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Int J Pediatr Otorhinolaryngol ; 146: 110749, 2021 Jul.
Article En | MEDLINE | ID: mdl-34004386

OBJECTIVE: To determine whether the two most common genetic mutations seen in Stickler Syndrome (SS) (COL2A1 and COL11A1) affect the incidence of mandibular distraction osteogenesis (MDO) and what impact Robin sequence (RS) has on diagnosis. SS is an autosomal dominant connective tissue disorder characterized by almost complete penetrance. COL2A1 and COL11A1 are the two most common mutations seen in SS patients. SS often presents at birth with RS, which is characterized by the triad of micrognathia, glossoptosis, and tongue-based airway obstruction. MDO is one surgical intervention that has been shown to be successful in relieving tongue base obstruction and is the surgical intervention of choice for this condition. METHODS: A retrospective chart review was performed on all patients with a diagnosis of SS at a tertiary pediatric hospital between January 1, 2003 and December 31, 2018. The included patient charts were reviewed for demographic information, SS mutation, and history of MDO. Forty-six patients had a clinical diagnosis of SS. Of those, 31 met inclusion criteria which involved having a molecular diagnosis of SS and sufficient follow up information to determine if MDO was indicated or performed. Twenty-two of the 31 included patients had a diagnosis of RS (70.96%). Thirteen of the 31 patients (41.94%) included in this study required MDO as a neonate. RESULTS: Fifty-percent of patients with type I (COL2A1) required MDO as a neonate compared to only 31% of patients with type II (COL11A1), though the difference between the two groups was not statistically significant. CONCLUSION: The findings of this study suggest that patients with type I mutation may have a higher incidence of MDO than patients with a type II mutation, though further research with larger sample sizes is needed. This information is helpful in counseling those with SS or family history of SS about what they can expect related to RS and need for MDO based on genetic findings. LEVEL OF EVIDENCE: 3.

Airway Obstruction , Collagen Type II/genetics , Collagen Type XI/genetics , Osteogenesis, Distraction , Pierre Robin Syndrome , Arthritis , Child , Connective Tissue Diseases , Hearing Loss, Sensorineural , Humans , Incidence , Infant , Infant, Newborn , Mandible , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/surgery , Retinal Detachment , Retrospective Studies , Treatment Outcome
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(4): 369-372, 2021 Apr 10.
Article Zh | MEDLINE | ID: mdl-33834468

OBJECTIVE: To explore the genetic basis for a neonate with Pierre-Robin sequence. METHODS: The child was subjected to chromosomal karyotyping, single nucleotide polymorphism array (SNP-array)-based comparative genomic hybridization and fluorescence in situ hybridization (FISH) analysis. RESULTS: The child has featured microgthnia, glossoptosis, upper airway obstruction, mandible dehiscence and short neck. He was found to have a karyotype of 46,XY,der(4)add(4)(q34). Her mother's karyotype was determined as 46,XX,t(1;4)(q43;q34), while his father was 46,XY. SNP-array analysis suggested the child to be arr [hg19] 1q42.2q44 (232 527 958-249 202 755)× 3; 4q34.3q35.2 (168 236 901-190 880 409)× 1. The result of SNP-array for both parents was normal. FISH analysis confirmed that his mother has carried a balanced t(1;4)(q42;34) translocation. The aberrant chromosome 4 in the child has derived from his mother's translocation, which gave rise to partial 1q trisomy and 4q monosomy. CONCLUSION: The 1q42.2q44 duplication and 4q34.3q35.2 deletion of the child probably underlay his abnormal phenotype of Pierre-Robin sequence.

Pierre Robin Syndrome , Trisomy , Child , Comparative Genomic Hybridization , Female , Humans , In Situ Hybridization, Fluorescence , Infant, Newborn , Male , Monosomy , Pierre Robin Syndrome/genetics , Translocation, Genetic , Trisomy/genetics
Muscle Nerve ; 63(4): 516-524, 2021 04.
Article En | MEDLINE | ID: mdl-33389762

INTRODUCTION: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW. METHODS: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography. RESULTS: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement. DISCUSSION: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.

Facial Paralysis/congenital , Facial Paralysis/diagnosis , Mobius Syndrome/diagnosis , Muscular Diseases/diagnosis , Pierre Robin Syndrome/diagnosis , Adult , Diagnosis, Differential , Facial Paralysis/genetics , Facial Paralysis/physiopathology , Female , Heterozygote , Humans , Male , Mobius Syndrome/genetics , Mobius Syndrome/physiopathology , Muscular Diseases/genetics , Muscular Diseases/physiopathology , Mutation/genetics , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/physiopathology
Cleft Palate Craniofac J ; 58(4): 514-517, 2021 04.
Article En | MEDLINE | ID: mdl-32909813

Robin sequence (RS) has been reported in association with single gene disorders and chromosomal abnormalities; however, it has not previously been described in connection with chromosome 1q21 microduplication. We present the first known case of a neonate diagnosed with chromosome 1q21.1 microduplication syndrome and RS requiring surgical airway intervention. This case demonstrates the value of genetic testing in cases of RS presenting with other congenital anomalies.

Pierre Robin Syndrome , Chromosomes , Genetic Testing , Humans , Infant, Newborn , Pierre Robin Syndrome/genetics
Medicine (Baltimore) ; 99(45): e23033, 2020 Nov 06.
Article En | MEDLINE | ID: mdl-33157955

INTRODUCTION: Microdeletion syndromes occur from deletion of 5Mb of a chromosome in approximately 5% of patients with unexplained intellectual disability. Interstitial microdeletions at bands 1p33 and 1p32.2 of the short arm of chromosome 1 are rare and have not been previously reported in relation to disease. PATIENT CONCERNS: We present a case of a 39-month boy with Pierre Robin sequence, development delay/intellectual disability, growth retardation, short stature, leukoencephalopathy, craniofacial dysplasia, and speech delay. The child was referred to the Child health care department in October 2014 for his delayed language development and aggravated aggression. DIAGNOSIS: Molecular diagnostic testing with G-band karyotyping was normal but clinical microarray analysis detected a 10 Mb microdeletion at 1p33p32.2. INTERVENTIONS: The patient received rehabilitation. OUTCOMES: Three candidate genes were pinpointed to the deleted area, including ORC1, SCP2, and DAB1. Phenotype-genotype analysis suggested that these three genes are likely to be responsible for the main phenotypes observed in the patient, such as microcephaly, growth retardation, short stature, leukoencephalopathy, and development delay/intellectual disability. CONCLUSIONS: The spectrum of phenotypes this case presented with are likely to be caused by 1p33p32.2 deletion which could represent a new microdeletion syndrome.

Karyotyping/methods , Microarray Analysis/methods , Pierre Robin Syndrome/diagnosis , Pierre Robin Syndrome/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Adult , Carrier Proteins/genetics , Child , Child, Preschool , Chromosome Deletion , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/genetics , Dwarfism/diagnosis , Dwarfism/genetics , Female , Humans , Infant , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Language Development Disorders/diagnosis , Language Development Disorders/genetics , Leukoencephalopathies/diagnosis , Leukoencephalopathies/genetics , Male , Microcephaly/diagnosis , Microcephaly/genetics , Nerve Tissue Proteins/genetics , Origin Recognition Complex/genetics , Phenotype , Pierre Robin Syndrome/rehabilitation
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
Childs Nerv Syst ; 36(7): 1367-1377, 2020 07.
Article En | MEDLINE | ID: mdl-32399800

INTRODUCTION: The Pierre-Robin sequence (PRS) is a pattern of congenital facial abnormalities comprising micrognathia, glossoptosis, and airway obstruction. Associated spinal pathologies have rarely been reported with PRS. METHODS: We explore the molecular genetic basis of this association through a systematic review of spinal disease in patients with PRS. We also present an illustrative case of a PRS patient with tethered cord in the setting of chromosome 10q terminal deletion. RESULTS: Our systematic literature review of spinal disease in patients with PRS revealed several patterns in the underlying genetic syndromes causing these conditions to co-occur. These principles are illustrated in the case of a 6-month-old female with PRS and a 14.34-Mb terminal deletion of chromosome 10q, who was found to have a sacral dimple during a routine outpatient checkup. Magnetic resonance imaging of the spine revealed a lumbar syrinx associated with tethered spinal cord. Surgical de-tethering was undertaken, with subsequent improvement in motor function and decrease in the size of the syrinx. The deletion of chromosome 10q in our patient had not previously been described in association with tethered cord or PRS. CONCLUSION: Spinal pathologies are understudied contributors to disease burden in patients with PRS. The range of predisposing syndromes and mutations in patients with both PRS and spinal disorders remains poorly characterized but may be more defined than previously conceived. Clinical screening is most critical during neonatal and adolescent developmental periods with continued neurological assessment. This study emphasizes the need for early genetic testing and counseling in this patient population, in parallel with research efforts to develop molecular classifications to guide clinical management.

Airway Obstruction , Pierre Robin Syndrome , Spinal Diseases , Adolescent , Chromosome Deletion , Chromosomes, Human, Pair 10 , Female , Humans , Infant , Infant, Newborn , Pierre Robin Syndrome/complications , Pierre Robin Syndrome/diagnostic imaging , Pierre Robin Syndrome/genetics
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
J Craniofac Surg ; 31(4): e356-e359, 2020 Jun.
Article En | MEDLINE | ID: mdl-32217860

Robin sequence with cleft mandible and limb anomalies, known as Richieri-Costa-Pereira syndrome (RCPS), is an autosomal recessive acrofacial dysostosis characterized by mandibular cleft and other craniofacial anomalies and respiratory complications. The aim of this cross-sectional study was to describe the hyoid and head posture of 9 individuals with RCPS using cephalometric measurements and provide a discussion about its implications in obstructive sleep apnea syndrome (OSAS). The study was conducted on lateral cephalograms of patients with RCPS and 9 selected age-matched controls in tertiary cleft center in Brazil. The cephalograms were digitized and analyzed on a software to obtain the vertical and horizontal hyoid position, its relationship with the mandible and the relation of the cranial base and postvertebral line. The t test was used for analysis of means and Levene's test for equality of variances.Cephalometric measurements H-S (vertical distance between hyoid bone and sella) (Supplemental Digital Content, Figure 1, and H-C4lp (horizontal position of the hyoid in relation to the post-pharyngeal space) showed statistically significant difference compared to controls (P < 0.05). Therefore, the hyoid bone was more inferiorly and posteriorly positioned in the study group compared with the control group. The vertebrae measurements did not present differences compared to controls. The described position of hyoid bone could be involved in the severe OSAS of RCPS patients.

Clubfoot , Hand Deformities, Congenital , Head , Hyoid Bone , Pierre Robin Syndrome , Posture , Adolescent , Cephalometry , Child , Clubfoot/diagnostic imaging , Clubfoot/genetics , Cross-Sectional Studies , DEAD-box RNA Helicases/genetics , Eukaryotic Initiation Factor-4A/genetics , Hand Deformities, Congenital/diagnostic imaging , Hand Deformities, Congenital/genetics , Humans , Infant , Male , Pierre Robin Syndrome/diagnostic imaging , Pierre Robin Syndrome/genetics , Sleep Apnea, Obstructive/etiology
Am J Med Genet A ; 182(3): 431-436, 2020 03.
Article En | MEDLINE | ID: mdl-31769200

Catel-Manzke syndrome, also known as micrognathia-digital-syndrome, is a rare autosomal recessive disorder characterized by the combination of the two cardinal features Pierre-Robin sequence and bilateral hyperphalangy leading to ulnar clinodactyly (ulnar curvature of the phalanges) and radial deviation (radial angulation at the metacarpophalangeal joint) of the index fingers. Individuals without one of these major hallmarks or with additional hand malformations have been described as atypical or Catel-Manzke-like syndrome. Biallelic TGDS pathogenic variants have thus far been detected in eight individuals with typical Catel-Manzke syndrome and in one fetus with additional features. Here we report on two individuals with TGDS pathogenic variants who presented with mild radial deviation and ulnar clinodactyly of the index fingers but without radiologic signs of hyperphalangy. Furthermore, both individuals have disproportionate short stature, a feature that has not yet been associated with Catel-Manzke syndrome. Our data broaden the phenotypic spectrum of TGDS-associated Catel-Manzke syndrome and expand the indication for diagnostic testing.

Hand Deformities, Congenital/genetics , Hydro-Lyases/genetics , Pierre Robin Syndrome/genetics , Polydactyly/genetics , Abnormalities, Multiple/genetics , Abnormalities, Multiple/physiopathology , Adolescent , Alleles , Child , Child, Preschool , Female , Hand Deformities, Congenital/diagnosis , Hand Deformities, Congenital/physiopathology , Humans , Male , Mutation/genetics , Pierre Robin Syndrome/diagnosis , Pierre Robin Syndrome/physiopathology , Polydactyly/physiopathology
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
Am J Obstet Gynecol ; 221(6): B10-B12, 2019 12.
Article En | MEDLINE | ID: mdl-31787157
J Craniomaxillofac Surg ; 47(11): 1699-1705, 2019 Nov.
Article En | MEDLINE | ID: mdl-31477439

Various treatments, many of them considerably invasive, are currently applied to infants with Robin sequence (RS) and accompanying upper airway obstruction (UAO). We present a narrative review of our data on the Tübingen palatal plate (TPP) which show the following: a) in a randomized trial, the TPP was superior to a sham procedure in alleviating UAO; b) children treated with the TPP in infancy showed an intellectual development within the reference range; c) prone positioning is no alternative, as it is ineffective and associated with an increased risk of sudden death; d) the TPP reduces the mixed-obstructive apnea index to near-normal values, both in isolated and most (83%) syndromic RS, e) of 443 infants (129 syndromic) treated with the TPP in our center, 23 (5%) ultimately received a tracheostomy (all with syndromic RS), f) recent data suggest that the TPP may induce mandibular catch-up growth, g) the TPP may also help to reduce respiratory complications following cleft closure in RS, and h) TPP treatment is applied by various centers around the world, although it is unclear if its effectiveness is invariably controlled by endoscopy and sleep studies, although both are necessary. Given these data from peer-reviewed studies, it may be questioned whether the "First do no harm" principle is always adhered to when subjecting RS infants to more invasive procedures such as mandibular distraction osteogenesis or tongue-lip adhesion.

Airway Obstruction/therapy , Osteogenesis, Distraction , Pierre Robin Syndrome/therapy , Sleep Apnea, Obstructive/therapy , Airway Obstruction/diagnosis , Airway Obstruction/etiology , Child , Humans , Infant , Mandible/growth & development , Mandible/pathology , Pierre Robin Syndrome/complications , Pierre Robin Syndrome/diagnosis , Pierre Robin Syndrome/genetics , Polysomnography , Retrospective Studies , Sleep Apnea, Obstructive/diagnosis , Treatment Outcome
Head Face Med ; 15(1): 17, 2019 Jun 22.
Article En | MEDLINE | ID: mdl-31228944

BACKGROUND: Robin sequence (RS) is characterized by mandibular retrognathia, glossoptosis and upper airway obstruction. Whether mandibular catch-up growth may occur in RS is yet controversial. Our functional and less invasive treatment including the Tübingen Palatal Plate (TPP), early oral feeding and orofacial stimulation may promote mandibular catch-up growth. We evaluated the effect of the Tübingen Palatal Plate on mandibular growth, expressed by the Jaw index, sleep study results and weight gain in infants admitted with isolated and syndromic RS, born at or referred to our center between 6/2015 and 5/2018. METHODS: Retrospective analysis of our electronic patient database that included data on jaw index measurements, sleep study results and standard deviation (Z-)scores for weight. RESULTS: Of 31 patients referred for RS treatment (22 isolated, 9 syndromic), we had data on the above parameters, determined at admission, discharge and 3 months after discharge, in 20. Jaw index at admission and 3-month follow-up was 8.8 (6.3-11.3) and 2.1 (2.0-4.0), respectively (median (IQR); p < 0.0001). Mixed-obstructive apnea index (MOAI) decreased from 9.7 (4.8-24.2) to 0.0 (0-1.3; p < 0.002). No significant correlation was observed between MOAI and Jaw Index, but MOAI correlated with the Maxillary/Mandibular arch ratio (r = 0.58; p < 0.001). Z-scores for weight were similar at both time points at - 1.34 (- 1.76 - - 0.57) and - 1.50 (- 1.89 - - 0.54), while the proportion of infants requiring nasogastric tube feeding decreased from 84 to 8%. No infant had craniofacial surgery; one with syndromic RS required tracheostomy. CONCLUSION: These longitudinal cohort data suggest that the Tübingen Palatal Plate as used here may alleviate upper airway obstruction by promoting mandibular growth. TRIAL REGISTRATION: N.A.

Pierre Robin Syndrome , Retrospective Studies , Sleep Apnea Syndromes , Sleep Apnea, Obstructive , Humans , Infant , Mandible/growth & development , Mandible/pathology , Pierre Robin Syndrome/complications , Pierre Robin Syndrome/genetics , Treatment Outcome
Rev. bras. oftalmol ; 78(1): 46-48, jan.-fev. 2019. tab, graf
Article Pt | LILACS | ID: biblio-990797

Resumo A síndrome de Pierre Robin (PRS) consiste em uma tríade de anomalias caracterizada por micrognatia, glossoptose e fissura de palato, comumente associada com outras síndromes e ocasionalmente com alterações oculares. Na Síndrome de Duane (DRS), há uma falha na inervação do reto lateral pelo VI nervo, com inervação anômala do reto lateral por fibras do III nervo. Ainda que a PRS já tenha sido associada com mais de 50 outras síndromes, não existe na literatura relato de casos de associação com a DRS familiar. Dessa forma, esse trabalho tem por objetivo relatar um caso dessa associação em um paciente de 29 anos com recorrência das síndromes na família.

Abstract The Pierre Robin Syndrome (PRS) consists of a triad of anomalies characterized by micrognathia, glossoptosis and fissure of the palate, usually associated with other syndromes e occasionally associated with ocular variations. In Duane Retraction Syndrome (DRS), there is a failure in the lateral rectus innervation by the VI cranial nerve, with anomalous innervation of the lateral rectus by fibers of the III nerve. Even though PRS has already been associated with more than 50 other syndromes, there is not any report in literature of association with familial DRS. Thus, this work aims to report a case of this association in a 29 years old patient with recurrence of the syndromes in the family.

Humans , Male , Adult , Abducens Nerve/abnormalities , Pierre Robin Syndrome/diagnosis , Pierre Robin Syndrome/genetics , Eye Diseases, Hereditary/diagnosis , Duane Retraction Syndrome/diagnosis
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