Objectifying Micrognathia Using Three-Dimensional Photogrammetric Analysis.

BACKGROUND: Micrognathia occurs isolated and as part of entities like Robin sequence (RS). An objective measurement of mandible size and growth is needed to determine the degree of micrognathia and enable a comparison of treatment outcomes. A pilot study was conducted to investigate the usability of 3-dimensional (3D) facial photogrammetry, a fast, noninvasive method, to estimate mandible size and growth in a small cohort of newborns and infants. METHODS: Exterior mandibular volume was estimated using a tetrahedron defined by 4 facial landmarks. Twelve patients with RS with different etiologies were selected and photogrammetric images were obtained prospectively in 3 patients with RS in whom mandibular growth in the first year of life was determined. We used 3 tetrahedra defined by 6 landmarks on mandibular computed tomography (CT) scans to estimate an interior mandibular volume, which we compared to the exterior mandibular volume in 10 patients. RESULTS: The exterior mandibular volume using 3D photography could be determined in all patients. Signature heat maps allowed visualization of facial dysmorphism in 3D; signature graphs demonstrated similarities of facial dysmorphism in patients with the same etiology and differences from those with other diagnoses and from controls. The correlation between interior (3D photogrammetry) and exterior mandibular volumes (CT imaging) was 0.8789. CONCLUSION: The 3D facial photogrammetry delineates the general facial characteristics in patients with different syndromes involving micrognathia, and can objectively estimate mandibular volume and growth, with excellent correlation with bony measurement. It has been concluded that 3D facial photogrammetry could be a clinically effective instrument for delineating and quantifying micrognathia.

Health-related quality of life in children with Robin sequence.

This patient-reported outcome (PRO) study reports on 102 children with Robin sequence (RS) and their parents. There has been differentiated between those with isolated RS and those with RS as part of a syndrome, and take various treatments into account. All RS families from an earlier described cohort were invited to participate. Parents and RS children completed online questionnaires regarding health-related quality of life (HRQoL), satisfaction with appearance, parental distress, and RS specific topics. Results were compared with the Dutch norm population if available. There was no major difference in HRQoL in RS children and the Dutch norm population, nor between children with isolated RS and those with RS as part of a syndrome. The latter is likely due to the large percentage of children with Stickler syndrome, and small number of RS children with intellectual disability. Parental distress was higher in RS children with syndromes compared to parents of isolated RS children. When comparing various treatments, the subgroup treated by mandibular distraction showed a tendency of lower HRQoL scores, less satisfaction with appearance, and more parental distress. Also in the NPA group parents showed a tendency of more parental distress. Subgroups for each treatment were very small, however, and firm conclusions cannot be drawn. In this study, HRQoL in RS children is demonstrated comparable to the norm population, despite variations in treatment, possibly with less favorable outcome for children who received mandibular distraction. Markedly larger studies are needed to allow more reliable comparison of PROs in various treatments, and to incorporate PROs in management guidelines to obtain optimal patient care. © 2016 Wiley Periodicals, Inc.

Best Practices for the Diagnosis and Evaluation of Infants With Robin Sequence: A Clinical Consensus Report.

IMPORTANCE: Robin sequence (RS) is a congenital condition characterized by micrognathia, glossoptosis, and upper airway obstruction. Currently, no consensus exists regarding the diagnosis and evaluation of children with RS. An international, multidisciplinary consensus group was formed to begin to overcome this limitation. OBJECTIVE: To report a consensus-derived set of best practices for the diagnosis and evaluation of infants with RS as a starting point for defining standards and management. EVIDENCE REVIEW: Based on a literature review and expert opinion, a clinical consensus report was generated. FINDINGS: Because RS can occur as an isolated condition or as part of a syndrome or multiple-anomaly disorder, the diagnostic process for each newborn may differ. Micrognathia is hypothesized as the initiating event, but the diagnosis of micrognathia is subjective. Glossoptosis and upper airway compromise complete the primary characteristics of RS. It can be difficult to judge the severity of tongue base airway obstruction, and the possibility of multilevel obstruction exists. The initial assessment of the clinical features and severity of respiratory distress is important and has practical implications. Signs of upper airway obstruction can be intermittent and are more likely to be present when the infant is asleep. Therefore, sleep studies are recommended. Feeding problems are common and may be exacerbated by the presence of a cleft palate. The clinical features and their severity can vary widely and ultimately dictate the required investigations and treatments. CONCLUSIONS AND RELEVANCE: Agreed-on recommendations for the initial evaluation of RS and clinical descriptors are provided in this consensus report. Researchers and clinicians will ideally use uniform definitions and comparable assessments. Prospective studies and the standard application of validated assessments are needed to build an evidence base guiding standards of care for infants and children with RS.

