CDK13-related disorder, also known as congenital heart defects, dysmorphic facial features and intellectual developmental disorder (CHDFIDD) is associated with mutations in the CDK13 gene encoding transcription-regulating cyclin-dependent kinase 13 (CDK13). Here, we focused on the development of craniofacial structures and analyzed early embryonic stages in CHDFIDD mouse models, with one model comprising a hypomorphic mutation in Cdk13 and exhibiting cleft lip/palate, and another model comprising knockout of Cdk13, featuring a stronger phenotype including midfacial cleft. Cdk13 was found to be physiologically expressed at high levels in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme. We also uncovered that Cdk13 deficiency leads to development of hypoplastic branches of the trigeminal nerve including the maxillary branch. Additionally, we detected significant changes in the expression levels of genes involved in neurogenesis (Ache, Dcx, Mef2c, Neurog1, Ntn1, Pou4f1) within the developing palatal shelves. These results, together with changes in the expression pattern of other key face-specific genes (Fgf8, Foxd1, Msx1, Meis2 and Shh) at early stages in Cdk13 mutant embryos, demonstrate a key role of CDK13 in the regulation of craniofacial morphogenesis.

• MeSH
• cyklin-dependentní kinasy metabolismus   genetika   MeSH
• embryo savčí metabolismus   MeSH
• embryonální vývoj * genetika   MeSH
• fenotyp MeSH
• lebka embryologie   patologie   MeSH
• mentální retardace genetika   MeSH
• modely nemocí na zvířatech * MeSH
• mutace genetika   MeSH
• myši MeSH
• nervus trigeminus embryologie   MeSH
• neurogeneze * genetika   MeSH
• obličej embryologie   abnormality   MeSH
• protein doublecortin MeSH
• rozštěp patra genetika   patologie   embryologie   MeSH
• rozštěp rtu genetika   patologie   embryologie   MeSH
• vývojová regulace genové exprese * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: To assess modelled facial development of infants with unilateral cleft lip (CL) and cleft lip and palate (UCLP) compared to controls up to two years of age. DESIGN AND PARTICIPANTS: A total of 209 facial images of children (CL: n = 37; UCLP: n = 39; controls: n = 137) were obtained in four age categories (T0 = 0.2-0.5; T1 = 0.6-1.0; T2 = 1.1-1.5; T3 = 1.6-2.0 years) and were evaluated using stereophotogrammetry and geometric morphometry. All patients underwent lip surgery before T0, patients with UCLP underwent palatoplasty (T0, T1 before palatoplasty; T2, T3 after palatoplasty). RESULTS: In patients with CL, the forehead was significantly retracted (p ≤ 0.001), while the supraorbital and ocular regions were prominent (p ≤ 0.001). The oronasal region appeared convex (p ≤ 0.001). The lower lip and chin were non-significantly protruded. In patients with UCLP, a significantly retracted forehead and prominent supraorbital region were apparent (p ≤ 0.001). A retrusive oronasal region (p ≤ 0.001) was observed in the middle face. The chin was anteriorly protruded (p ≤ 0.01). No progression of deviations was found with increasing age. After the first year, a slight improvement in the morphological features became apparent. The shape variability of the clefts and controls overlapped, suggesting a comparable modelled facial development. CONCLUSIONS: The facial morphology of individuals with cleft was comparable to the norm. Shape deviation was apparent in the oronasal region, forehead, and chin, which minimised with increasing age even in complete clefts.

• MeSH
• fotogrammetrie * metody   MeSH
• kefalometrie MeSH
• kojenec MeSH
• lidé MeSH
• maxilofaciální vývoj MeSH
• obličej anatomie a histologie   abnormality   MeSH
• předškolní dítě MeSH
• průřezové studie MeSH
• rozštěp patra * chirurgie   diagnostické zobrazování   patologie   MeSH
• rozštěp rtu * chirurgie   patologie   MeSH
• studie případů a kontrol MeSH
• zobrazování trojrozměrné * MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Tularemie patří mezi celosvětově rozšířené zoonózy a i přes její relativně nízkou incidenci v našich podmínkách by neměla být v rámci diferenciální diagnostiky opomíjena. V popisované kazuistice bychom chtěli upozornit na klíště jako možný vektor přenosu ulceroglandulární formy tularemie u dětí a současně vyzvednout výhody metody PCR, která může být použita jako časná a spolehlivá metoda detekce obtížně kultivovatelné bakterie Francisella tularensis.

