RESUMO
Membrane interaction constitutes to be an essential parameter in the mode of action of entities such as proteins, as well as cell-penetrating and antimicrobial peptides, resulting in noninvasive or lytic activities depending on the membrane compositions and interactions. Recently, a nanobody able to interact with the top priority, multidrug-resistant bacterial pathogen Acinetobacter baumannii was discovered, although binding took place with fixed cells only. To potentially overcome this limitation, linear peptides corresponding to the complementarity-determining regions (CDR) were synthesized and fluorescently labeled. Microscopy data indicated clear membrane interactions of the CDR3 sequence with living A. baumannii cells, indicating both the importance of the CDR3 as part of the parent nanobody paratope and the improved binding ability and thus avoiding the need for permeabilization of the cells. In addition, cyclization of the peptide with an additionally introduced rigidifying 1,2,3-triazole bridge retains its binding ability while proteolytically protecting the peptide. Overall, this study resulted in the discovery of novel peptides binding a multidrug-resistant pathogen.
Assuntos
Acinetobacter baumannii , Peptídeos , Peptídeos/farmacologia , Peptídeos/química , Microscopia , Bactérias , Antibacterianos , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Considering an evolutionary perspective, psychiatric conditions present us with a paradox. How can the high prevalence of those conditions be explained, given the importance of genetic factors in many of them? Evolutionary principles predict that traits with an adverse effect on reproduction undergo negative selection. AIM: To try to formulate an answer to this paradox from the perspective of evolutionary psychiatry by integrating different disciplines. METHOD: We describe some important evolutionary models: the adaptive and maladaptive model, the mismatch model, the trade-off model and the balance model. By way of illustration, we have searched the literature for evolutionary perspectives on autism spectrum disorder. RESULTS: In this narrative review we describe several evolutionary hypotheses about autism spectrum disorder with a framing within the different evolutionary models. We discuss, among others, evolutionary hypotheses regarding gender differences in social skills, the link with more recent evolutionary cognitive development, and autism spectrum disorder as an extreme cognitive outlier. CONCLUSION: We conclude that evolutionary psychiatry offers a complementary point of view on psychiatric conditions and specifically on autism spectrum disorder. A link to neurodiversity and an impetus to clinical translation is made.
Assuntos
Transtorno do Espectro Autista , Psiquiatria , Humanos , Transtorno do Espectro Autista/psicologia , Prevalência , Habilidades Sociais , Fatores SexuaisRESUMO
BACKGROUND After decades of research and clinical experience, autism spectrum disorder (ASD) turns out to be heterogeneous in every sense, including phenotype and etiology. How is this heterogeneous view translated in information that is useful and significant to parents and clinicians?
AIM: To formulate recommendations with regard to clinical ASD care in young children.
METHOD: We conducted in-depth interviews on how parents (11 mothers and 6 fathers of 11 children) and physicians (n = 16) view and experience a young child's ASD diagnosis. The interviews were analysed in Nvivo 11 according to the guidelines of interpretative phenomenological analysis.
RESULTS: The interviewed parents and physicians addressed psycho-relational implications of an ASD diagnosis as much as treatment-oriented implications. Twelve months after their child got an ASD diagnosis, some disappointment regarding these implications led parents to a pragmatic understanding of an ASD diagnosis.
CONCLUSION: Our results may be useful to both clinicians and policy makers with regard to clinical ASD care in young children. An ASD diagnosis in itself may be of limited help to parents and clinicians but can be of use if it is embedded in a request-oriented diagnostic process guided by a communication model of shared decision making and aimed at elaborating a treatment-oriented profile of the child.
Assuntos
Transtorno do Espectro Autista , Médicos , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Pai , Feminino , Humanos , Masculino , Mães , PaisRESUMO
Genetic factors play an important role in the development of psychotic disorders. With increasing evidence, several rare copy number variants (cnvs) have been identified as risk factors. We describe a patient who had two psychotic episodes during his adolescence. In this patient, a 16p11.2 duplication was detected. This duplication is a recurrent cnv associated with various somatic and psychiatric phenotypes including psychosis and schizophrenia. The potential clinical relevance of this finding is discussed.
Assuntos
Transtornos Psicóticos/genética , Adolescente , Cromossomos Humanos Par 16 , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Transtornos Psicóticos/diagnóstico , Adulto JovemRESUMO
BACKGROUND: Antipsychotics are frequently prescribed for a wide range of psychiatric and non-psychiatric indications. Over the last few years there has been a marked increase in the use of antipsychotics, in European and non-European countries. The use has also increased in children.
AIM: To assess trends in the sales of antipsychotics for Belgian children and adolescents (7 to 17 years old) between 2005 and 2014.
METHOD: We used data supplied by Farmanet, the official Belgian organisation responsible for collecting information about the prescription behaviour of doctors in Belgium.
RESULTS: Between 2005 and 2014 there was a 53% increase in the number of prescriptions for antipsychotics issued by doctors in Belgium. This period also saw a 75.5% increase in the number of prescriptions for antipsychotics issued for the treatment of children and adolescents. There was a particularly large increase in the number of prescriptions for aripiprazole, the increase being only very slightly compensated by a simultaneous decrease in the number of prescriptions issued for other antipsychotics. In 2014, 21 different antipsychotics were prescribed for children, the majority of these prescriptions being for risperidone and aripiprazole. A large proportion of antipsychotics are used off-label. In exceptional cases, antipsychotics were prescribed for children under the age of six, and even for children younger than two.
CONCLUSION: Between 2005 and 2014 there was an increase in the number of prescriptions for antipsychotics issued for children and adolescents in Belgium. During that period of time there was a similar increase in the use of antipsychotics by children and adolescents in other European and non-European countries. It is not clear whether these increases are justified.
Assuntos
Antipsicóticos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Padrões de Prática Médica/tendências , Adolescente , Bélgica , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Uso Off-Label/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricosRESUMO
BACKGROUND: In the last decades, researchers often used measures to quantify autism spectrum disorder (ASD) traits, paralleling the tendency to describe psychiatric and developmental disorders more dimensionally. The broader autism phenotype (BAP) concept originates from this kind of research. AIM: The primary aim of our studies was to study the existence of the BAP and the familial transmission of quantitative autism traits (QAT). METHOD: We measured ASD-traits with interviews and questionnaires in all members of 170 families with at least one child with ASD. RESULTS: We confirmed the existence of the BAP in fathers, as well as the familial transmission of QAT. The results also suggest that what is measured with these questionnaires might depend on the population and the context. CONCLUSION: Based on our results and additional data from scientific literature, we reflect on the interpretations of research results and the use of quantitative scales in both research and clinical practice.
Assuntos
Transtorno do Espectro Autista/classificação , Transtorno do Espectro Autista/diagnóstico , Família/psicologia , Pai/psicologia , Adolescente , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Mães/psicologia , Irmãos/psicologiaRESUMO
Anxiety is common in children and adolescents with autism spectrum disorders and can cause severe dysfunction and suffering. An 11-year-old boy with an autism spectrum disorder and suffering from anxiety and mood problems responded positively to treatment with fluoxetine. After four weeks he developed clinically observable paroxysmal events accompanied by absence and confusion.
Assuntos
Ansiolíticos/efeitos adversos , Transtornos de Ansiedade/tratamento farmacológico , Fluoxetina/efeitos adversos , Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/epidemiologia , Criança , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Transtornos Globais do Desenvolvimento Infantil/psicologia , Comorbidade , Relação Dose-Resposta a Droga , Esquema de Medicação , Fluoxetina/uso terapêutico , Humanos , MasculinoRESUMO
We describe the identification and delineation of an inherited 2.07 Mb microduplication in 1q42.2 in two brothers with autism and mild mental retardation. Since this duplication was not present in 1577 Belgian persons, we consider this as an extremely rare variant which has the potential to provide further insight into the genetics of autism. The duplication contains seven genes including the DISC1 gene, an interesting candidate gene that has been associated to schizophrenia, bipolar disorder, autism and Asperger syndrome. In this report we describe additional analyses undertaken to investigate the causal relationship of the duplication to the autism phenotype. We conclude that the 1q42.2 microduplication probably confers susceptibility to autism in the current family. This study is a typical illustration of the difficult interpretation of causality of a very rare variant in neuropsychiatric disease and the challenge of genetic counselling in a particular family.
Assuntos
Transtorno Autístico/complicações , Transtorno Autístico/genética , Duplicação Gênica , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Irmãos , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 1/genética , Família , Feminino , Humanos , Recém-Nascido , Masculino , Linhagem , GravidezRESUMO
Dyslexia is the most common childhood learning disorder and it is a significantly heritable trait. At least nine chromosomal loci have been linked to dyslexia, and additional susceptibility loci on other chromosomes have been suggested. Within two of these loci, DYX1C1 (15q21) and ROBO1 (3p12) have recently been proposed as dyslexia candidate genes through the molecular analysis of translocation breakpoints in dyslexic individuals carrying balanced chromosomal translocations. Moreover, genetic association studies have indicated a cluster of five dyslexia candidate genes in another linkage region on chromosome 6p22, although there is currently no consensus about which of these five genes contributes to the genetic susceptibility for dyslexia. In this article, we report the identification of four new dyslexia candidate genes (PCNT, DIP2A, S100B, and PRMT2) on chromosome region 21q22.3 by FISH and SNP microarray analyses of a very small deletion in this region, which cosegregates with dyslexia in a father and his three sons.
Assuntos
Deleção Cromossômica , Dislexia/genética , Adolescente , Cromossomos Humanos Par 21 , Feminino , Ligação Genética , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Masculino , Testes Neuropsicológicos , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Cohen syndrome is an autosomal recessive, multiple congenital anomalies/mental retardation (MCA/MR) syndrome, caused by a mutation in the COH1 gen, localized on chromosome 8q22. COH1 encodes a transmembrane protein of 4.022 amino-acids with a presumed role in vesicle-mediated sorting and intracellular protein transport. Clinical features are non progressive psychomotor retardation and microcephaly, characteristic facial features, retinal dystrophy, and intermittent neutropenia. Examination of the long-term evolution of 6 patients with Cohen syndrome shows that the clinical features are rather stable during evolution. Description of their actual behavior on the basis of standardized questionnaires shows that no severe behavior problems are observed in any of the 6 patients. Taking into account their mental age, their behavior is quiet and easy to handle by their environment.
Assuntos
Transtorno da Personalidade Antissocial/genética , Deficiência Intelectual/genética , Adulto , Transtorno da Personalidade Antissocial/complicações , Transtorno da Personalidade Antissocial/diagnóstico , Progressão da Doença , Fácies , Feminino , Genes Recessivos/genética , Nível de Saúde , Humanos , Deficiência Intelectual/complicações , Pais/psicologia , Inquéritos e Questionários , Síndrome , Temperamento , Fatores de Tempo , Gêmeos/genéticaRESUMO
Nucleoside hydrolase (NH) is a key enzyme in the purine salvage pathway. The purine specificity of the IAG-NH from Trypanosoma vivax is at least in part due to cation-pi-stacking interactions. Guanidinium ions can be involved in cation-pi-stacking interactions, therefore a series of guanidino-alkyl-ribitol derivatives were synthesized in order to examine the binding affinity of these compounds towards the target enzyme. The compounds show moderate to good inhibiting activity towards the IAG-NH from T. vivax.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , N-Glicosil Hidrolases/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , N-Glicosil Hidrolases/química , Espectrometria de Massas por Ionização por Electrospray , Trypanosoma vivax/enzimologiaRESUMO
A range of novel 1,2,3-triazolylalkylribitol derivatives were synthesized and evaluated as nucleoside hydrolase inhibitors. The most active compound (11a) has low micromolar potency and is structurally diverse from previously reported nucleoside hydrolase inhibitors, which, along with the simplicity of the chemistry involved in its synthesis, makes it a good lead for the further development of novel nucleoside hydrolase inhibitors.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , N-Glicosil Hidrolases/antagonistas & inibidores , Ribitol/análogos & derivados , Ribitol/química , Triazóis/química , Animais , Desenho de Fármacos , Cinética , Modelos Químicos , Conformação Molecular , Trypanosoma brucei brucei/enzimologiaRESUMO
Verbal fluency was operationalized as the number of words produced in a restricted category (i.e., semantic category [SCF] and words beginning with a given letter [ILF]) in 60 seconds. Word production in the first 15 seconds of either type of fluency task was defined as a measure of automatic information processing, whereas word production in the remaining 45 seconds (in 15-second periods) was taken as a measure of controlled information processing. Data revealed that over 60 seconds healthy children aged 8.4-9.7 years (n = 91) produced significantly more words and less incorrect responses on the SCF task than on the ILF task. Although word production was a function of both type of task and time, it was highest in the initial time slice of either type of fluency and decreased as time on task increased. Finally, no sex differences were found for any measure of performance on either type of fluency task. In contrast, the level of occupational achievement of the caregiver (LOA) appeared to be a determinant of the child's performance on either type of fluency task, indicating that LOA affects higher-order processes, such as the automation of newly learned verbal skills and effortful processing.
Assuntos
Desenvolvimento da Linguagem , Processos Mentais/fisiologia , Tempo de Reação/fisiologia , Fala , Comportamento Verbal/fisiologia , Criança , Classificação , Feminino , Seguimentos , Humanos , Masculino , Valores de Referência , Semântica , Fatores Sexuais , Estatística como Assunto , Fatores de TempoRESUMO
Nucleoside hydrolases cleave the N-glycosidic bond of ribonucleosides. Crystal structures of the purine-specific nucleoside hydrolase from Trypanosoma vivax have previously been solved in complex with inhibitors or a substrate. All these structures show the dimeric T. vivax nucleoside hydrolase with an "open" active site with a highly flexible loop (loop 2) in its vicinity. Here, we present the crystal structures of the T. vivax nucleoside hydrolase with both soaked (TvNH-ImmH(soak)) and co-crystallised (TvNH-ImmH(co)) transition-state inhibitor immucillin H (ImmH or (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol) to 2.1 A and 2.2 A resolution, respectively. In the co-crystallised structure, loop 2 is ordered and folds over the active site, establishing previously unobserved enzyme-inhibitor interactions. As such this structure presents the first complete picture of a purine-specific NH active site, including leaving group interactions. In the closed active site, a water channel of highly ordered water molecules leads out from the N7 of the nucleoside toward bulk solvent, while Trp260 approaches the nucleobase in a tight parallel stacking interaction. Together with mutagenesis results, this structure rules out a mechanism of leaving group activation by general acid catalysis, as proposed for base-aspecific nucleoside hydrolases. Instead, the structure is consistent with the previously proposed mechanism of leaving group protonation in the T. vivax nucleoside hydrolase where aromatic stacking with Trp260 and an intramolecular O5'-H8C hydrogen bond increase the pKa of the N7 sufficiently to allow protonation by solvent. A mechanism that couples loop closure to the positioning of active site residues is proposed based on a comparison of the soaked structure with the co-crystallized structure. Interestingly, the dimer interface area increases by 40% upon closure of loop 2, with loop 1 of one subunit interacting with loop 2 of the other subunit, suggesting a relationship between the dimeric form of the enzyme and its catalytic activity.
Assuntos
N-Glicosil Hidrolases , Estrutura Quaternária de Proteína , Estrutura Secundária de Proteína , Trypanosoma vivax/enzimologia , Animais , Sítios de Ligação , Cristalografia por Raios X , Ligantes , Modelos Moleculares , Estrutura Molecular , N-Glicosil Hidrolases/antagonistas & inibidores , N-Glicosil Hidrolases/química , N-Glicosil Hidrolases/metabolismo , Dobramento de Proteína , Nucleosídeos de Purina , Pirimidinonas/metabolismo , Pirróis/metabolismoRESUMO
BACKGROUND: Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l-dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. OBJECTIVE: To delineate the neurological and psychiatric phenotype in all affected individuals of three extended families. METHODS: GTP cyclohydrolase deficiency was documented by biochemical analyses, enzymatic measurements in fibroblasts, and molecular investigations. All affected individuals were examined neurologically, and psychiatric data were systematically reviewed. RESULTS: Eighteen affected patients from three families with proven GTP cyclohydrolase deficiency were identified. Eight patients presenting at less than 20 years of age had typical motor symptoms of dystonia with diurnal variation. Five family members had late-presenting mild dopa-responsive symptoms of rigidity, frequent falls, and tendonitis. Among mutation carriers older than 20 years of age, major depressive disorder, often recurrent, and obsessive-compulsive disorder were strikingly more frequent than observed in the general population. Patients responded well to medication increasing serotonergic neurotransmission and to l-dopa substitution. Sleep disorders including difficulty in sleep onset and maintenance, excessive sleepiness, and frequent disturbing nightmares were present in 55% of patients. CONCLUSION: Physicians should be aware of this expanded phenotype in affected members of families with GTP cyclohydrolase deficiency.
Assuntos
Distonia/enzimologia , Distonia/genética , GTP Cicloidrolase/deficiência , GTP Cicloidrolase/genética , Paraparesia Espástica/genética , Transtornos Parkinsonianos/genética , Tremor/genética , Adolescente , Adulto , Ritmo Circadiano/fisiologia , Distonia/complicações , Feminino , Fibroblastos/enzimologia , Expressão Gênica , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica/complicações , Transtornos Parkinsonianos/complicações , Linhagem , Fenótipo , Fenilalanina/sangue , Reação em Cadeia da Polimerase , Reflexo Anormal , Síndrome , Tendinopatia/complicações , Tremor/complicaçõesRESUMO
Longitudinal follow-up data on males with Klinefelter syndrome are still scarce. In the present study we collected data on the general and psychosocial development of 12 prenatally diagnosed boys with Klinefelter syndrome.
Assuntos
Síndrome de Klinefelter/genética , Biometria , Criança , Feminino , Seguimentos , Humanos , Síndrome de Klinefelter/complicações , Masculino , Idade Materna , Transtornos Mentais/complicações , Gravidez , Resultado da Gravidez , Diagnóstico Pré-Natal , Inquéritos e QuestionáriosRESUMO
MOTIVATION: A k-point mutant of a given RNA sequence s = s(1), ..., s(n) is an RNA sequence s' = s'(1),..., s'(n) obtained by mutating exactly k-positions in s; i.e. Hamming distance between s and s' equals k. To understand the effect of pointwise mutation in RNA, we consider the distribution of energies of all secondary structures of k-point mutants of a given RNA sequence. RESULTS: Here we describe a novel algorithm to compute the mean and standard deviation of energies of all secondary structures of k-point mutants of a given RNA sequence. We then focus on the tail of the energy distribution and compute, using the algorithm AMSAG, the k-superoptimal structure; i.e. the secondary structure of a < or =k-point mutant having least free energy over all secondary structures of all k'-point mutants of a given RNA sequence, for k' < or = k. Evidence is presented that the k-superoptimal secondary structure is often closer, as measured by base pair distance and two additional distance measures, to the secondary structure derived by comparative sequence analysis than that derived by the Zuker minimum free energy structure of the original (wild type or unmutated) RNA.
Assuntos
Biologia Computacional/métodos , Mutação , RNA/química , Algoritmos , Bactérias/genética , Sequência de Bases , Genes Bacterianos , Modelos Genéticos , Modelos Estatísticos , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Mutação Puntual , Software , TermodinâmicaRESUMO
To the best of the authors' knowledge, there are no published reports on visuomotor preparation in attention-deficit/hyperactivity disorder (ADHD). This is unfortunate, because research suggests that ADHD is an output-related deficit, and suboptimal execution of tasks may be the result of incomplete visuomotor preparation. The authors compared 19 children with ADHD with 124 healthy and 120 pathological controls in terms of their performance (speed, speed variability, and accuracy) on the finger precuing test, a test measuring (automatic and controlled) visuomotor preparation. The data implied that children with ADHD have an impaired ability to engage in effortful, controlled visuomotor preparation activities. Fast, automatic response preparation was not affected by ADHD. In addition, children with ADHD showed more variability in overall test performance than other children. No group differences were found in response accuracy.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Desempenho Psicomotor/fisiologia , Percepção Espacial/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Comorbidade , Feminino , Dedos/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Transtornos Mentais/fisiopatologia , Testes Neuropsicológicos/estatística & dados numéricos , Tempo de Reação/fisiologiaRESUMO
The performance of ADHD children on semantic category fluency (SCF) versus initial letter fluency (ILF) tasks was examined. For each participant, word production was recorded for each 15-s time slice on each task. Performance on both fluency tasks was compared to test the hypothesis that children with ADHD are characterized by a performance deficit on the ILF task because performance on this task is less automated than performance on the SCF. Children classified with ADHD (N = 20) were compared to children with other psychopathology (N = 118) and healthy controls (N = 130). Results indicated that the groups could not be differentiated by the total number of words produced in 60 s in either fluency task. As hypothesized, a significant interaction of group by productivity over time by type of fluency task was found: ADHD children had more problems finding words in the first 15 s of the IFL than did children in the other two groups, and as compared with their performance on the SCF. Results were taken to indicate that children with ADHD symptoms show a delay in the development of automating skills for processing abstract verbal information.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Desenvolvimento da Linguagem , Processos Mentais/fisiologia , Semântica , Fala , Comportamento Verbal/fisiologia , Criança , Feminino , Seguimentos , Humanos , Masculino , Transtornos Mentais/fisiopatologia , Tempo de Reação/fisiologia , Leitura , Valores de ReferênciaRESUMO
We present a 6-year-old boy with moderate developmental delay, gait disturbance, autism related disorder and mild dysmorphic features. He was seen for evaluation of his retardation since the age of 2.8 years. At first sight, a cytogenetic analysis showed a normal 46,XY karyotype. Neurological examination at the age of 5.5 years revealed a motor and sensory polyneuropathy. A quantitative Southern blot with probes PMP22 and VAW409 specific for Charcot-Marie-Tooth type 1 (CMT1) disclosed a duplication which confirmed the diagnosis HMSN Ia. Subsequently, GTG banded metaphases were re-evaluated and a small duplication 17p was seen on retrospect. Additional FISH with probe LSISMS (Vysis) specific for the Smith-Magenis region at 17p11.2 again showed a duplication. Both parents had a normal karyotype and the duplication test for CMT1 showed normal results for both of them. The boy had a de novo 46,XY,dup(17)(p11.2p12) karyotype. The present observation confirms previous findings of mild psychomotor delay, neurobehavioural features and minor craniofacial anomalies as the major phenotypic features of dup(17)(p11.2) and dup(17)(p11.2p12); in cases of duplications comprising the PMP22 locus HMSN1 is associated. A recognizable facial phenotype emerges characterized by a broad forehead, hypertelorism, downslant of palpebral fissures, smooth philtrum, thin upper lip and ear anomalies.