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Laryngoscope ; 131(12): 2811-2816, 2021 12.
Article En | MEDLINE | ID: mdl-34117782

OBJECTIVES/HYPOTHESIS: Robin sequence (RS) consists of associated micrognathia, glossoptosis, and respiratory dysfunction, with or without cleft palate. Studies on how different patient characteristics impact the severity of respiratory dysfunction are scarce and contradictory; this study investigates how different features affect respiratory obstruction severity at diagnosis of RS in controlled analysis. STUDY DESIGN: Retrospective cohort study that enrolled 71 RS patients under 90 days old who received care in our institution from 2009 to 2020. METHODS: The primary outcome, respiratory dysfunction, was categorized into four severity groups and analyzed using a multinomial logistic regression model that considered age, sex, mandible length, cleft palate, syndromic diagnosis, other airway anomalies, and degree of glossoptosis. RESULTS: Mandible length, syndromic diagnosis, and Yellon grade 3 glossoptosis were related to poorer respiratory outcomes (need for respiratory support). In univariate analysis, for each additional 1 mm of mandible length at diagnosis, a mean reduction of 28% in the risk of needing respiratory support was observed (OR = 0.72; 0.58-0.89); syndromic diagnosis and grade 3 glossoptosis also raised the risk (OR = 6.50; 1.59-26.51 and OR = 12.75; 1.03-157.14, respectively). In multivariate analysis, only mandible length significantly maintained its effects (OR = 0.73; 0.56-0.96), a 27% reduction. CONCLUSIONS: Mandible length was an independent predictor for more severe respiratory dysfunction in RS patients, with larger mandibles showing protective effects. Syndromic diagnosis and Yellon grade 3 glossoptosis are also likely to be associated with poorer respiratory outcomes, although this was not demonstrated in multivariate analysis. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2811-2816, 2021.

Glossoptosis/complications , Pierre Robin Syndrome/complications , Respiration Disorders/epidemiology , Female , Glossoptosis/diagnosis , Glossoptosis/pathology , Humans , Imaging, Three-Dimensional , Infant , Infant, Newborn , Male , Mandible/diagnostic imaging , Mandible/pathology , Organ Size , Pierre Robin Syndrome/diagnosis , Pierre Robin Syndrome/pathology , Prognosis , Protective Factors , Respiration Disorders/diagnosis , Respiration Disorders/etiology , Retrospective Studies , Risk Assessment/methods , Risk Assessment/statistics & numerical data , Risk Factors , Severity of Illness Index , Tomography, X-Ray Computed
Clin Genet ; 98(6): 606-612, 2020 12.
Article En | MEDLINE | ID: mdl-32812661

RBM10, is an RNA binding protein that is important for development by regulating the expression of multiple genes. RBM10 is on the X chromosome, and nonsense and frameshift RBM10 variants cause TARP syndrome in males. In a 4-year-old male, we identified a novel maternally inherited missense RBM10 variant in the RRM2 RNA binding domain, c.965C>T, p.Pro322Leu. His clinical features included intellectual disability, developmental delay, growth restriction, hypotonia, and craniofacial malformations. These features were much milder than those described in previously reported cases of TARP syndrome. By in vitro assays, we found that the mutant p.Pro322Leu RBM10 protein retained its specific RNA binding capacity, while gaining a low-affinity nonspecific RNA binding. It was normally localized to the nucleus, but its expression level was significantly reduced with a significantly short half-life. These results indicated that the p.Pro322Leu missense variant causes a developmental disorder in humans through a unique loss-of-function mechanism.