Tularaemia is a widespread zoonosis, which should be considered in differential diagnostics of lymphadenopathy despite of relatively low incidence of the disease. In the presented case we would like to point out a tick bite as a possible way of transmission of an ulceroglandular form of tularaemia in children as well as underline PCR method as an early and reliable form of detection.

• MeSH
• antibakteriální látky MeSH
• ciprofloxacin aplikace a dávkování   terapeutické užití   MeSH
• Francisella tularensis patogenita   MeSH
• lidé MeSH
• lymfadenopatie chirurgie   etiologie   MeSH
• nemoci přenášené klíšťaty diagnóza   farmakoterapie   patologie   MeSH
• obličej abnormality   chirurgie   patologie   MeSH
• předškolní dítě MeSH
• tularemie * diagnóza   farmakoterapie   patologie   MeSH
• zoonózy diagnóza   farmakoterapie   patologie   MeSH
• Check Tag
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Úvod a cíl práce: Okulo-aurikulo-vertebrální spektrum (OAVS) je vrozený komplex malformací s extrémně variabilním fenotypem. Jsou postiženy jednostranně obličejové struktury vznikající během embryonálního vývoje z prvního a druhého žaberního oblouku a zasahující první žaberní váček, první žaberní štěrbinu a základ temporální kosti. Cílem předkládané práce je seznámit čtenáře s klinickým obrazem onemocnění, jehož nejnápadnějším projevem je faciální asymetrie provázená řadou funkčních poruch, a dále představit neinvazivní vyšetřovací metody 3D morfometrie, která umožňuje systematické sledování a vyhodnocování rozvoje a rozsahu morfologické deviace a asymetrie obličeje. Metoda: U šesti pacientů (ve věkovém rozmezí od šesti do 15 let; 5 , 1 ) s okulo-aurikulo-vertebrálním spektrem bylo vytvořeno přesné geometrické 3D zobrazení obličeje pacientů optickou metodou – stereofotogrammetrií. Pomocí metody CPD-DCA (coherent point drift – dense correspondence analysis) byla provedena vzájemná registrace faciálních modelů. U každého pacienta byl zkonstruován dokonale symetrický obličej. Rozdíly mezi konstruovaným symetrickým obličejem a skutečným obličejem byly znázorněny pomocí barevné mapy. Takto zobrazené individuální asymetrie pacientů byly kvantitativně zpracovány a analyzovány v časovém rozpětí 9–23 měsíců. Výsledky: Prokázaly se pouze malé rozdíly ve změně asymetrie obličeje pacientů s OAVS, což svědčí o nevýznamné dynamice rozvoje faciálních malformací u pacientů s tímto onemocněním. Nenašli jsme závislost mezi změnami reliéfu obličeje a věkem pacienta během sledovaného období. Taktéž nebyla nalezena korelace mezi závažností vady a rozvojem asymetrie. Oproti předpokladům se nepotvrdilo významné zhoršování morfologie obličeje u rostoucích pacientů s OAVS, což umožňuje uspokojivou kompenzaci vady včasnou ortodontickou léčbou. Neinvazivní 3D morfometrické vyšetření obličeje je optimální metodou pro sledování vývoje obličejových asymetrií.

Introduction and aim: Oculo-auriculo-vertebral spectrum (OAVS) is a congenital complex of extremely variable phenotypes. Typically, unilaterally aff ected structures are facial structures developing from the fi rst and second branchial arches and fi rst pharyngeal pouch and fi rst branchial cleft and the basis of temporal bone. The aim is to introduce the clinical conditions of the disease whose facial asymmetry is accompanied by a number of functional disorders. Moreover, it presents non-invasive 3D morphometry, that enables evaluation of the morphological deviation of the aff ected area. Methods: An accurate geometric 3D image of the patient's face was created by the optical method – stereophotogrammetry in six patients (age from 6 to 15; 5 , 1 ) with OAVS. Using the construction of dense correspondence mapping by CPD-DCA (coherent point drift – dense correspondence analysis) method between facial meshes, model registration were performed. A perfectly symmetrical face was constructed for each patient. The diff erences between the constructed symmetrical face and the real patient's face were shown using a color map. The individual asymmetry thus displayed was quantitatively processed and analyzed over a period of nine to 23 months. Results: Only minor differences in facial asymmetry of OAVS patients have been demonstrated, suggesting an insignificant dynamics in the development of facial malformations in patients with this disease. We did not find a dependence between face relief changes and patient age during the reference period. There was also no correlation between the severity of the defect and the development of asymmetry. Conclusion: Significant worsening of facial morphology in growing OAVS patients has not been confirmed as supposed. That allows satisfactory compensation of defects by early orthodontic treatment. Non-invasive 3D morphometric facial scanning is an optimal method for monitoring the development of facial asymmetries.

