Immunoexpression of ALDH1A1, FGFR2, CD44 and Caspase-3 in Oral Squamous Cell Carcinoma and Leukoplakia: A pilot study

Current research highlighted the importance to recognize feasible biomarkers for early diagnoses and treatment in oral cancer. Our study analyzed the expression and spatial distribution of ALDH1A1, FGFR2, caspase-3, and CD44 in Oral Squamous Cell Carcinoma (OSCC) and leukoplakia with and without oral mucosal dysplasia. Paraffin-embedded samples of OSCC (n=5), leukoplakia with (n=5) and without (n=5) dysplasia obtained by incisional biopsies were processed using conventional histochemical techniques. Immunohistochemistry was performed using antibodies against ALDH1A1, FGFR2, caspase-3, and CD44. Images of the immunohistochemically stained tissue sections were analyzed according to the intensity of the immunostaining of each marker and classified in Scores. The Kruskal- Wallis test was performed (p≤0.05). Our results demonstrated a statically difference in the expression of all immunomarkers between OSCC and leukoplakia without dysplasia, being more significant in FGFR2 and ALDH1A1. Within the limitations of this study, our data showed that all biomarkers were overexpressed in OSCC and leukoplakia with oral mucosa dysplasia, suggesting that the presence of dysplasia is a significant clinic-pathologic predictor for malignant transformation.

La actual evidencia científica enfatiza la importancia de reconocer biomarcadores viables para el diagnóstico y tratamiento temprano del cáncer oral. Nuestro estudio piloto analizó la expresión y distribución espacial de ALDH1A1, FGFR2, caspasa-3 y CD44 en carcinoma oral de células escamosas (COCE) y en leucoplasia con o sin displasia de la mucosa oral. Las muestras incluidas en parafina de COCE (n=5), con (n=5) y sin (n=5) displasia fueron obtenidas mediante biopsias incisionales, las cuales se procesaron utilizando técnicas histoquímicas convencionales. El análisis inmunohistoquímico se realizó utilizando anticuerpos contra ALDH1A1, FGFR2, caspasa-3 y CD44. Las imágenes de las secciones de cada muestra fueron analizadas según la intensidad de inmunoexpresión de cada marcador y se clasificaron en diferentes escalas (scores). Se realizó la prueba de Kruskal-Wallis (valores de p<0,05). Nuestros resultados demostraron una diferencia estadística en la expresión de todos los inmunomarcadores entre COCE y las muestras con leucoplasia sin displasia, siendo más significativa en FGFR2 y ALDH1A1. Considerando las limitaciones de este estudio, los datos sugieren que la presencia de displasia en la mucosa oral es un importante predictor clínico-patológico de transformación maligna.

Manga traqueal cartilaginosa. Reporte de dos casos

La manga traqueal cartilaginosa es una malformación de la vía aérea donde no se distinguen anillos traqueales. Un segmento continuo de cartílago se extiende desde el cricoides, pudiendo llegar hasta los bronquios principales. Está asociada a síndromes de craneosinostosis con la mutación FGFR2, además de muertes prematuras por oclusión de la tráquea con tapones mucosos. Se presenta el curso clínico de pacientes portadores de manga traqueal cartilaginosa en el contexto de una malformación craneofacial. Caso 1. Masculino, al nacer hipoplasia del tercio medio facial. Polisomnografía: índice de apnea/hipopnea de 37,7/hr. Laringotraqueobroncoscopía (LTBC): tráquea sin anillos cartilaginosos desde cricoides hasta bronquios fuentes. Se indica traqueostomía. Caso 2. Masculino, al nacer cráneo en trébol. Poligrafía: Síndrome de apnea/hipopnea obstructiva del sueño (SAHOS) leve. Revisión vía aérea: desde subglotis hasta bronquios principales se extiende tráquea en manga. Se indica traqueostomía. En el contexto de una craneosinostosis en niños, especialmente con mutación FGFR2, creemos necesario realizar una LTBC en búsqueda de manga traqueal, ya que si es diagnosticada se debe recomendar traqueostomía, mejorando su expectativa de vida. Si la indicación de traqueostomía fuese por SAHOS, es obligatoria una LTBC preoperatoria, para evitar el no tener referencias anatómicas en el proceso.

