INTRODUCTION: Ankyloblepharon filiforme adnatum associated with Hay-Wells syndrome is a rare congenital disease caused by mutations in TP63 gene on the 3q27 chromosome. Here, we report a case of a new-born suffering from this syndrome in whom we detected a mutation c.1709T>C not previously included in the Ensemble database. CASE DESCRIPTION: A girl delivered in the 34th week of gestation from a physiological pregnancy was born with extensive burn-like skin defects, ankyloblepharon filiforme adnatum, palate cleft, onychodystrophy of all limbs and syndactyly of toes. Hay-Wells syndrome was suspected and confirmed by genetic examination. A heterozygous missense change c.1709T>C was found in the TP63 gene. This variant leads to a 570th codon exchange of leucine for proline (p.Leu570Pro) on the protein level. The eyelid separation was performed surgically, burns were treated locally and cosmetic surgeries correcting other defects are planned for the near future. The girl is still monitored by a multidisciplinary team. CONCLUSIONS: The mutation was not previously described in the literature or databases and should be included into these as probably pathogenic. A multidisciplinary approach is necessary to care for a patient with Hay-Wells syndrome, such care however can provide good results.

• Klíčová slova
• Ankyloblepharon filiforme adnatum, Hay–Wells syndrome, TP63 gene, congenital eyelids disorders, ectodermal dysplasia, p63 protein,
• MeSH
• abnormality očí diagnóza   genetika   chirurgie   MeSH
• ektodermální dysplazie diagnóza   genetika   chirurgie   MeSH
• genetické testování MeSH
• gestační stáří MeSH
• heterozygot MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• mladý dospělý MeSH
• nádorové supresorové proteiny genetika   MeSH
• novorozenec MeSH
• oční víčka abnormality   chirurgie   MeSH
• oftalmologické chirurgické výkony MeSH
• rozštěp patra diagnóza   genetika   chirurgie   MeSH
• rozštěp rtu diagnóza   genetika   chirurgie   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové supresorové proteiny MeSH
• TP63 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

BACKGROUND: Increased frequency of chromosomal aberration in children of mothers aged 35 years and older is very well known and since 1973 it is an indication to investigate the foetal karyotype in cells obtained by invasive method (amniocentesis), because the genetic risk of severe affection is higher than the risk of necessary invasive method. Mutagenic effect of advanced paternal age is known only among geneticists (1-4). The reason is not only low absolute risk of new mutation but particularly a high number of involved genes and last not least the limited spectrum of autosomal dominant disorders without abiotrofic character. Therefore the preventive methods for elimination of this risk are very limited. Only a few of them could be recognized prenatally by noninvasive methods of prenatal diagnostics. METHODS: Genealogical, anamnestic and clinical data of 83 patients were studied with clinical suspection on neurocardiofaciocutaneous syndrome (NCFCs) (5-7). The diagnosis has not been confirmed in 29 patients, no mutation was detected in 8 investigated genes (PTPN11, SOS1, HRAS, BRAF, RAF1, MEK1, KRAS, NRAS). In 54 patients with autosomal dominant inherited Noonan syndrome, Costello syndrome and cardiofaciocutaneous syndrome the diagnosis was confirmed on DNA level and the biological fitness was estimated for each disorder. Paternal age at conception was compared in the group of patients with familial and sporadic occurrence of Noonan and NCFC syndromes. The clinical prognosis of this disorder is represented by biological fitness of patients. Coefficient of selection is 0,6 in Noonan and LEOPARD syndromes (29 from 48). All 6 patients with Costello and cardiofaciocutaneous syndromes developed due to a new mutation. CONCLUSION: Paternal age at birth was studied in 83 children patients with autosomal dominant Neurocardiofaciocutaneous syndrome (Noonan, LEOPARD, Costello, CFC) with a high population incidence and decreased biological fitness. Due to severe congenital heart defects, failure to thrive in infancy, increased risk for malignancy and further health problems the clinical prognosis of patients in the past was not good. Therefore high mutation rate is expected until now. Identification of genes responsible for manifestation of this disorder, enables to confirm the diagnosis and to recognize inherited and de novo mutations. Genealogy and DNA analysis of PTPN11, SOS1, HRAS, BRAF, RAF1, MEK1, KRAS and NRAS were obtained in cohort of 54 patients with NCFC syndromes and their parents. There were 48 patients with Noonan and LEOPARD syndromes, in 29 cases due to mutation de novo, 19 patients inherited the mutation from one of parents. All 6 patients with Costello syndrome and CFC syndrome were affected due to new mutation. DNA analysis revealed 32 mutations in PTPN11 gene, mutation in SOS1 gene was found in 10 patients, RAF1 mutation was present in 3 patients; mutation in MEK1, KRAS and NRAS genes was present in one patient each. In Costello syndrome and CFC syndrome mutations in HRAS (4 patients) and BRAF (2 patients) genes were detected. Genealogic data allow analysing parental age in the group of patients with new mutation and inherited mutation. Paternal age at conception of patients with Noonan syndrome due to new mutation was significantly increased in comparison to the group of fathers of Noonan patients with inherited mutation - 38,4 years and 29,6 years, resp., range 28 to 55 years and 25 to 35 years, resp. Maternal age was slightly increased too, -30,9 and 27,7, resp. and range 24 to 42 years and 21 to 36 years, resp. but not significantly. The results support the mutagenic effect of paternal age, espec. autosomal dominant mutations.

• MeSH
• chromozomální aberace MeSH
• dítě MeSH
• dominantní geny genetika   MeSH
• ektodermální dysplazie diagnóza   genetika   MeSH
• faciální stigmatizace MeSH
• genetická predispozice k nemoci genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mutační analýza DNA * MeSH
• neprospívání diagnóza   genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prenatální diagnóza MeSH
• těhotenství MeSH
• věk otce * MeSH
• věkové faktory MeSH
• vrozené srdeční vady diagnóza   genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH