise coupling of spatially separated intracellular adenosine triphosphate (ATP)-producing and ATP-consuming, catalyzed by creatine kinase (CK), adenylate kinase (AK), and pyruvate kinase (PK), is a critical process in the bioenergetics of tissues with high energy demand, such as the branchial tissue. The effects of Citrobacter freundii infection on gills remain poorly understood, limited only to histopathological studies. Thus, the aim of this study was to evaluate whether experimental infection by C. freundii impairs the enzymes of the phosphoryl transfer network in gills of silver catfish (Rhamdia quelen). The CK (cytosolic and mitochondrial) and AK activities decreased in infected compared to uninfected animals, while the PK activity did not differ between groups. The gill histopathology of infected animals revealed extensive degeneration with fusion and necrosis of secondary lamellae, detachment of superficial epithelium, aneurysm, vessel congestion and inflammatory process. Based on these evidences, the inhibition and absence of an efficient communication between CK compartments caused the impairment of the branchial bioenergetics homeostasis, which was not compensated by the augmentation on branchial AK activity in an attempt to restore energy homeostasis. In summary, these alterations contribute to disease pathogenesis linked to branchial tissue in animals infected with C. freundii.

[Relationship between Work â ¡ type of congenital first branchial cleft anomaly and facial nerve and surgical strategies].

Objective: To investigate the relationship between Work Ⅱ type of congenital first branchial cleft anomaly (CFBCA) and facial nerve and discuss surgical strategies. Methods: Retrospective analysis of 37 patients with CFBCA who were treated from May 2005 to September 2016. Among 37 cases with CFBCA, 12 males and 25 females; 24 in the left and 13 in the right; the age at diagnosis was from 1 to 76 ( years, with a median age of 20, 24 cases with age of 18 years or less and 13 with age more than 18 years; duration of disease ranged from 1 to 10 years (median of 6 years); 4 cases were recurren after fistula resection. According to the classification of Olsen, all 37 cases were non-cyst (sinus or fistula). External fistula located over the mandibular angle in 28 (75.7%) cases and below the angle in 9 (24.3%) cases. Results: Surgeries were performed successfully in all the 37 cases. It was found that lesions located at anterior of the facial nerve in 13 (35.1%) cases, coursed between the branches in 3 cases (8.1%), and lied in the deep of the facial nerve in 21 (56.8%) cases. CFBCA in female with external fistula below mandibular angle and membranous band was more likely to lie deep of the facial nerve than in male with external fistula over the mandibular angle but without myringeal web. Conclusions: CFBCA in female patients with a external fistula located below the mandibular angle, non-cyst of Olsen or a myringeal web is more likely to lie deep of the facial nerve. Surgeons should particularly take care of the protection of facial nerve in these patients, if necessary, facial nerve monitoring technology can be used during surgery to complete resection of lesions.

Spectrum of lesions derived from branchial arches occurring in the thyroid: from solid cell nests to tumors.

There is a group of lesions in the head and neck region derived from branchial arches and related structures which, when inflamed, are characterized by the formation of cysts lined by squamous or glandular epithelium and surrounded by a heavy inflammatory infiltrate rich in germinal centers. In the thyroid, the main source of various structures which may cause diagnostic dilemma is the ultimobranchial body. To investigate the spectrum of such thyroid lesions, the consultation files were reviewed for thyroid samples containing pathological structures regarded to arise from the ultimobranchial body. Positive reaction with antibodies against CK5/6, p63, galectin 3, and CEA, and negative reaction with antibodies against thyroglobulin, TTF-1, and calcitonin were used to confirm the diagnosis. The specific subtype of the ultimobranchial body-derived lesion was then determined based on histological examination of H&E-stained slides. Twenty-one cases of ultimobranchial body-derived lesions were retrieved from the consultation files, 20 of them along with clinical information (M/F = 6/14, mean age 55 years, range 36-68 years). Lesions derived from the ultimobranchial body were classified as follows: (hyperplastic) solid cell nests (nine cases), solid cell nests with focal cystic change (five cases), cystic solid cell nests (two cases), branchial cleft-like cyst (four cases), and finally a peculiar Warthin tumor-like lesion (one case). We suggest that the common denominator of these structures is that they all arise due to activation of inflammatory cells around the vestigial structures, which leads to cystic dilatation and proliferation of the epithelial component.

Determinants of orofacial clefting I: Effects of 5-Aza-2'-deoxycytidine on cellular processes and gene expression during development of the first branchial arch.

In this study, we identify gene targets and cellular events mediating the teratogenic action(s) of 5-Aza-2'-deoxycytidine (AzaD), an inhibitor of DNA methylation, on secondary palate development. Exposure of pregnant mice (on gestation day (GD) 9.5) to AzaD for 12h resulted in the complete penetrance of cleft palate (CP) in fetuses. Analysis of cells of the embryonic first branchial arch (1-BA), in fetuses exposed to AzaD, revealed: 1) significant alteration in expression of genes encoding several morphogenetic factors, cell cycle inhibitors and regulators of apoptosis; 2) a decrease in cell proliferation; and, 3) an increase in apoptosis. Pyrosequencing of selected genes, displaying pronounced differential expression in AzaD-exposed 1-BAs, failed to reveal significant alterations in CpG methylation levels in their putative promoters or gene bodies. CpG methylation analysis suggested that the effects of AzaD on gene expression were likely indirect.