• Klíčová slova
• 3D morfometrie, morfometrie,
• MeSH
• asymetrie obličeje diagnostické zobrazování   patofyziologie   MeSH
• dítě MeSH
• Goldenharův syndrom * dějiny   diagnostické zobrazování   patofyziologie   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• mladiství MeSH
• mnohočetné abnormality diagnostické zobrazování   patofyziologie   MeSH
• obličej abnormality   diagnostické zobrazování   MeSH
• zobrazování trojrozměrné metody   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH

BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

• MeSH
• abnormality očí genetika   MeSH
• DNA vazebné proteiny chemie   genetika   MeSH
• genetické asociační studie MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• mutace * MeSH
• novorozenec MeSH
• obličej abnormality   MeSH
• proteiny Drosophily chemie   genetika   MeSH
• strukturní homologie proteinů MeSH
• svalová hypotonie etiologie   genetika   MeSH
• syndrom MeSH
• těhotenství MeSH
• transkripční faktory chemie   genetika   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Microdeletions of 17q24.2-q24.3 have been described in several patients with developmental and speech delay, growth retardation, and other features. The relatively large size and limited overlap of the deletions complicate the genotype-phenotype correlation. We identified a girl with intellectual disability, growth retardation, dysmorphic features, and a de novo 2.8 Mb long deletion of 17q24.2-q24.3. Her phenotype was strikingly similar to one previously described boy with Dubowitz syndrome (MIM 223370) and a de novo 3.9 Mb long deletion encompassing the deletion of our patient. In addition, both patients had the shortest telomeres among normal age-matched controls. Our review of all 17q24.2-q24.3 deletion patients revealed additional remarkable phenotypic features shared by the patients, some of which have consequences for their management. Proposed novel genotype-phenotype correlations based on new literature information on the region include the role of PSMD12 and BPTF, the genes recently associated with syndromic neurodevelopmental disorders, and a possible role of the complex topologically associated domain structure of the region, which may explain some of the phenotypic discrepancies observed between patients with similar but not identical deletions. Nevertheless, although different diagnoses including the Dubowitz, Nijmegen breakage (MIM 251260), Silver-Russell (MIM 180860), or Myhre (MIM 139210) syndromes were originally considered in the 17q24.2-q24.3 deletion patients, they clearly belong to one diagnostic entity defined by their deletions and characterized especially by developmental delay, specific facial dysmorphism, abnormalities of extremities and other phenotypes, and possibly also short telomere length.

• MeSH
• chromozomální delece MeSH
• dítě MeSH
• ekzém etiologie   MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• fibromatóza dásní genetika   MeSH
• hypertrichóza genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 17 * genetika   MeSH
• mentální retardace etiologie   MeSH
• mikrocefalie etiologie   MeSH
• obličej abnormality   MeSH
• poruchy růstu etiologie   MeSH
• telomery * MeSH
• vývojové poruchy u dětí etiologie   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

OBJECTIVES: To evaluate facial asymmetry changes in pre-school patients with orofacial clefts after neonatal cheiloplasty and to compare facial asymmetry with age-matched healthy controls. METHODS AND MATERIALS: The sample consisted of patients with unilateral cleft lip (UCL), unilateral cleft lip and palate (UCLP), and bilateral cleft lip and palate (BCLP). The patients were divided in two age groups with a mean age of 3 years (n = 51) and 4.5 years (n = 45), respectively, and 78 age-matched individuals as controls. Three-dimensional (3D) facial scans were analyzed using geometric morphometry and multivariate statistics. RESULTS: Geometric morphometry showed positive deviations from perfect symmetry on the right side of the forehead in the intervention groups and the controls. The UCL groups showed the greatest asymmetric nasolabial area on the cleft-side labia and the contralateral nasal tip. The UCLP group showed, moreover, asymmetry in buccal region due to typical maxillar hypoplasia, which was accentuated in the older group. The BCLP groups showed slightly similar but greater asymmetry than the control groups, except for the philtrum region. CONCLUSIONS: Asymmetry of each of the cleft groups significantly differed from the controls. Except for the buccal region in the UCLP and BCLP groups, asymmetry did not significantly increase with age.

