ABSTRACT
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.
Subject(s)
Alopecia/genetics , Mandibulofacial Dysostosis/genetics , Receptor, Endothelin A/genetics , Alopecia/pathology , Animals , Base Sequence , Endothelin-1/metabolism , Exome/genetics , Humans , In Situ Hybridization , Mandibulofacial Dysostosis/pathology , Molecular Sequence Data , Morpholinos/genetics , Mutation, Missense/genetics , Pedigree , RNA, Messenger/administration & dosage , Real-Time Polymerase Chain Reaction , Receptor, Endothelin A/metabolism , Sequence Analysis, DNA , Syndrome , Tomography, X-Ray Computed , Zebrafish , Zygoma/pathologyABSTRACT
Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated â¼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).
Subject(s)
Abnormalities, Multiple/genetics , Hearing Loss/genetics , Intellectual Disability/genetics , Mandibulofacial Dysostosis/genetics , Microcephaly/genetics , Mutation , Peptide Elongation Factors/genetics , Ribonucleoprotein, U5 Small Nuclear/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Amino Acid Motifs , Databases, Genetic , Gene Expression , Haploinsufficiency , Hearing Loss/diagnosis , Hearing Loss/pathology , Humans , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Mandibulofacial Dysostosis/diagnosis , Mandibulofacial Dysostosis/pathology , Microcephaly/diagnosis , Microcephaly/pathology , Models, Molecular , Molecular Sequence Data , Penetrance , Phenotype , Protein Structure, Secondary , Protein Structure, Tertiary , RNA Splicing , Spliceosomes/geneticsABSTRACT
Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch. Mutations in the genes coding for phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 (GNAI3), predicted to function as signal transducers downstream of EDNRA, have recently been reported in ACS. By whole-exome sequencing (WES), we identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents. WES of two cases with vertical transmission of isolated QMEs revealed a stop mutation in EDN1 in one family and a missense substitution of a highly conserved residue in the mature EDN1 peptide in the other. Targeted sequencing of EDN1 in an ACS individual with related parents identified a fourth, homozygous mutation falling close to the site of cleavage by endothelin-converting enzyme. The different modes of inheritance suggest that the degree of residual EDN1 activity differs depending on the mutation. These findings provide further support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway.
Subject(s)
Ear Diseases/genetics , Ear/abnormalities , Genes, Dominant , Genes, Recessive , Mutation , Phenotype , Amino Acid Sequence , Amino Acid Substitution , DNA Mutational Analysis , Ear Diseases/diagnosis , Ear Diseases/metabolism , Endothelin-1/genetics , Endothelin-1/metabolism , Female , Genotype , Humans , Male , Molecular Sequence Data , Pedigree , Sequence Alignment , Signal TransductionABSTRACT
Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome.
Subject(s)
GTP Phosphohydrolases/genetics , Haploinsufficiency/genetics , Mandibulofacial Dysostosis/genetics , Microcephaly/genetics , Ribonucleoprotein, U5 Small Nuclear/genetics , Abnormalities, Multiple/genetics , Alleles , Amino Acid Sequence , Child , Child, Preschool , Cohort Studies , Exome , Female , Humans , Infant , Male , Molecular Sequence Data , Mutation/genetics , Protein Structure, Tertiary/genetics , RNA Splicing/genetics , Spliceosomes/geneticsABSTRACT
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.
Subject(s)
Anion Transport Proteins/genetics , Carpal Bones/pathology , Dwarfism/genetics , Extremities/pathology , Mutation/genetics , Osteogenesis , Pierre Robin Syndrome/genetics , Adult , Brazil , Child , Dwarfism/diagnosis , Female , Heterozygote , Humans , Male , Osteochondrodysplasias , Phenotype , Pierre Robin Syndrome/diagnosis , Siblings , Sulfate TransportersABSTRACT
We describe a girl with a phenotype characterized by frontonasal dysplasia, callosal agenesis, basal encephalocele, and eye anomalies who presents a 46,XX,r(21) karyotype. Array-comparative genomic hybridization using the Afflymetrix 100K DNA oligoarray set showed an interstitial deletion 21q22.3 of approximately 219 kb. Conventional karyotype of both parents was normal, and it was not possible to perform the molecular studies. In this report we raise the hypothesis that the deleted genes located at 21q22.3 could account to the phenotype.
Subject(s)
Abnormalities, Multiple/genetics , Chromosome Deletion , Chromosomes, Human, Pair 21 , Abnormalities, Multiple/diagnosis , Agenesis of Corpus Callosum/diagnosis , Agenesis of Corpus Callosum/genetics , Comparative Genomic Hybridization , Congenital Abnormalities/diagnosis , Congenital Abnormalities/genetics , Craniofacial Abnormalities , Encephalocele/diagnosis , Encephalocele/genetics , Eye Abnormalities/diagnosis , Eye Abnormalities/genetics , Face/abnormalities , Facies , Female , Humans , Infant , Karyotype , Magnetic Resonance Imaging , Neuroimaging , Polymorphism, Single Nucleotide , SyndromeABSTRACT
The authors describe on a Brazilian girl with coronal synostosis, facial asymmetry, ptosis, brachydactyly, significant learning difficulties, recurrent scalp infections with marked hair loss, and elevated serum immunoglobulin E. Standard lymphocyte karyotype showed a small additional segment in 7p21[46,XX,add(7)(p21)]. Deletion of the TWIST1 gene, detected by Multiplex Ligation Probe-dependent Amplification (MPLA) and array-CGH, was consistent with phenotype of Saethre-Chotzen syndrome. Array CGH also showed deletion of four other genes at 7p21.1 (SNX13, PRPS1L1, HD9C9, and FERD3L) and the deletion of six genes (CACNA2D2, C3orf18, HEMK1, CISH, MAPKAPK3, and DOCK3) at 3p21.31. Our case reinforces FERD3L as candidate gene for intellectual disability and suggested that genes located in 3p21.3 can be related to hyper IgE phenotype.
Subject(s)
Acrocephalosyndactylia/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 3 , Chromosomes, Human, Pair 7 , Job Syndrome/genetics , Learning Disabilities/genetics , Acrocephalosyndactylia/complications , Acrocephalosyndactylia/diagnosis , Child , Child, Preschool , Chromosome Banding , Chromosome Deletion , Comparative Genomic Hybridization , Facies , Female , Humans , Infant , Job Syndrome/complications , Job Syndrome/diagnosis , Learning Disabilities/complications , Learning Disabilities/diagnosis , PhenotypeABSTRACT
Auriculo-condylar syndrome (ACS) is characterized by typical ears malformation (so-called "question mark" ears), prominent cheeks, microstomia, and abnormality of the temporomandibular joint and condyle of the mandible. In this report we describe a new simplex case and a previously unreported family with affected individuals in three generations documenting clinical variability. Linkage study for markers located in candidate region for ACS1 (1p21.1-q23.3) was excluded in our familial case, reinforcing the hypothesis of genetic heterogeneity for this condition. A review of the literature focusing diagnostic criteria and features of ACS was performed.
Subject(s)
Ear Diseases/diagnosis , Ear Diseases/genetics , Brazil , Child , Chromosomes, Human, Pair 1/genetics , Ear/abnormalities , Female , Genetic Heterogeneity , Genetic Linkage , Humans , Mandible/abnormalities , Microstomia/genetics , Pedigree , Temporomandibular Joint/abnormalitiesABSTRACT
We reported on 16 new Brazilian patients and review findings in 12 previously reported cases (25 apparently unrelated Brazilian families) from Hospital of Rehabilitation of Craniofacial Anomalies, presenting with Richieri-Costa-Pereira syndrome. All patients display a unique pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of mandible, cleft palate/Robin sequence, absence of central lower incisors, minor ears anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability was also a common finding. The sex-ratio showed deviation toward to female (1.8F:1M). Recurrence in sibs was observed in nine instances and consanguinity in 11, supporting the hypothesis of autosomal recessive inheritance. Nineteen of the 25 families lived in São Paulo State, seven of them (10 affected individuals) from an isolated region named "Vale do Ribeira." The geographic barrier of this region associated with the high incidence of the consanguineous matting suggested that this condition is caused by a rare mutation with a founder effect. With the exception of one patient in France, all known cases are of Brazilian origin. The causative gene of this rare syndrome remains unknown.
Subject(s)
Clubfoot , Hand Deformities, Congenital , Pierre Robin Syndrome , Brazil/epidemiology , Clubfoot/epidemiology , Clubfoot/genetics , Clubfoot/pathology , Female , Genes, Recessive , Hand Deformities, Congenital/epidemiology , Hand Deformities, Congenital/genetics , Hand Deformities, Congenital/pathology , Humans , Male , Pedigree , Pierre Robin Syndrome/epidemiology , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Sex RatioABSTRACT
We report on two unrelated Brazilian boys with craniofacial anomalies that involve the frontonasal process and the first branchial arch associated with pericallosal lipoma. To our knowledge this condition seems to have been reported only once previously, but may represent a new condition within the group of the frontonasal dysgenesis. Clinical and imaging data, phenotypic evolution, and differential diagnosis are discussed.
Subject(s)
Branchial Region/abnormalities , Craniofacial Abnormalities/pathology , Frontal Bone/abnormalities , Lipoma/diagnosis , Nose/abnormalities , Adult , Branchial Region/pathology , Female , Frontal Bone/pathology , Humans , Infant, Newborn , Male , Nose/pathology , Young AdultABSTRACT
We describe a patient with a phenotype characterized by mandibulofacial dysostosis with severe lower eyelid coloboma, cleft palate, abnormal ears, alopecia, delayed eruption and crowded teeth, and sensorioneural hearing loss. The karyotype and the screening for mutations in the coding region of TCOF1 gene were normal. The clinical signs of our case overlap the new mandibulofacial dysostosis described by Stevenson et al. [2007] and the case with Johnson-McMillin syndrome described by Cushman et al. [2005]. The similar clinical signs, mainly, the severe facial involvement observed in these cases suggest that they can represent a new distinct form of mandibulofacial dysostosis or the end of the spectrum of Johnson-McMillin syndrome.
Subject(s)
Alopecia/complications , Cleft Palate/complications , Coloboma/complications , Eyelids/abnormalities , Mandibulofacial Dysostosis/complications , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Pregnancy , SyndromeABSTRACT
The authors describe the clinical findings observed in a Brazilian girl that are suggestive of microphthalmia and linear skin defects (MLS) also known as MIDAS syndrome (OMIM #309801). She also presented with short stature, agenesis of corpus callosum, cleft palate, enamel defects, and genitourinary anomalies, which are rarely reported within the clinical spectrum of MLS. The 11,5 Mb deletion in Xp22.3p22.2 observed in the patient includes the entire HCCS gene (responsible for the MLS phenotype) and also encompasses several other genes involved with behavioral phenotypes, craniofacial and central nervous system development such as MID1, NLGN4X, AMELX , ARHGAP6, and TBL1X. The whole clinical features of our proband possibly represents an unusual MLS syndromic phenotype caused by an Xp22.3p22.2 continuous gene deletion.
ABSTRACT
Nonsyndromic alar clefts are rare and they range from a small notch to variable size of clefts of the nasal ala. Usually they are restricted to the alar region, but other minor anomalies such as midline nasal sinuses and small midline or "northbound" clefts can be present. To date all reported cases of nonsyndromic alar clefts have been sporadic. Here we report on five new cases of isolated and nonsyndromic alar clefts.
Subject(s)
Nose/abnormalities , Brazil , Child, Preschool , Facies , Female , Humans , Infant , MaleABSTRACT
Here we report on 10 male patients with frontonasal dysplasia, cleft lip/palate, mental retardation, lack of language acquisition, and severe central nervous system involvement. Imaging studies disclosed absence of the corpus callosum, midline cysts, and an abnormally modeled cerebellum. Neuronal heterotopias were present in five patients and parieto-occipital encephalocele in three patients. We suggest that this pattern found exclusively in males, most likely represents a newly recognized syndrome distilled from the group of disorders subsumed under frontonasal dysplasia.
Subject(s)
Central Nervous System/abnormalities , Developmental Disabilities/diagnosis , Frontal Bone/abnormalities , Intellectual Disability/diagnosis , Language Development Disorders/diagnosis , Nose/abnormalities , Adult , Brazil , Child , Child, Preschool , Developmental Disabilities/genetics , Humans , Infant , Intellectual Disability/genetics , Language Development Disorders/genetics , Male , SyndromeABSTRACT
We report on a Brazilian mother and her son affected with mandibulofacial dysostosis, growth and mental retardation, microcephaly, first branchial arch anomalies, and cleft palate. To date only three males and one female, all sporadic cases, with a similar condition have been reported. This article describes the first familial case with this rare condition indicating autosomal dominant or X-linked inheritance.
Subject(s)
Cleft Palate/complications , Ear/abnormalities , Genes, X-Linked/genetics , Intellectual Disability/complications , Mandibulofacial Dysostosis/genetics , Microcephaly/complications , Skin Abnormalities/complications , Abnormalities, Multiple/genetics , Child , Child, Preschool , Female , Genes, Dominant , Humans , Infant , Infant, Newborn , Male , Mandibulofacial Dysostosis/complications , Mothers , Nuclear Family , Pregnancy , SyndromeABSTRACT
We describe a Brazilian boy with semilobar holoprosencephaly, ectrodactyly, bilateral cleft of lip and palate, and severe mental retardation. The karyotype was normal and the screening for mutations in the genes SHH, TGIF, SIX3, GLI2, TP73L, and DHCR7 did not show any change. This rare condition was described previously in seven male patients. Clinical and genetic aspects are discussed.
Subject(s)
Cleft Lip/genetics , Cleft Palate/genetics , Hand Deformities, Congenital/genetics , Holoprosencephaly/genetics , Abnormalities, Multiple/genetics , Brazil , Child, Preschool , Eye Proteins/genetics , Hedgehog Proteins/genetics , Homeodomain Proteins/genetics , Humans , Intellectual Disability/genetics , Kruppel-Like Transcription Factors/genetics , Male , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Oxidoreductases Acting on CH-CH Group Donors/genetics , Repressor Proteins/genetics , Severity of Illness Index , Trans-Activators/genetics , Transcription Factors , Tumor Suppressor Proteins/genetics , Zinc Finger Protein Gli2 , Homeobox Protein SIX3Subject(s)
Ear Diseases/diagnosis , Ear Diseases/etiology , Ear/abnormalities , Mandible/embryology , Maxilla/embryology , HumansABSTRACT
Auriculo-condylar syndrome (ACS), an autosomal dominant disorder of first and second pharyngeal arches, is characterized by malformed ears ('question mark ears'), prominent cheeks, microstomia, abnormal temporomandibular joint, and mandibular condyle hypoplasia. Penetrance seems to be complete, but there is high inter- and intra-familial phenotypic variation, with no evidence of genetic heterogeneity. We herein describe a new multigeneration family with 11 affected individuals (F1), in whom we confirm intra-familial clinical variability. Facial asymmetry, a clinical feature not highlighted in other ACS reports, was highly prevalent among the patients reported here. The gene responsible for ACS is still unknown and its identification will certainly contribute to the understanding of human craniofacial development. No chromosomal rearrangements have been associated with ACS, thus mapping and positional cloning is the best approach to identify this disease gene. To map the ACS gene, we conducted linkage analysis in two large ACS families, F1 and F2 (F2; reported elsewhere). Through segregation analysis, we first excluded three known loci associated with disorders of first and second pharyngeal arches (Treacher Collins syndrome, oculo-auriculo-vertebral spectrum, and Townes-Brocks syndrome). Next, we performed a wide genome search and we observed evidence of linkage to 1p21.1-q23.3 in F2 (LOD max 3.01 at theta=0). Interestingly, this locus was not linked to the phenotype segregating in F1. Therefore, our results led to the mapping of a first locus of ACS (ACS1) and also showed evidence for genetic heterogeneity, suggesting that there are at least two loci responsible for this phenotype.
Subject(s)
Chromosome Mapping , Ear, External/abnormalities , Genetic Heterogeneity , Mandibular Condyle/abnormalities , Chromosomes, Human, Pair 1/genetics , Facial Asymmetry/congenital , Facial Asymmetry/genetics , Female , Genetic Linkage , Genetic Markers , Humans , Lod Score , Male , Pedigree , SyndromeABSTRACT
We present clinical and molecular evaluation from a large cohort of patients with Stickler syndrome: 78 individuals from 21 unrelated Brazilian families. The patients were selected in a Hospital with a craniofacial dysmorphology assistance service and clinical diagnosis was based on the presence of cleft palate associated to facial and ocular anomalies of Stickler syndrome. Analysis of COL2A1 gene revealed 9 novel and 4 previously described pathogenic mutations. Except for the mutation c.556G>T (p.Gly186X), all the others were located in the triple helical domain. We did not find genotype/phenotype correlation in relation to type and position of the mutation in the triple helical domain. However, a significantly higher proportion of myopia in patients with mutations located in this domain was observed in relation to those with the mutation in the non-tripe helical domain (c.556G>T; P<0.04). A trend towards a higher prevalence of glaucoma, although not statistically significant, was observed in the presence of the mutation c.556G>T. It is possible that this mutation alters the splicing of the mRNA instead of only creating a premature stop codon and therefore it can lead to protein products of different ocular effects. One novel DNA variation (c.1266+7G>C) occurs near a splice site and it was observed to co-segregate with the phenotype in one of the two families with this DNA variation. As in silico analysis predicted that the c.1266+7G>C DNA variation can affect the efficiency of the splicing, we still cannot rule it out as non-pathogenic. Our study also showed that ascertainment through cleft palate associated to other craniofacial signs can be very efficient for identification of Stickler syndrome patients. Still, high frequency of familial cases and high frequency of underdevelopment of distal lateral tibial epiphyses observed in our patients suggested that the inclusion of this information can improve the clinical diagnosis of Stickler syndrome.