Oculoauriculofrontonasal syndrome: Refining the phenotype through a new case series and literature review.

The oculoauriculofrontonasal syndrome (OAFNS) is a rare condition, with unknown etiology, characterized by the association of frontonasal dysplasia (FND) and oculoauriculovertebral spectrum (OAVS). Main clinical findings include widely spaced eyes, epibulbar dermoid, broad nose, mandibular hypoplasia, and preauricular tags. Here, we describe a case series of 32 Brazilian individuals with OAFNS and review the literature ascertaining individuals presenting phenotypes compatible with the diagnosis of OAFNS, aiming to refine the phenotype. This series emphasizes the phenotypic variability of the OAFNS and highlights the occurrence of rare craniofacial clefts as a part of the phenotype. The ectopic nasal bone, a hallmark of OAFNS, was frequent in our series, reinforcing the clinical diagnosis. The absence of recurrence, consanguinity, chromosomal, and genetic abnormalities reinforces the hypothesis of a nontraditional inheritance model. The phenotypic refinement provided by this series contributes to an investigation regarding the etiology of OAFNS.

Three-dimensional comparison of mandibular morphology in young people with Treacher Collins syndrome and Pierre Robin sequence.

INTRODUCTION: Treacher Collins syndrome (TCS) and nonsyndromic Pierre Robin sequence (PRS) share mandibular deficiency as a similar clinical finding. This study aimed to compare the mandibular size and morphology of subjects with TCS and PRS. METHODS: Group TCS was composed of 17 subjects (7 male, 10 female) with a mean age of 11.5 years (standard deviation, 4.4) from a single center. Group PRS was composed of 17 subjects paired by age and sex with group TCS. Preorthodontic cone-beam computed tomography examinations of all patients were evaluated using Mimics Innovation Suite 17.0 (Materialise, Leuven, Belgium). Nine 3-dimensional measurements were performed in segmented 3D images of the mandible. Intragroup comparisons were performed using paired t tests. Intergroup comparisons were performed using analysis of variance and Tukey tests. The significance level considered was 5%. RESULTS: TCS showed a significant dimensional difference between less and more affected sides for ramus, condyles, and mandibular body. The mandibular dimensions in PRS were more symmetrical. Group TCS presented a smaller mandibular effective length and mandibular body length compared with PRS. The condyle width and height and the ramus width were also decreased in TCS. The gonial angle was greater in TCS compared with the PRS group. CONCLUSIONS: Young subjects with TCS presented a smaller, more vertical, and more asymmetrical mandible compared with nonsyndromic PRS.

Comparison Between Treacher Collins Syndrome and Pierre Robin Sequence: A Cephalometric Study.

OBJECTIVE: The aim of this study was to compare the dentoskeletal pattern of Treacher Collins syndrome (TCS) and nonsyndromic Pierre Robin sequence (PRS). DESIGN: Retrospective. SETTING: Single center. PATIENTS: Eighteen patients diagnosed with TCS (Group TCS) or PRS (Group PRS) in rehabilitation treatment at a single center. Group TCS was composed of 9 patients (4 male, 5 female) with a mean age of 12.9 years (standard deviation = 4.8). Group PRS was composed of 9 patients paired by age and sex with group TCS. MAIN OUTCOME MEASURE(S): Cone beam computed tomography-derived cephalometric images taken before the orthodontic or the orthodontic-surgical treatment were analyzed using Dolphin Imaging (Dolphin Imaging 11.0 & Management Solutions). Variables evaluating the cranial base, the maxillary and mandibular skeletal components, maxillomandibular relationship, the vertical components and the dentoalveolar region were measured. Intergroup comparisons were performed using t tests. The significance level considered was 5%. RESULTS: Intergroup differences in the mandible size and growth pattern were observed. Group TCS showed a smaller mandibular length (Co-Go, Co-Gn) and a higher palatal plane (SN-Palatal Plane) and mandibular plane angles (SN-Go.Gn) compared to group PRS. No differences between TCS and PRS were observed for the sagittal position of the maxilla, maxillomandibular relationship, and dental components. CONCLUSIONS: Treacher Collins syndrome presented a decreased mandible and a more severe vertical growth pattern compared to PRS.

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia.

The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.

A compound heterozygote SLC26A2 mutation resulting in robin sequence, mild limbs shortness, accelerated carpal ossification, and multiple epiphysial dysplasia in two Brazilian sisters. A new intermediate phenotype between diastrophic dysplasia and recessive multiple epiphyseal dysplasia.

Mutations in solute carrier family 26 (sulfate transporter), member 2 (SLC26A2) gene result in a spectrum of autosomal recessive chondrodysplasias that range from the mildest recessive form of multiple epiphysial dysplasia (rMED) through the most common diastrophic dysplasia (DTD) to lethal atelosteogenesis type II and achondrogenesis IB. The clinical variability has been ascribed to quantitative effect of mutations of the sulfate transporter activity. Here we describe two Brazilian sisters, born to healthy and non consanguineous parents, with Robin sequence, mild shortening of upper and lower limbs, brachymetacarpalia/tarsalia, additional and accelerated carpal ossification, marked genu valgum, and multiple epiphysial dysplasia. This phenotype was intermediate between DTD and rMED, and both girls have a compound heterozygous mutations for the SLC26A2, a Finnish founder mutation (c.-26 + 2T>C), and R279W. This combination of mutations has been observed in individuals with different phenotypes, including DTD, DTD variant, and rMED. The distinct phenotype of our cases reinforces the hypothesis that other factors may be influencing the phenotype as previously suggested.