A tracheal cartilaginous sleeve is a malformation of the airway in which the tracheal rings are indistinguishable. A continuous segment of cartilage extends from the cricoid, and it may reach all the way to the main bronchi. It is associated with various craniosynostosis syndromes with the FGFR2 mutation, in addition to premature deaths due to occlusions caused by mucus plugs in the trachea. Here we present the clinical course of patients who suffer from Tracheal Cartilaginous Sleeve in the context of a craniofacial malformation. First case. Male, presenting at birth a midfacial hypoplasia. Polysomnography: presents a 37,7/h index of apnea/hypopnea. Laryngotracheobronchoscopy (LTB): trachea is without cartilaginous rings from the cricoid to the main bronchi. A tracheostomy is indicated. Second case. Male, cloverleaf skull at birth. Polysomnography: Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) non-severe degree. Revision of the airway: the trachea in sleeve extends from the subglottis to the main bronchi. A tracheostomy is indicated. In the context of craniosynostosis in children, especially with FGFR2 mutation, we believe it is necessary to do an LTB in the search of a tracheal sleeve, since if it is diagnosed a tracheostomy must be indicated, to better the life expectancy of the patient. If the tracheostomy indication comes from an OSAHS, a preoperatory LTB is obligatory to avoid not having anatomical references during the procedure.

Cordycepin inhibits pancreatic cancer cell growth in vitro and in vivo via targeting FGFR2 and blocking ERK signaling / 中国天然药物

Cordycepin (3'-deoxyadenosine) from Cordyceps militaris has been reported to have anti-tumor effects. However, the molecular target and mechanism underlying cordycepin impeding pancreatic cancer cell growth in vitro and in vivo remain vague. In this study, we reported functional target molecule of cordycepin which inhibited pancreatic cancer cells growth in vitro and in vivo. Cordycepin was confirmed to induce apoptosis by activating caspase-3, caspase-9 and cytochrome c. Further studies suggested that MAPK pathway was blocked by cordycepin via inhibiting the expression of Ras and the phosphorylation of Erk. Moreover, cordycepin caused S-phase arrest and DNA damage associated with activating Chk2 (checkpoint kinase 2) pathway and downregulating cyclin A2 and CDK2 phosphorylation. Very interestingly, we showed that cordycepin could bind to FGFR2 (K = 7.77 × 10) very potently to inhibit pancreatic cancer cells growth by blocking Ras/ErK pathway. These results suggest that cordycepin could potentially be a leading compound which targeted FGFR2 to inhibit pancreatic cells growth by inducing cell apoptosis and causing cell cycle arrest via blocking FGFR/Ras/ERK signaling for anti-pancreatic cancer new drug development.

Ponatinib inhibits growth of patient-derived xenograft of cholangiocarcinoma expressing FGFR2-CCDC6 fusion protein in nude mice / 南方医科大学学报

OBJECTIVE@#To investigate the antitumor effect of ponatinib on the growth of cholangiocarcinoma xenograft derived from a clinical patient in a mouse model expressing FGFR2-CCDC6 fusion protein.@*METHODS@#Lung metastatic tumor tissue was collected from a patient with advanced intrahepatic cholangiocarcinoma and implanted subcutaneously a NOD/SCID/ Il2rg-knockout (NSG) mouse. The tumor tissues were harvested and transplanted in nude mice to establish mouse models bearing patient-derived xenograft (PDX) of cholangiocarcinoma expressing FGFR2-CCDC6 fusion protein. The PDX mouse models were divided into 4 groups for treatment with citrate buffer (control group), intragastric administration of 20 mg/kg ponatinib dissolved in citrate buffer (ponatinib group), weekly intraperitoneal injections of 50 mg/kg gemcitabine and 2.5 mg/ kg cisplatin (gemcitabine group), or ponatinib combined with gemcitabine and cisplatin at the same doses (10 mice in each group, and 9 mice were evaluated in ponatinib group). The expressions of p-FGFR, p-FRS2, p-AKT, p-ERK, CD31, and Ki-67 in the xenografts were evaluated with immunohistochemistry, and cell apoptosis was analyzed with cleaved caspase-3 (CC3) staining and TUNEL staining. Western blotting was used to detect the expressions of FGFR2, p-FGFR, AKT, p-AKT, ERK, p-ERK, FRS2 and p-FRS2 in the tumor tissues.@*RESULTS@#Compared with those in the control group, the mice in ponatinib group showed a significantly reduced tumor volume (@*CONCLUSIONS@#Ponatinib can regulate FGFR signaling to inhibit the proliferation and induce apoptosis of tumor cells in mice bearing patient-derived cholangiocarcinoma xenograft with FGFR2 fusion. FGFR inhibitor can serve as a treatment option for patients with cholangiocarcinoma with FGFR2 fusion.

Síndrome de Apert. Reporte de caso / Apert syndrome. Case report

Introducción: El síndrome de Apert, o acrocefalosindactilia tipo I, es un síndrome caracte­rizado por craneosinostosis, acompañada de sindactilia simétrica en las cuatro extremidades, alteraciones maxilofaciales, cutáneas y retardo mental variable. Este síndrome se debe a una mutación en el gen del receptor 2 del factor del crecimiento fibroblástico (FGFR2), el cual se expresa de manera autosómica dominante (AD) Caso clínico: Se presenta caso de adolescente masculino de 24 años de edad, con las características fenotípicas clásicas de este síndrome como la acrocefalia y la sindactilia en manos y pies. Discusión: El síndrome de Apert hace parte de lo que hoy se denomina un espectro de enfermedades causadas por la mutación en el gen FGFR2 que se caracterizan por anorma­lidades en el cráneo y las extremidades. Este gen es necesario para la osificación normal y también está implicado en la diferenciación neural. Sus mutaciones producen un receptor anormal que funciona aun sin la unión de su ligando "ganancia de función", lo que se traduce en una osificación temprana de los huesos, en grados variables, dependiendo del sitio exacto de la mutación.

Introduction: Apert's syndrome or acrocefalosindactyly tipe I, is a syndrome character­ized by craniosynostosis, symmetric syndactylia in hands and feet's, maxillofacial and cutaneous disorders, and variable mental retardation. This syndrome is due to a mutation in the gene that encode the fibroblast growth factor Receptor 2 (FGFR2), which has an autosomal dominant inheritance (AD). Case report: We report a male24 yearsoldteen, with the classical phenotypic characteristics of this syndrome, as acrocefalia and syndactyly of hands and feet. Discussion: Apert's syndrome is part of what today is called a spectrum of disease caused by a mutation in the FGFR2 gene, which is characterized by abnormalities in the skull and extremities. This gene is required for normal ossification and is also involved in neural differentiation. Mutations cause an abnormal receptor that functions even without the binding of its ligand "gain of function", which translates into an early ossification of the bones, in varying degrees, depending on the exact site of the mutation.

Clinical and genetic findings of two cases with Apert syndrome / Hallazgos clínicos y genéticos de dos casos con síndrome de Apert

Abstract Background: Craniosynostosis is described as the premature fusion of cranial sutures that belongs to a group of alterations which produce an abnormal phenotype. Case report: Two unrelated female patients with clinical findings of Apert syndrome-characterized by acrocephaly, prominent frontal region, flat occiput, ocular proptosis, hypertelorism, down-slanted palpebral fissures, midfacial hypoplasia, high-arched or cleft palate, short neck, cardiac anomalies and symmetrical syndactyly of the hands and feet-are present. In both patients, a heterozygous missense mutation (c.755C>G, p.Ser252Trp) in the FGFR2 gene was identified. Conclusions: Two cases of Apert syndrome are described. It is important to recognize this uncommon entity through clinical findings, highlight interdisciplinary medical evaluation, and provide timely genetic counseling for the family.

Resumen Introducción: Las craneosinostosis se describen como la fusión prematura de las suturas craneales y resultan un grupo de alteraciones que producen un fenotipo anormal. Caso clínico: En este informe de casos se presentan dos pacientes de sexo femenino no emparentadas con hallazgos clínicos del síndrome de Apert, caracterizado por acrocefalia, región frontal prominente, occipucio plano, proptosis ocular, hipertelorismo, fisuras palpebrales hacia abajo, hipoplasia mediofacial, paladar alto o hendido, cuello corto, cardiopatía congénita y sindactilia simétrica en manos y pies. En ambas pacientes se identificó una mutación cambio de sentido en heterocigosis (c.755C>G, p.Ser252Trp) en el gen FGFR2. Conclusiones: Se presentan dos casos de síndrome de Apert. Es importante reconocer a través de los hallazgos clínicos esta entidad infrecuente, resaltar la evaluación médica interdisciplinaria y proporcionar un oportuno asesoramiento genético a la familia.