• MeSH
• asymetrie obličeje diagnóza   epidemiologie   etiologie   MeSH
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• obličej abnormality   chirurgie   MeSH
• předškolní dítě MeSH
• ret abnormality   chirurgie   MeSH
• rozštěp patra komplikace   chirurgie   MeSH
• rozštěp rtu komplikace   chirurgie   MeSH
• zákroky plastické chirurgie škodlivé účinky   metody   MeSH
• zobrazování trojrozměrné metody   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Kabuki syndrome is mainly caused by dominant de-novo pathogenic variants in the KMT2D and KDM6A genes. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult, even for experienced clinical geneticists. Herein we present molecular genetic findings of causal genetic variation using array comparative genome hybridization and a Mendeliome analysis, utilizing targeted exome analysis focusing on regions harboring rare disease-causing variants in Kabuki-like patients which remained KMT2D/KDM6A-negative. The aCGH analysis revealed a pathogenic CNV in the 14q11.2 region, while targeted exome sequencing revealed pathogenic variants in genes associated with intellectual disability (HUWE1, GRIN1), including a gene coding for mandibulofacial dysostosis with microcephaly (EFTUD2). Lower values of the MLL2-Kabuki phenotypic score are indicative of Kabuki-like phenotype (rather than true Kabuki syndrome), where aCGH and Mendeliome analyses have high diagnostic yield. Based on our findings we conclude that for new patients with Kabuki-like phenotypes it is possible to choose a specific molecular testing approach that has the highest detection rate for a given MLL2-Kabuki score, thus fostering more precise patient diagnosis and improved management in these genetically- and phenotypically heterogeneous clinical entities.

• MeSH
• dítě MeSH
• DNA vazebné proteiny genetika   MeSH
• elongační faktory genetika   MeSH
• exom MeSH
• fenotyp * MeSH
• genetická heterogenita * MeSH
• genotyp * MeSH
• histondemethylasy genetika   MeSH
• jaderné proteiny genetika   MeSH
• krevní nemoci diagnóza   genetika   patofyziologie   MeSH
• lidé MeSH
• lidské chromozomy, pár 14 MeSH
• malý jaderný ribonukleoprotein U5 genetika   MeSH
• mandibulofaciální dysostóza genetika   MeSH
• mentální retardace genetika   MeSH
• mikrocefalie genetika   MeSH
• mnohočetné abnormality diagnóza   genetika   patofyziologie   MeSH
• nádorové proteiny genetika   MeSH
• nádorové supresorové proteiny genetika   MeSH
• obličej abnormality   patofyziologie   MeSH
• předškolní dítě MeSH
• proteiny nervové tkáně genetika   MeSH
• receptory N-methyl-D-aspartátu genetika   MeSH
• srovnávací genomová hybridizace MeSH
• ubikvitinligasy genetika   MeSH
• vestibulární nemoci diagnóza   genetika   patofyziologie   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

• MeSH
• fenotyp MeSH
• forkhead transkripční faktory chemie   genetika   metabolismus   MeSH
• genetická transkripce MeSH
• jazykové poruchy genetika   MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• missense mutace MeSH
• mutace MeSH
• neurovývojové poruchy genetika   MeSH
• obličej abnormality   MeSH
• poruchy autistického spektra genetika   MeSH
• poruchy motorických dovedností genetika   MeSH
• represorové proteiny chemie   genetika   metabolismus   MeSH
• stabilita proteinů MeSH
• syndrom MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.

• MeSH
• dítě MeSH
• DNA vazebné proteiny genetika   MeSH
• fenotyp MeSH
• genom lidský MeSH
• histondemethylasy genetika   MeSH
• jaderné proteiny genetika   MeSH
• kojenec MeSH
• krevní nemoci diagnóza   genetika   patofyziologie   MeSH
• lidé MeSH
• mladiství MeSH
• mnohočetné abnormality diagnóza   genetika   patofyziologie   MeSH
• nádorové proteiny genetika   MeSH
• obličej abnormality   patofyziologie   MeSH
• předškolní dítě MeSH
• srovnávací genomová hybridizace MeSH
• vestibulární nemoci diagnóza   genetika   patofyziologie   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH