Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

SARS-CoV-2 pandemic in the Brazilian community of rare diseases: A patient reported survey.

The COVID-19 pandemic has led to a reorganization of health systems to prioritize the fight against the virus. The adoption of social distancing interfered with the flow of existing policies, and may thus negatively affect the most vulnerable groups, such as the rare disease community. Aimming at characterizing the perception of the impact of COVID-19 on the health care of the Brazilian rare disease community, an online questionnaire addressed to patients with rare diseases and their caregivers was disseminated in the Brazilian territory between June 1st to July 5th, 2020. The questions dealt with the sanitary measures adopted; access to medical services; and mental suffering during the pandemic. The survey was answered by 1,466 participants (<18 yo = 53.3%) representing 192 rare diseases. Regarding physical distancing, 1,372 (93.6%) participants did not leave their residence, or did so only when essential; 1,321 (90.1%) always wore masks when leaving home. 1,042 (71.1%) and 995 (67.9%) participants, respectively, referred medical genetics appointments and rehabilitation therapies were postponed/canceled. Telemedicine was experienced by 1,026 (70%), and 68.3% agreed this is a good strategy for health care. Patients with Inborn Errors of Metabolism (IEM, n = 624, 42.5%) appear to have more access to information and ability to overcome difficulties, and feel less threatened, lonely and depressed than the non-IEM group (p < .05). There was an increment of the rare disease patients' vulnerability in the pandemic scenario. The cooperation of patients/caregivers along with adaptation of the health system is crucial and may be so even post-pandemic.

Sclerocornea in a patient with van den Ende-Gupta syndrome homozygous for a SCARF2 microdeletion.

Van den Ende-Gupta Syndrome (VDEGS) is an autosomal recessive disorder characterized by blepharophimosis, distinctive nose, hypoplastic maxilla, and skeletal abnormalities. Using homozygosity mapping in four VDEGS patients from three consanguineous families, Anastacio et al. [Anastacio et al. (2010); Am J Hum Genet 87:553-559] identified homozygous mutations in SCARF2, located at 22q11.2. Bedeschi et al. [2010] described a VDEGS patient with sclerocornea and cataracts with compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 mutation. Because sclerocornea had been described in DiGeorge-velo-cardio-facial syndrome but not in VDEGS, they suggested that the ocular abnormalities were caused by the 22q11.2 microdeletion. We report on a 23-year-old male who presented with bilateral sclerocornea and the VDGEGS phenotype who was subsequently found to be homozygous for a 17 bp deletion in exon 4 of SCARF2. The occurrence of bilateral sclerocornea in our patient together with that of Bedeschi et al., suggests that the full VDEGS phenotype may include sclerocornea resulting from homozygosity or compound heterozygosity for loss of function variants in SCARF2.

Clinical, cytogenetic, and molecular characterization of six patients with ring chromosomes 22, including one with concomitant 22q11.2 deletion.

We report here on six patients with a ring chromosome 22 and the range of cytogenetic and phenotypic features presented by them. Genomic analysis was carried out using classical and molecular cytogenetics, MLPA (Multiplex Ligation-dependent Probe Amplification) and genome-wide SNP-array analysis. The ring was found in all patients, but Patient 6 displayed constitutional mosaicism with a normal cell line. Five patients had deletions in the ring chromosome 22, and in four of them the breakpoints--unique for each patient--could be identified by genome-wide SNP-array analysis. One patient presented with a 22q11.2 deletion concomitant with the deletion caused by the ring formation. Common phenotypic features included autism, speech delay and seizures, as previously reported for individuals with r(22) and/or 22q13.3 deletions. Investigation of the genes within the deletions revealed multiple genes related to development of the central nervous system, psychomotor delay, severe language impairment, hypotonia, and autistic symptoms. There was no clear correlation between the severity of clinical features and the size of the deleted segment. This study underscores the variability in ring structure and clinical presentation of the r(22) and adds information to the limited literature on this rare disorder.

Exploring the Acquisition of Social Communication Skills in Children with Autism: Preliminary Findings from Applied Behavior Analysis (ABA), Parent Training, and Video Modeling.

Social communication skills, especially eye contact and joint attention, are frequently impaired in autism spectrum disorder (ASD) and predict functional outcomes. Applied behavior analysis is one of the most common evidence-based treatments for ASD, but it is not accessible to most families in low- and middle-income countries (LMICs) as it is an expensive and intensive treatment and needs to be delivered by highly specialized professionals. Parental training has emerged as an effective alternative. This is an exploratory study to assess a parental intervention group via video modeling to acquire eye contact and joint attention. Four graded measures of eye contact and joint attention (full physical prompt, partial physical prompt, gestural prompt, and independent) were assessed in 34 children with ASD and intellectual disability (ID). There was a progressive reduction in the level of prompting required over time to acquire eye contact and joint attention, as well as a positive correlation between the time of exposure to the intervention and the acquisition of abilities. This kind of parent training using video modeling to teach eye contact and joint attention skills to children with ASD and ID is a low-cost intervention that can be applied in low-resource settings.

1H NMR Metabolomics and Lipidomics To Monitor Positive Responses in Children with Autism Spectrum Disorder Following a Guided Parental Intervention: A Pilot Study.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by patients displaying at least two out of the classical symptoms, such as impaired social communication, impaired interactions, and restricted repetitive behavior. Early parent-mediated interventions, such as video modeling for parental training, were demonstrated to be a successful low-cost way to deliver care for children with ASD. Nuclear magnetic resonance (NMR)-based metabolomics/lipidomics has been successfully employed in several mental disorder studies. Metabolomics and lipidomics of 37 ASD patients (children, aged 3-8 years), who were divided into two groups, one control group with no parental-training intervention (N = 18) and the other in which the parents were trained by a video modeling intervention (ASD parental training, N = 19), were analyzed by proton NMR spectroscopy. Patients in the ASD parental-training group sera were seen to have increased glucose, myo-inositol, malonate, proline, phenylalanine, and gangliosides in their blood serum, while cholesterol, choline, and lipids were decreased, compared to the control group, who received no parental-training. Taken together, we demonstrated here significant changes in serum metabolites and lipids in ASD children, previously demonstrated to show clinical positive effects following a parental training intervention based on video modeling, delivered over 22 weeks. We demonstrate the value of applying metabolomics and lipidomics to identify potential biomarkers for clinical interventions follow-up in ASD.

Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.

Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of approximately 1.3 Mb was performed. A microduplication of approximately 5.5 kb in a noncoding sequence approximately 110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. The duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb.

Environmental Influences Measured by Epigenetic Clock and Vulnerability Components at Birth Impact Clinical ASD Heterogeneity.

Although Autism Spectrum Disorders (ASD) is recognized as being heavily influenced by genetic factors, the role of epigenetic and environmental factors is still being established. This study aimed to identify ASD vulnerability components based on familial history and intrauterine environmental stress exposure, explore possible vulnerability subgroups, access DNA methylation age acceleration (AA) as a proxy of stress exposure during life, and evaluate the association of ASD vulnerability components and AA to phenotypic severity measures. Principal Component Analysis (PCA) was used to search the vulnerability components from 67 mothers of autistic children. We found that PC1 had a higher correlation with psychosocial stress (maternal stress, maternal education, and social class), and PC2 had a higher correlation with biological factors (psychiatric family history and gestational complications). Comparing the methylome between above and below PC1 average subgroups we found 11,879 statistically significant differentially methylated probes (DMPs, p < 0.05). DMPs CpG sites were enriched in variably methylated regions (VMRs), most showing environmental and genetic influences. Hypermethylated probes presented higher rates in different regulatory regions associated with functional SNPs, indicating that the subgroups may have different affected regulatory regions and their liability to disease explained by common variations. Vulnerability components score moderated by epigenetic clock AA was associated with Vineland Total score (p = 0.0036, adjR2 = 0.31), suggesting risk factors with stress burden can influence ASD phenotype.

Cytogenetic and molecular evaluation and 20-year follow-up of a patient with ring chromosome 14.

We present a 20-year follow-up on a patient with a ring chromosome 14. The ring chromosome was studied by fluorescence in-situ hybridization (FISH), multiplex-ligation probe amplification (MLPA), and genome wide SNP array, and no deletions of chromosome 14 were detected, although the telomeric repeat sequence was absent from the ring chromosome. The patient had skeletal abnormalities, and susceptibility to infections, as well as seizures and retinal pigmentation, which are commonly found in individuals with a ring 14. Our patient corroborates the idea that even when no genes are lost during ring formation, a complete ring chromosome can produce phenotypic alterations, which presumably result from ring instability or gene silencing due to the new chromosomal architecture.

TRANSLATION, CULTURAL ADAPTATION, AND EVIDENCE OF INSTRUMENT VALIDITY FOR A MORPHOLOGICAL EXAMINATION PERFORMED IN CHILDREN WITH AUTISM SPECTRUM DISORDER.

OBJECTIVE: For every 100 random children diagnosed with autism, at least 20 have morphological abnormalities, often associated with syndromes. Brazil does not have a standardized and validated instrument for morphological physical examination. This study aimed to translate into Brazilian Portuguese and culturally adapt the clinical signs described in the Autism Dysmorphology Measure, as well as validate the instrument in a sample of children with autism. METHODS: The original instrument was translated, culturally adapted, and published in full, following traditional procedures for translation, back-translation, and terminology adaptation according to the Nomina Anatomica. The sample included 62 children from a published multicenter study, with intelligence quotient between 50-69, of both genders, with chronological age between 3-6 years. Two clinical geneticists performed the morphological physical examination, which consisted of investigating 82 characteristics assessing 12 body areas. We used Cohen's Kappa coefficient to evaluate the agreement between the two observers. RESULTS: The final version of the instrument - translated into Brazilian Portuguese and culturally adapted - showed high agreement between the two observers. CONCLUSIONS: The translated instrument meets all international criteria, and minor anomalies and their clinical descriptions were standardized and are recognizable for physicians not specialized in genetics.

Instrument to screen cases of pervasive developmental disorder: a preliminary indication of validity.

OBJECTIVE: To translate into Portuguese, back-translate, culturally adapt and validate a screening instrument for pervasive developmental disorder, the Autism Screening Questionnaire, for use in Brazil. METHOD: A sample of 120 patients was selected based on three groups of 40: patients with a clinical diagnosis of pervasive developmental disorder, Down syndrome, or other psychiatric disorders. The self-administered questionnaire was applied to the patients' legal guardians. Psychometric measures of the final version of the translated questionnaire were tested. RESULTS: The score of 15 had sensitivity of 92.5% and specificity of 95.5% as a cut-off point for the diagnosis of pervasive developmental disorder. Internal validity for a total of 40 questions was 0.895 for alpha and 0.896 for KR-20, ranging from 0.6 to 0.8 for both coefficients. Test and retest reliability values showed strong agreement for most questions. CONCLUSIONS: The final version of this instrument, translated into Portuguese and adapted to the Brazilian culture, had satisfactory measurement properties, suggesting preliminary validation proprieties. It was an easy-to-apply, useful tool for the diagnostic screening of individuals with pervasive developmental disorder.

Evaluation of clinical checklists for fragile X syndrome screening in Brazilian intellectually disabled males: proposal for a new screening tool.

Patients with fragile X syndrome present a variable phenotype, which contributes to the underdiagnosing of this condition. The use of clinical checklists in individuals with intellectual disability can help in selecting patients to be given priority in the molecular investigation of the fragile X mutation in the FMR1 gene. Some features included in checklists are better predictors than others, but they can vary among different populations and with patient age. In the present study, we evaluated 20 features listed in four clinical checklists from the literature, using a sample of 192 Brazilian male patients presenting with intellectual disability (30 positive and 162 negative for fragile X mutation). After statistical analysis, 12 out of the 20 items analyzed showed significant differences in their distributions between the two groups. These features were grouped in a new checklist that can help clinicians in their referral for fragile X testing in patients with developmental delay.

Complex toe syndactyly with characteristic facial phenotype: a new syndrome?

Nonsyndromic syndactyly is a common, heterogeneous hereditary condition of webbed fingers and toes that can be cutaneous or bony, unilateral or bilateral. We describe a patient with complex toe syndactyly and oligodactyly, some interesting skeletal hand findings and atypical facial features without other case like this described before. Cenani-Lenz syndrome (CLS) is a rare disorder with total syndactyly and irregular synostosis of carpal, metacarpal and phalanges, it may involve ulna and radius and digital rays may be absent, some of these were described with atypical facial features and one patient had renal hypoplasia and vertebral anomalies but our patient does not have the oligodactyly or syndactyly of the hands that is consistently present in all patients with CLS. The atypical facial features of our patient resemble Kabuki syndrome but oligodactyly and complex syndactyly have not been described in Kabuki syndrome and this patient has normal intelligence, and extreme eyelid defect (resembling ablepharon). Therefore, for our patient, we suggested to treat in a new condition of limb anomalies and atypical face.

Pure duplication 1q41-qter: further delineation of trisomy 1q syndromes.

Several authors have attempted to characterize the partial 1q trisomy syndrome, reporting clinical features such as mental retardation, macrocephaly, large fontanels, prominent forehead, broad flat nasal bridge, high-arched palate, micro/retrognathia, low-set ears, and cardiac defects. However, defining the partial trisomy 1q syndrome is difficult, because it is a rare chromosomal abnormality and in most instances the trisomy 1q is combined with partial monosomy of another autosomal segment. We report on the clinical and molecular cytogenetic study of a patient who presents pure partial 1q duplication. This is the first case of pure duplication 1q41-qter in the literature.

Mandibulofacial dysostosis, acral anomalies and frontonasal dysplasia: a new form of acrofacial dysostosis.

We describe a stillborn female with acrofacial dysostosis and frontonasal dysplasia. She had protrusion of the forehead, with marked hypertelorism and absence of the nose but with the rhinencephalon present. Autopsy showed wide cranial sutures, severe hydrocephalus with separation of the right and left hemispheres of the brain, preservation of the olfactory bulb and first and second cranial nerves. The child also had small kidneys bilaterally, rectal atresia and an absent anus with rectovaginal fistula. These clinical findings suggest a new form of acrofacial dysostosis.

Identifying Autism with a Brief and Low-Cost Screening Instrument-OERA: Construct Validity, Invariance Testing, and Agreement Between Judges.

Simple and low-cost observational-tools to detect symptoms of Autism Spectrum Disorder (ASD) are still necessary. The OERA is a new assessment tool to screen children eliciting observable behaviors with no substantial knowledge on ASD required. The sample was 99 children aged 3-10: 76 with ASD and 23 without ASD (11/23 had intellectual disability). The 13 remained items exhibited high interrater agreement and high reliability loaded onto a single latent trait. Such model showed excellent fit indices evaluated via confirmatory factor analysis and no item showed differential function in terms of age/sex/IQ. A cutoff of five points or higher resulted in the highest sensitivity (92.75) and specificity (90.91) percentages. OERA is a brief, stable, low-cost standardized observational-screening to identify ASD children.

Prevalence of pervasive developmental disorder in Down's syndrome.

The frequencies of pervasive developmental disorder (PDD) in Down's syndrome (DS) have been reported from 1% to 11%. However, it is not clear if the frequency of this co-occurrence is higher or lower than in other mental retardations. We study a large sample of DS population, finding a PDD frequency of 15.6%, with 5.58% of autism (eight males and two females) and 10.05% of PDD non autism (nine males and nine females. The meaning of this frequency is discussed.

Determining the frequency of morphological characteristics in a sample of Brazilian children.

OBJECTIVE: To establish the frequency of 82 morphological features in a sample of Brazilian children (between 3 and 13 years old), to understand the influence of age, gender, and ethnicity. METHODS: This was a cross-sectional study that evaluated 239 children with typical development (between 3 and 13 years old) regarding the presence of 82 morphological characteristics. A previously described protocol, based on the London Dysmorphology Database, was applied to evaluate the sample. This protocol was culturally adapted to Brazilian Portuguese. RESULTS: The frequency of 82 morphological characteristics was established in the sample; of 82 characteristics, 50% were considered morphological anomalies (frequency less than 4%). At least 25% of the sample presented more than one minor morphological anomaly. Age was shown to influence the frequency of the following morphological characteristics: widow's peak, prominent antihelix, prominent upper lip, irregular or crowded teeth, and clinodactyly, but had no influence on the frequency of minor morphological anomalies. Gender influenced dysplastic ears and attached earlobe, but had no influence on the frequency of minor morphological anomalies; ethnicity showed influence on camptodactyly and prominent antihelix. A statistically significant divergence was observed regarding 43 of the 73 morphological characteristics that could be compared with literature data (58.9%). CONCLUSIONS: The study determined the frequency of 82 morphological characteristics in 239 children with typical development. Age was the variable that showed more influence on the frequency of morphological characteristics, and comparison with literature data showed that the frequency depends on variables such as age and ethnicity.

Procedures and compliance of a video modeling applied behavior analysis intervention for Brazilian parents of children with autism spectrum disorders.

Video modeling using applied behavior analysis techniques is one of the most promising and cost-effective ways to improve social skills for parents with autism spectrum disorder children. The main objectives were: (1) To elaborate/describe videos to improve eye contact and joint attention, and to decrease disruptive behaviors of autism spectrum disorder children, (2) to describe a low-cost parental training intervention, and (3) to assess participant's compliance. This is a descriptive study of a clinical trial for autism spectrum disorder children. The parental training intervention was delivered over 22 weeks based on video modeling. Parents with at least 8 years of schooling with an autism spectrum disorder child between 3 and 6 years old with an IQ lower than 70 were invited to participate. A total of 67 parents fulfilled the study criteria and were randomized into two groups: 34 as the intervention and 33 as controls. In all, 14 videos were recorded covering management of disruptive behaviors, prompting hierarchy, preference assessment, and acquisition of better eye contact and joint attention. Compliance varied as follows: good 32.4%, reasonable 38.2%, low 5.9%, and 23.5% with no compliance. Video modeling parental training seems a promising, feasible, and low-cost way to deliver care for children with autism spectrum disorder, particularly for populations with scarce treatment resources.

Mismatch between diagnostic reports and special educational needs classification in a public educational system.

OBJECTIVE: To assess the diagnostic status, the sociodemographic and health profiles for students with special educational needs (SEN) in a public educational system, and to map their use of educational/social services. METHODS: The sample comprised 1,202 SEN students from a total of 59,344 students. RESULTS: Only 792 students of the 1,202 had an established diagnosis. The most prevalent SEN condition was intellectual disability. There was a low percentage (29.4%) of use of specialized educational services or support. It was found that, for some neurodevelopmental disorders, prevalence data suggest an under-reporting in the school system. CONCLUSION: Results suggest that there is a mismatch between the diagnostic reports and the SEN condition legally recognized according to Brazilian law, in addition to the under-reporting and under specialized service use of students with disabilities.