Etiology and pathogenesis of robin sequence in a large Dutch cohort.

Robin sequence (RS) can be defined as the combination of micrognathia and upper airway obstruction/glossoptosis causing neonatal respiratory problems, with or without a cleft palate and either isolated or non-isolated. Pathogenesis varies widely. We hypothesize that optimal treatment depends on pathogenesis and therefore patients should be stratified according to diagnosis. Here, we evaluate diagnoses and (presumed) pathogeneses in an RS cohort. Medical records of all RS patients presenting between 1995-2013 in three academic hospitals were evaluated. Four clinical geneticists re-evaluated all information, including initial diagnosis. Diagnoses were either confirmed, considered uncertain, or rejected. If uncertain or rejected, patients were re-evaluated. Subsequent results were re-discussed and a final conclusion was drawn. We included 191 RS patients. After re-evaluation and changing initial diagnoses in 48 of the 191 patients (25.1%), 37.7% of the cohort had isolated RS, 8.9% a chromosome anomaly, 29.3% a Mendelian disorder, and 24.1% no detectable cause. Twenty-two different Mendelian disorders were diagnosed, of which Stickler syndrome was most frequent. Stratification of diagnoses according to (presumed) pathogenic mechanism in 73 non-isolated patients with reliable diagnoses showed 43.9% to have a connective tissue dysplasia, 5.5% a neuromuscular disorder, 47.9% a multisystem disorder, and 2.7% an unknown mechanism. We diagnosed more non-isolated RS patients compared to other studies. Re-evaluation changed initial diagnosis in a quarter of patients. We suggest standardized re-evaluation of all RS patients. Despite the relatively high diagnostic yield pathogenesis could be determined in only 59.7% (71/119), due to limited insight in pathogenesis in diagnosed entities. Further studies into pathogenesis of entities causing RS are indicated.

Birth prevalence of Robin sequence in the Netherlands from 2000-2010: a retrospective population-based study in a large Dutch cohort and review of the literature.

The birth prevalence of Robin sequence (RS) is frequently cited to be 1 in 8,500 to 14,000 live births (range: 7,1-11,8 per 100.000), which is based on just a few epidemiological studies. The objective of this study is to contribute to the limited knowledge of the epidemiology of RS by determining the frequency of RS in a cleft palate (CP) population and the estimated birth prevalence in live births in the Netherlands, using distinct diagnostic criteria. A retrospective population-based analysis of the National Cleft Registry was performed in order to obtain all CP patients registered in the Netherlands from 2000-2010, in addition to a thorough review of the medical records in three Dutch Academic Pediatric Hospitals for the same period. Furthermore, a systematic search of the literature was conducted to allow for comparison of our findings. The Dutch birth prevalence of RS was estimated to be 1:5,600 live births (or 17.7 per 100,000), with a slight female predominance. RS was estimated to occur in a third of the CP population and patients with RS had a more severe cleft grade than the general CP population. The literature search yielded 42 studies reporting the birth prevalence for RS, which varied between 1:3,900 and 1:122,400 (0.8-32.0 per 100,000), with a mean prevalence of 1:24,500 (8.0 per 100,000). The birth prevalence of RS in the Netherlands was higher than reported for most other countries when similar diagnostic criteria were used, with a slight female predominance. A third of the general CP could be classified as RS.

Frontometaphyseal dysplasia and keloid formation without FLNA mutations.

Frontometaphyseal dysplasia (FMD) is a distinctive sclerosing skeletal dysplasia associated with a number of non-skeletal manifestations including hearing loss, cardiac malformations, and stenosis, particularly of the upper airway and urinary tract. Some, but not all, patients have mutations in FLNA causing the condition. Consonant with the X chromosomal location of FLNA males are generally more severely affected than females. FLNA mutations can be detected in 82% of affected males. We describe seven patients (one male, six females) all of whom have the major clinical and radiological features of FMD, but without detectable mutations in FLNA. The females in our cohort are affected to a similar degree as is usually found in males. In addition, all patients have marked keloid formation at various body sites, including the eye, from an early age. Other features that may indicate a different etiology in these patients are the increased frequency of cleft palate, Robin sequence, tracheal stenosis, and mild intellectual disability, which all occur in three of more patients in the present group. All patients are isolated. We hypothesize that the presently reported patients represent further evidence that phenotypes strongly resembling FMD exist that are not accounted for by mutations in FLNA. Since the frequency of several of the manifestations, their sporadic presentations, and the presence of keloid formation differ from the X-linked form of this condition we propose de novo autosomal dominant acting mutations in a gene functionally related to FLNA, underpin this disorder.

Will the right Robin patient rise, please? Definitions and criteria during management of Robin sequence patients in the Netherlands and Belgium.

BACKGROUND: Robin Sequence (RS) is characterized by micrognathia and upper airway obstruction (UAO), with or without cleft palate, causing respiratory and feeding problems. Management options are: positioning; nasopharyngeal airway (NPA); tongue-lip adhesion (TLA); mandibular distraction (MDO); and tracheostomy. Controversy exists in literature regarding RS definition and management. Here we describe definitions, management strategies and criteria in opting for management strategies, used by Dutch and Belgian cleft teams. METHODS: A specifically designed questionnaire was sent to members of all 16 Dutch and Belgian cleft teams. RESULTS: 14 cleft teams returned 35 questionnaires. All used micrognathia as definition criterion, 93.4% cleft palate, 51.5%glossoptosis and 45.7% UAO. Six different RS definitions were used; even within a single team >1 definition was used. All teams used different management strategies: all used positioning, 10 NPA, 6 TLA, 7 MDO, 8 tracheostomy, 5 refer patients with invasive treatment indication. Criteria in opting management modalities were: O2-saturation (89.3%), clinical presentation (86.2%), growth and feeding problems (69.0%), polysomnography (62.1%), and differed within teams. CONCLUSION: The Dutch and Belgian cleft teams use variable RS definitions, different management modalities and criteria in choosing management strategies. A single, strict definition and evidence-based management guidelines should be formulated for optimal patient care.

Monocyte gene expression signature of patients with early onset coronary artery disease.

The burden of cardiovascular disease (CVD) cannot be fully addressed by therapy targeting known pathophysiological pathways. Even with stringent control of all risk factors CVD events are only diminished by half. A number of additional pathways probably play a role in the development of CVD and might serve as novel therapeutic targets. Genome wide expression studies represent a powerful tool to identify such novel pathways. We compared the expression profiles in monocytes from twenty two young male patients with premature familial CAD with those from controls matched for age, sex and smoking status, without a family history of CVD. Since all patients were on statins and aspirin treatment, potentially affecting the expression of genes in monocytes, twelve controls were subsequently treated with simvastatin and aspirin for 6 and 2 weeks, respectively. By whole genome expression arrays six genes were identified to have differential expression in the monocytes of patients versus controls; ABCA1, ABCG1 and RGS1 were downregulated in patients, whereas ADRB2, FOLR3 and GSTM1 were upregulated. Differential expression of all genes, apart from GSTM1, was confirmed by qPCR. Aspirin and statins altered gene expression of ABCG1 and ADBR2. All finding were validated in a second group of twenty four patients and controls. Differential expression of ABCA1, RSG1 and ADBR2 was replicated. In conclusion, we identified these 3 genes to be expressed differently in CAD cases which might play a role in the pathogenesis of atherosclerotic vascular disease.

Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits.

Turning genetic discoveries identified in genome-wide association (GWA) studies into biological mechanisms is an important challenge in human genetics. Many GWA signals map outside exons, suggesting that the associated variants may lie within regulatory regions. We applied the formaldehyde-assisted isolation of regulatory elements (FAIRE) method in a megakaryocytic and an erythroblastoid cell line to map active regulatory elements at known loci associated with hematological quantitative traits, coronary artery disease, and myocardial infarction. We showed that the two cell types exhibit distinct patterns of open chromatin and that cell-specific open chromatin can guide the finding of functional variants. We identified an open chromatin region at chromosome 7q22.3 in megakaryocytes but not erythroblasts, which harbors the common non-coding sequence variant rs342293 known to be associated with platelet volume and function. Resequencing of this open chromatin region in 643 individuals provided strong evidence that rs342293 is the only putative causative variant in this region. We demonstrated that the C- and G-alleles differentially bind the transcription factor EVI1 affecting PIK3CG gene expression in platelets and macrophages. A protein-protein interaction network including up- and down-regulated genes in Pik3cg knockout mice indicated that PIK3CG is associated with gene pathways with an established role in platelet membrane biogenesis and thrombus formation. Thus, rs342293 is the functional common variant at this locus; to the best of our knowledge this is the first such variant to be elucidated among the known platelet quantitative trait loci (QTLs). Our data suggested a molecular mechanism by which a non-coding GWA index SNP modulates platelet phenotype.