Clubfoot/genetics , Developmental Disabilities/genetics , Genetic Predisposition to Disease , Heart Defects, Congenital/genetics , Pierre Robin Syndrome/genetics , RNA-Binding Proteins/genetics , Child, Preschool , Clubfoot/complications , Clubfoot/pathology , Craniofacial Abnormalities/complications , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/pathology , Developmental Disabilities/complications , Developmental Disabilities/pathology , Heart Defects, Congenital/complications , Heart Defects, Congenital/pathology , Humans , Intellectual Disability/complications , Intellectual Disability/genetics , Intellectual Disability/pathology , Male , Musculoskeletal Abnormalities/complications , Musculoskeletal Abnormalities/genetics , Musculoskeletal Abnormalities/pathology , Mutation, Missense/genetics , Phenotype , Pierre Robin Syndrome/complications , Pierre Robin Syndrome/pathology , Whole Exome Sequencing
Am J Med Genet A ; 182(9): 2068-2076, 2020 09.
Article En | MEDLINE | ID: mdl-32592542

Hand hyperphalangism leading to shortened index fingers with ulnar deviation, hallux valgus, mild facial dysmorphism and respiratory compromise requiring assisted ventilation are the key features of Chitayat syndrome. This condition results from the recurrent heterozygous missense variant NM_006494.2:c.266A>G; p.(Tyr89Cys) in ERF on chromosome 19q13.2, encoding the ETS2 repressor factor (ERF) protein. The pathomechanism of Chitayat syndrome is unknown. To date, seven individuals with Chitayat syndrome and the recurrent pathogenic ERF variant have been reported in the literature. Here, we describe six additional individuals, among them only one presenting with a history of assisted ventilation, and the remaining presenting with variable pulmonary phenotypes, including one individual without any obvious pulmonary manifestations. Our findings widen the phenotype spectrum caused by the recurrent pathogenic variant in ERF, underline Chitayat syndrome as a cause of isolated skeletal malformations and therefore contribute to the improvement of diagnostic strategies in individuals with hand hyperphalangism.

Fingers/abnormalities , Genetic Predisposition to Disease , Hallux Valgus/genetics , Pierre Robin Syndrome/genetics , Repressor Proteins/genetics , Adolescent , Adult , Child , Child, Preschool , Facies , Female , Fingers/diagnostic imaging , Fingers/pathology , Hallux Valgus/diagnostic imaging , Hallux Valgus/pathology , Humans , Pierre Robin Syndrome/diagnostic imaging , Pierre Robin Syndrome/pathology , Whole Exome Sequencing , Young Adult
J Neuromuscul Dis ; 7(3): 309-313, 2020.
Article En | MEDLINE | ID: mdl-32333597

Carey-Fineman-Ziter syndrome is a congenital myopathy associated with mutations in the MYMK gene. It is clinically defined by the combination of hypotonia, Moebius-Robin sequence, facial anomalies and motor delay. Historically it was considered a brainstem dysgenesis syndrome. We provide detailed information of a Spanish boy with compound heterozygous variants in MYMK gene. A muscle biopsy performed as a toddler only disclosed minimal changes, but muscle MRI showed severe fatty infiltration of gluteus muscles and to a lesser extent in adductors magnus, sartorius and soleus muscles. Clinical course is fairly static, but the identification of new well characterized genetic cases will help to delineate the complete phenotype.

Membrane Proteins/genetics , Mobius Syndrome/diagnosis , Mobius Syndrome/genetics , Mobius Syndrome/pathology , Muscle Proteins/genetics , Muscular Diseases/diagnosis , Muscular Diseases/genetics , Muscular Diseases/pathology , Pierre Robin Syndrome/diagnosis , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Brain Diseases/diagnosis , Brain Stem/abnormalities , Child , Diagnosis, Differential , Humans , Male
Am J Med Genet A ; 182(3): 437-440, 2020 03.
Article En | MEDLINE | ID: mdl-31833187

Catel-Manzke syndrome is characterized by hand anomalies, Robin sequence, cardiac defects, joint hyperextensibility, and characteristic facial features. Approximately 40 patients with Catel-Manzke have been reported, all with the pathognomonic bilateral or unilateral hyperphalangy caused by an accessory bone between the second metacarpal and proximal phalanx known as Manzke dysostosis. Here we present the first case of molecularly confirmed Catel-Manzke syndrome with Robin sequence but without Manzke dysostosis.

Hand Deformities, Congenital/genetics , Hydro-Lyases/genetics , Mandibulofacial Dysostosis/genetics , Pierre Robin Syndrome/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Adolescent , Child , Child, Preschool , Female , Hand Deformities, Congenital/diagnosis , Hand Deformities, Congenital/pathology , Humans , Mandibulofacial Dysostosis/diagnosis , Mandibulofacial Dysostosis/pathology , Mutation/genetics , Pierre Robin Syndrome/diagnosis , Pierre Robin Syndrome/pathology
Eur J Med Genet ; 62(6): 103534, 2019 Jun.
Article En | MEDLINE | ID: mdl-30189253

TARP syndrome (TARPS) is an X-linked syndromic condition including Robin sequence, congenital heart defects, developmental delay, feeding difficulties and talipes equinovarus, as major features. The disease is caused by inactivating mutations in RBM10 which encodes for a RNA binding motif protein involved in transcript processing. We herein report a male born from healthy and non-consanguineous parents, presenting prenatal record of intrauterine fetal growth retardation, and postnatal features including growth and developmental delays, CNS abnormalities, facial dysmorphisms, bilateral syndactyly at the hands, talipes equinovarus and congenital heart defects. By using trio-based Whole Exome Sequencing approach, a maternally inherited RBM10 frameshift variant causing decay of the RBM10 transcript was identified. Despite the syndrome is considered lethal in affected males, our subject with molecularly confirmed TARPS is still alive at 11 years of age supporting the chance of surviving. Long-term surviving in TARPS is extremely rare and should be considered in genetic counselling and clinical follow up of the syndrome. We provide the natural history of the syndrome, reviewing the major clinical characteristics. Congenital heart defects are confirmed as specific diagnostic markers for the syndrome. In addition, cardiac anatomical details are defining a possible clinical overlap with syndromic conditions related to the hedgehog pathway and/or primary cilium anomalies as Oral-Facial-Digital or Smith-Lemli-Opitz syndromes.

Clubfoot/genetics , Heart Defects, Congenital/genetics , Pierre Robin Syndrome/genetics , RNA-Binding Proteins/genetics , Child , Clubfoot/pathology , Diagnosis, Differential , Heart Defects, Congenital/pathology , Humans , Male , Pierre Robin Syndrome/pathology
Cell Tissue Res ; 376(2): 199-210, 2019 May.
Article En | MEDLINE | ID: mdl-30413887

Bone morphogenetic protein (BMP) signaling plays a crucial role in the development of craniofacial organs. Mutations in numerous members of the BMP signaling pathway lead to several severe human syndromes, including Pierre Robin sequence (PRS) caused by heterozygous loss of BMP2. In this study, we generate mice carrying Bmp2-specific deletion in cranial neural crest cells using floxed Bmp2 and Wnt1-Cre alleles to mimic PRS in humans. Mutant mice exhibit severe PRS with a significantly reduced size of craniofacial bones, cleft palate, malformed tongue and micrognathia. Palate clefting is caused by the undescended tongue that prevents palatal shelf elevation. However, the tongue in Wnt1-Cre;Bmp2f/f mice does not exhibit altered rates of cell proliferation and apoptosis, suggesting contribution of extrinsic defects to the failure of tongue descent. Further studies revealed obvious reduction in cell proliferation and differentiation of osteogenic progenitors in the mandible of the mutants, attributing to the micrognathia phenotype. Our study illustrates the pathogenesis of PRS caused by Bmp2 mutation, highlights the crucial role of BMP2 in the development of craniofacial bones and emphasizes precise coordination in the morphogenesis of palate, tongue and mandible during embryonic development.

Bone Morphogenetic Protein 2/genetics , Neural Crest/metabolism , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Animals , Bone Morphogenetic Protein 2/physiology , Cell Differentiation , Cell Proliferation , Cleft Palate/genetics , Disease Models, Animal , Gene Expression Regulation, Developmental , Mandible/embryology , Mice , Mice, Knockout , Osteogenesis , Palate/embryology , Sequence Deletion , Tongue/embryology , Wnt Signaling Pathway/genetics
J Craniomaxillofac Surg ; 46(8): 1343-1347, 2018 Aug.
Article En | MEDLINE | ID: mdl-29861406

INTRODUCTION: The optimal surgical technique for the management of patients with Robin Sequence (RS) has not been established. One of the most commonly used surgical techniques, mandibular distraction osteogenesis (MDO), is still controversial because of its potential risks and the lack of clear evidence of its efficacy. OBJECTIVES: To assess variations in airway patency, clinical symptoms, and polysomnographic parameters in children with RS who underwent MDO. METHODS: In this prospective cohort study, 38 patients with RS were evaluated before and after MDO. Symptom severity was classified using a grading scale for RS clinical manifestations. Patients underwent flexible fiberoptic laryngoscopy, and the images were classified by a blinded examiner using two validated grading scales for airway obstruction. Patients not requiring ventilatory support underwent a polysomnography. RESULTS: Patients' symptoms significantly improved after MDO, as shown by a decreased score in the grading scale for RS clinical manifestations (preoperative score of 2.20 vs. postoperative score of 0.81; P < 0.001). The two endoscopic grading scales also showed a statistically significant postoperative improvement in airway obstruction (first scale: preoperative score of 1.56 vs. postoperative score of 0.92; second scale: preoperative score of 2.19 vs. postoperative score of 1.16; P < 0.001 for both). Moreover, there was a statistically significant variation in the following polysomnographic parameters evaluated pre- and postoperatively: apnea-hypopnea index, total sleep time, oxygen desaturation nadir, and oxygen desaturation index (P < 0.05). CONCLUSIONS: MDO seems to be an effective surgical option for children, as shown by postoperative improvements in clinical symptoms, endoscopic grading scales, and polysomnographic parameters.

Airway Obstruction/surgery , Mandible/surgery , Osteogenesis, Distraction/methods , Pierre Robin Syndrome/surgery , Airway Obstruction/etiology , Airway Obstruction/pathology , Female , Humans , Infant , Infant, Newborn , Male , Pierre Robin Syndrome/complications , Pierre Robin Syndrome/pathology , Polysomnography , Prospective Studies , Treatment Outcome
J Craniofac Surg ; 29(6): 1596-1600, 2018 Sep.
Article En | MEDLINE | ID: mdl-29863549

The Richieri-Costa-Pereira syndrome (RCPS) is an autosomal-recessive acrofacial dysostosis caused by mutations in EIF4A3, characterized by mandibular cleft comprising other craniofacial anomalies and limb defects such as cleft palate/Robin Sequence, microstomia, absence of mandibular central incisors, minor ear anomalies, clubfeet and first and 5 ray defects. The findings from this study are useful for better understanding the morphological consequences of disorders of EIF4A3, and having a better picture of the anatomic characteristics of the syndrome for a better therapeutic planning. Twenty-four angular and linear variables were measured to assess anteroposterior and vertical (superior-inferior) position of the cranial base, maxilla, mandible, and facial profile. The cephalometric radiographic analysis was performed on 9 individuals with RCPS, obtained at a mean age of 10.3 years, and compared with randomly selected age-matched 9 controls, without clefts and with well-balanced faces, with mean age of 10.6 years (both groups range 8.1 to 13.7 years). t test was used for analysis of means and Levene test for equality of variances. The syndrome group presented severe mandibular hypoplasia and retrognathism (P = 0.009, P = 0.001), greater facial convexity (N'PnPog and N'SnPog, P < 0.05) in syndrome group compared with the control group (P = 0.003, P = 0.004). In conclusion, in the RCPS group, most craniofacial defects affect the lower facial third, considering the severely affected mandible.

Clubfoot/diagnostic imaging , Hand Deformities, Congenital/diagnostic imaging , Jaw Abnormalities/diagnostic imaging , Pierre Robin Syndrome/diagnostic imaging , Skull/diagnostic imaging , Adolescent , Case-Control Studies , Cephalometry , Child , Clubfoot/pathology , Female , Hand Deformities, Congenital/pathology , Humans , Jaw Abnormalities/pathology , Male , Pierre Robin Syndrome/pathology , Skull/pathology
J Craniofac Surg ; 29(2): 332-338, 2018 Mar.
Article En | MEDLINE | ID: mdl-29215441

BACKGROUND: The Pierre Robin sequence (PRS) has been defined as the presence of micrognathia, glossoptosis, and respiratory obstruction in the neonatal period. Since its original description, different therapeutic approaches have been proposed obtaining different success rates, but there is no consensus about its management. METHODS: A literature review was conducted in PubMed, Embase, and Cochrane databases, for the period of January,1985 to November, 2016. A number of 23 articles resulting from clinical studies, discussing diagnostic tests or therapeutic approaches, and directly or indirectly comparing diagnostic or treatment modalities were selected and assessed using the GRADE methodology. RESULTS: After reviewing and analyzing the selected articles, an evidence-based algorithm for diagnosis and integral management of PRS patients was designed. CONCLUSION: Based on the anatomical principles and natural evolution of PRS, the clinical scenario must be evaluated thoroughly as a dynamic event to develop a management sequence that minimizes morbidity and mortality and accelerates patients' reinsertion to normal life.

Pierre Robin Syndrome , Airway Obstruction , Glossoptosis , Humans , Micrognathism , Pierre Robin Syndrome/diagnosis , Pierre Robin Syndrome/pathology , Pierre Robin Syndrome/physiopathology , Pierre Robin Syndrome/therapy
Plast Reconstr Surg ; 141(4): 1003-1009, 2018 04.
Article En | MEDLINE | ID: mdl-29257005

BACKGROUND: The authors investigated the accuracy of virtual surgical planning in predicting airway volume changes after mandibular distraction in patients with Pierre Robin sequence and associated tongue-based airway obstruction. METHODS: The authors completed a single-institution retrospective review of patients for whom virtual surgical planning was used during mandibular distraction osteogenesis for treatment of tongue-based airway obstruction. Preoperative airway volume, virtual surgical planning-predicted airway volume, and postoperative airway volume were calculated from three-dimensional computed tomographic scans using industry software. A blinded institutional radiologist also calculated pre- and post-operative airway volumes. Pre- and post-operative polysomnography was used to titrate the endpoint of mandibular lengthening. RESULTS: Eleven patients were included in the study. Mean apnea-hypopnea index (5.42 ± 4.53 versus 44.96 ± 20.57; p < 0.001) and mean nadir oxygen saturation (70.3 ± 9.72 percent versus 82.9 ± 9.62 percent; p = 0.003) improved with mandibular distraction. There was moderate correlation between predicted and actual mandibular distraction lengths (R = 0.65; p = 0.003). There was a strong correlation between predicted and industry-calculated actual post-distraction airway volume (R = 0.99; p < 0.001). There was no significant correlation between actual mandibular distraction length and industry-calculated actual post-distraction airway volume for the entire cohort (R = 0.05; p = 0.49), but correlation approached significance by institutional calculations. No significant correlation existed between industry and institutional-calculated percentage change in post-distraction airway volume (R = 0.06; p = 0.57). CONCLUSIONS: Predictive airway volume calculation may be an effective adjunct to determine anatomic endpoint of mandibular distraction but small sample size, operator and software variability, and patient airway morphology may confound firm conclusions. Further studies are warranted.

Airway Obstruction/surgery , Mandible/surgery , Osteogenesis, Distraction , Pierre Robin Syndrome/surgery , Preoperative Care/methods , Airway Obstruction/diagnostic imaging , Airway Obstruction/etiology , Airway Obstruction/pathology , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Mandible/diagnostic imaging , Mandible/pathology , Osteogenesis, Distraction/methods , Pierre Robin Syndrome/complications , Pierre Robin Syndrome/diagnostic imaging , Pierre Robin Syndrome/pathology , Retrospective Studies , Tomography, X-Ray Computed , Treatment Outcome
Am J Med Genet A ; 173(10): 2763-2771, 2017 Oct.
Article En | MEDLINE | ID: mdl-28777491

Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.

Adaptor Proteins, Signal Transducing/genetics , Mobius Syndrome/genetics , Muscular Diseases/genetics , Mutation , Pierre Robin Syndrome/genetics , Adolescent , Adult , Child , Female , Humans , Male , Mobius Syndrome/complications , Mobius Syndrome/pathology , Muscular Diseases/complications , Muscular Diseases/pathology , Pedigree , Pierre Robin Syndrome/complications , Pierre Robin Syndrome/pathology , Prognosis , Young Adult
Nat Commun ; 8: 16077, 2017 07 06.
Article En | MEDLINE | ID: mdl-28681861

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymkinsT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.

Membrane Proteins/genetics , Mobius Syndrome/genetics , Morphogenesis/genetics , Muscle Proteins/genetics , Muscle, Skeletal/metabolism , Muscular Diseases/genetics , Mutation , Myoblasts/metabolism , Pierre Robin Syndrome/genetics , Zebrafish Proteins/genetics , Adult , Amino Acid Sequence , Animals , Cell Fusion , Child , Disease Models, Animal , Embryo, Nonmammalian , Female , Gene Expression , Genes, Recessive , Genetic Complementation Test , Humans , Infant , Male , Membrane Proteins/deficiency , Mobius Syndrome/metabolism , Mobius Syndrome/pathology , Muscle Proteins/deficiency , Muscle, Skeletal/growth & development , Muscle, Skeletal/pathology , Muscular Diseases/metabolism , Muscular Diseases/pathology , Myoblasts/pathology , Pedigree , Pierre Robin Syndrome/metabolism , Pierre Robin Syndrome/pathology , Sequence Alignment , Sequence Homology, Amino Acid , Zebrafish , Zebrafish Proteins/deficiency
Pathologe ; 38(4): 241-247, 2017 Jul.
Article De | MEDLINE | ID: mdl-28653248

BACKGROUND: Cleft lip and palate (CLP) represents a group of malformations of unknown etiology but similar phenotypes. This implies consequences for the diagnostics, therapy, prevention, prognosis and risk estimation. OBJECTIVE: Definition of CLP subtypes and the embryonic development, clarification of correlations and differences between entities using epidemiological data, overview of the present state of genetic analyses, correlation to syndromes, sequences and associations and resulting consequences for clinical practice. MATERIAL AND METHODS: Update on embryological development of the face, summary of epidemiological and genetic studies and considerations on pedopathological and forensic aspects. RESULTS: Syndromic and non-syndromic CLP exhibit different and highly variable etiologies, therapeutic needs and prognosis. A thorough understanding is mandatory to distinguish between the different subgroups. In addition to specific aspects of CLP for the pediatric (forensic) pathologist this article provides an overall view of the topic which aims to help understand these malformations.

Cleft Lip/pathology , Cleft Palate/pathology , Cleft Lip/embryology , Cleft Lip/epidemiology , Cleft Lip/genetics , Cleft Palate/embryology , Cleft Palate/epidemiology , Cleft Palate/genetics , Cross-Sectional Studies , Female , Forensic Medicine , Gingiva/embryology , Gingiva/pathology , Humans , Infant, Newborn , Lip/embryology , Lip/pathology , Palate/embryology , Palate/pathology , Pierre Robin Syndrome/embryology , Pierre Robin Syndrome/epidemiology , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Pregnancy , Prognosis , Risk Factors , Statistics as Topic
Rev. ADM ; 74(3): 146-151, mayo-jun. 2017. ilus
Article Es | LILACS | ID: biblio-908012

Durante la infancia es muy frecuente encontrar alteraciones del desarrollo,las cuales derivan de una defi ciente formación de las estructurasanatómicas durante la embriogénesis. Puede encontrarse un sinnúmerode alteraciones del desarrollo que afectan la región bucal y maxilofacial.La gran mayoría de estas alteraciones han sido catalogadas como síndromes de orden genético; sin embargo, no todas pueden describirse como tales, pues existen anomalías del desarrollo que aparecen como consecuencia de una deficiente embriogénesis de la región facial, provocando alteraciones anatómicas y funcionales, pero que se apartan de componentes genéticos y cromosómicos específi cos. La secuencia malformativa de Pierre Robin es una de ellas, ya que esta condición es producida por una afección inicial, de la cual derivarán otras afeccionesadicionales a nivel del paladar y de la mandíbula que ocasionarán en elpaciente dificultad para la alimentación y respiración. Debido a que las alteraciones de esta condición afectan directamente la cavidad bucal,es crucial que el odontólogo se encuentre familiarizado con esta anomalía. El objetivo del presente artículo es describir las característicasque configuran esta entidad nosológica mediante la exposición de un caso clínico y revisión de la literatura.

During childhood, it is frequent to find development disorders whichare linked to the weak formation of anatomic structures duringembryogenesis. It is possible to find a plethora of developmentdisorders that aff ect the oral and maxillofacial region. The majorityof these disorders has been classifi ed as genetic malformations butnot all can be described as such. That is because some developmentdisorders appear as a result of a defi cient embryogenesis of the face,producing thus anatomic and functional malformations but that standapart from genetic and chromosomic specifi c components. The Pierre Robin sequence is one of them, given that this condition is producedby an initial disorder, followed by other disorders in the palate andjaw; provoking alimentary and breathing disabilities in the patient.Due to these disorders and their impact on the mouth, it is crucial thatdentists be familiarized with such anomalies. The aim of this article isto describe the key characteristics that defi ne this disease through thepresentation of a clinical case and a literature review.

Male , Humans , Infant, Newborn , Dental Care for Chronically Ill/methods , Infant Care/methods , Pierre Robin Syndrome/etiology , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Cleft Palate/etiology , Deglutition Disorders/etiology , Mexico , Maxillofacial Development/physiology , Micrognathism/etiology , Palatal Obturators
Am J Med Genet A ; 173(4): 938-945, 2017 Apr.
Article En | MEDLINE | ID: mdl-28328130

Auriculocondylar syndrome, mainly characterized by micrognathia, small mandibular condyle, and question mark ears, is a rare disease segregating in an autosomal dominant pattern in the majority of the families reported in the literature. So far, pathogenic variants in PLCB4, GNAI3, and EDN1 have been associated with this syndrome. It is caused by a developmental abnormality of the first and second pharyngeal arches and it is associated with great inter- and intra-familial clinical variability, with some patients not presenting the typical phenotype of the syndrome. Moreover, only a few patients of each molecular subtype of Auriculocondylar syndrome have been reported and sequenced. Therefore, the spectrum of clinical and genetic variability is still not defined. In order to address these questions, we searched for alterations in PLCB4, GNAI3, and EDN1 in patients with typical Auriculocondylar syndrome (n = 3), Pierre Robin sequence-plus (n = 3), micrognathia with additional craniofacial malformations (n = 4), or non-specific auricular dysplasia (n = 1), which could represent subtypes of Auriculocondylar syndrome. We found novel pathogenic variants in PLCB4 only in two of three index patients with typical Auriculocondylar syndrome. We also performed a detailed comparative analysis of the patients presented in this study with those previously published, which showed that the pattern of auricular abnormality and full cheeks were associated with molecularly characterized individuals with Auriculocondylar syndrome. Finally, our data contribute to a better definition of a set of parameters for clinical classification that may be used as a guidance for geneticists ordering molecular testing for Auriculocondylar syndrome. © 2017 Wiley Periodicals, Inc.

Ear Diseases/diagnosis , Ear/abnormalities , Genetic Predisposition to Disease , Micrognathism/diagnosis , Mutation , Phospholipase C beta/genetics , Pierre Robin Syndrome/diagnosis , Adult , Child , Ear/pathology , Ear Diseases/classification , Ear Diseases/genetics , Ear Diseases/pathology , Endothelin-1/genetics , Female , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Gene Expression , Genes, Dominant , High-Throughput Nucleotide Sequencing , Humans , Male , Micrognathism/classification , Micrognathism/genetics , Micrognathism/pathology , Pedigree , Phenotype , Pierre Robin Syndrome/classification , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Terminology as Topic
J Craniomaxillofac Surg ; 45(2): 210-215, 2017 Feb.
Article En | MEDLINE | ID: mdl-28011184

OBJECTIVE: Systematically search literature for flexible fiberoptic laryngoscopy (FFL) use in Robin Sequence (RS) patients, in diverse clinical scenarios. DATA SOURCES: Pubmed, LILACS and SCIELO. REVIEW METHODS: Systematic review using a sensitive search strategy focused on RS patients and FFL. RESULTS: There were 48 full text articles included in this systematic review. No summary meta-analytic measurement could be calculated due to heterogeneity of interventions and outcomes. FFL approaches were grouped in five topics, as follows: Endoscopic classification: no evidence on superiority of awake over light sedation and correlation of grading scales with symptom severity. Airway abnormalities: high incidence of concomitant lesions besides glossoptosis. Swallowing evaluation: no validation against fluoroscopy (gold standard) yet. Intubation aid for mechanical ventilation: ultra-thin bronchoscopes improve success rates of intubation. Treatment outcome monitoring: no consensus on ideal parameters to be checked. CONCLUSION: Some applications have their roles already well established in the management of RS patients, like the evaluation of glossoptosis and associated lesions and as an intubation assistance tool, while others need to be the subject of further research, like the exact method of evaluation, its association with clinical manifestations, its role in swallowing investigation and as a postoperative success predictor.

Laryngoscopy/instrumentation , Pierre Robin Syndrome/diagnosis , Fiber Optic Technology/instrumentation , Fiber Optic Technology/methods , Humans , Laryngoscopes , Laryngoscopy/methods , Pierre Robin Syndrome/pathology
Clin Oral Investig ; 21(7): 2273-2281, 2017 Sep.
Article En | MEDLINE | ID: mdl-27933446

OBJECTIVES: Partial tooth agenesis is frequently observed in Robin sequence. Tooth anomalies are increasingly considered as an extended phenotype of the cleft palate population. The study objective was to compare the prevalence and patterns of tooth agenesis in a group of patients with non-syndromic Robin sequence (ns-RS) and a group with non-syndromic cleft palate (ns-CP). MATERIALS AND METHODS: The panoramic radiographs of 115 ns-RS and 191 ns-CP patients were assessed for agenesis of the permanent dentition (excluding third molars) and the patterns recorded using the Tooth Agenesis Code. RESULTS: Partial tooth agenesis was observed in 47.8% of ns-RS and 29.8% of ns-CP patients with a greater prevalence in the mandibula than in the maxilla, particularly in ns-RS. The teeth most frequently absent in both groups were the mandibular second premolars and maxillary lateral incisors. Tooth agenesis was bilateral in two-thirds of affected ns-RS patients and one-half of ns-CP patients. In ns-RS, bilateral agenesis of the mandibular second premolars was more frequently observed in female than that in male patients. Completely symmetrical patterns of hypodontia were found in around 45% of ns-RS patients with tooth agenesis compared to 35% in ns-CP. No association was found between the extent of the palatal cleft and the severity of hypodontia. CONCLUSION: Tooth agenesis is more prevalent in ns-RS than that in ns-CP, demonstrates a much greater predilection for the mandible in ns-RS, and bears no relation to the extent of the palatal cleft. CLINICAL RELEVANCE: When compared to ns-CP, additional developmental disturbances are likely involved in the etiology of tooth agenesis in ns-RS. Future research could help identify the underlying genetic traits and aid in classifying patients in those with and without expected tooth agenesis in order to facilitate orthodontic management strategies.

Anodontia/diagnostic imaging , Anodontia/epidemiology , Anodontia/pathology , Cleft Palate/pathology , Pierre Robin Syndrome/pathology , Radiography, Panoramic , Child , Female , Humans , Male , Netherlands/epidemiology , Phenotype , Prevalence