Sindrome de apert, reporte de caso clínico / Apert syndrome, clinical case report

El Síndrome de Apert llamado también acrocefalosin-dactilia tipo I, está caracterizado por craneosinostosis, sindactilia simétrica en las cuatro extremidades, retardo mental, alteraciones cutáneas y maxilofaciales; está ocasionado por una mutación en el gen receptor 2 del factor de crecimiento fibroblástico FGFR2 expresándo-se en forma autosómico dominante (AD).Caso Clínico: Se presenta caso de recién nacido masculino, Capurro de 38 semanas aproximadamente, con las características fenotípicas clásicas de este síndro-me: como es la acrocefalia y la sindactilia en manos y pies.

Apert syndrome also called acrocephalosyndactyly Type I is characterized by craniosynostosis , symmetric syndactyly in all four limbs , mental retardation , skin and maxillofacial disorders ; It is caused by a mutation in the gene receptor 2 fibrobroblástico growth factor expres-sing FGFR2 autosomal dominant (AD ) .Case report: as is the acrocephaly and syndactyly in the hands and feet of newborn male case, Capurro of 38 weeks approximately, with classical phenotypic characteristics of this syndrome is presented as is the acro-cephaly and syndactyly in hands and feet.

Sindrome de apert / Opening syndrome

El síndrome de Apert, o acrocefalosindactilia tipo I, es un síndrome caracterizado por craneosinostosis, acompañada de sindactilia simétrica en las cuatro extremidades, alteraciones maxilofaciales, cutáneas y retardo mental variable. Este síndrome se debe a una mutación en el gen del receptor 2 del factor del crecimiento FIbroblástico (FGFR2), el cual se expresa de manera autosómica dominante (AD). Caso Clínico: Se presenta caso de recién nacido masculino, Capurro de 38 semanas aproximadamente, con las características fenotípicas clásicas de este síndrome:(como) la acrocefalia y la sindactilia en manos y pies.

Apert syndrome, or acrocephalosyndactyly type I, is a syndrome characterized by craniosynostosis, syndactyly accompanied symmetrical in all four extremities, maxillofacial abnormalities, mental retardation, skin and variable. This syndrome is caused by a mutation in the gene for the receptor 2 broblástico growth factor (FGFR2), which is expressed as an autosomal dominant (AD). Case Report: We report the case of a newborn male, approximately 38 weeks Capurro, with classical phenotypic features of this syndrome as acrocephaly and syndactyly of hands and feet.

Genotype-phenotype analysis in Apert syndrome / 临床儿科杂志

Objectives To analyze the clinical features and gene types of Apert syndrome (AS). Methods The clinical data of one boy with AS were retrospectively revisited and FGFR 2 of the boy and his father were analyzed with PCR amplification and gene sequencing. The relevant literatures were reviewed. Results The boy was one year and one month old, with brachycephaly, exophthalmos, hypertelorism, low set ears, micrognathia, high-vaulted arch, without cleft palate, and with syndactyly of both ifngersⅠ-Ⅴ and toesⅠ-Ⅴ. A heterozygous mutation (c. 758 C?>?G,p.P 253 R) in exon 7 of FGFR 2 was detected in the boy, supporting the diagnosis of AS. The relevant gene mutation was not detected in his father. Among the 24 cases of AS retrieved from literature, 22 cases were with obvious craniofacial malformations, one with mild craniofacial malformations and one without craniofacial malformations. All cases were with syndactyly of both ifngers and toes. Thirteen cases of FGFR 2 were with S 252 W mutation, 3 cases with P 253 R , 3 cases with Alu insertion, one with 1 . 93-kb deletion, removing exon IIIc and substantial portions of the lfanking introns, one case with a heterozygous 1372 bp deletion between FGFR 2 exons IIIb and IIIc, 2 cases with (c.756_758delGCCinsCTT) in the IgIIe-IgIIIa linker region and one case with sequence variant T78.501A in intron 8. Conclusions Apert syndrome present with craniofacial malformations and syndactyly of hands and feet, S 252 W and P 253 R are main mutations of AS.

The correlation study between FGFR2 gene polymorphisms and breast cancer in Qinghai Tibetan areas / 重庆医学

Objective To explore the relationship between the fibroblast growth factor 2 (FGFR2) gene polymorphism (rs 2981582 ,rs 1219648 ,rs 2420946) and the breast cancer risk in Tibetan population ,Qinghai province .Methods This is a case con‐trol study .Peripheral blood samples from 210 breast cancer patients and 230 healthy women in Qinghai area were collected .DNA samples were extracted from peripheral blood cells .FGFR2 gene polymorphism (rs 2981582 ,rs 1219648 ,rs 2420946) were typed by Taqman‐MGB probe based on PCR and DNA sequencing ,then analyzed its correlation with breast cancer in Tibetan population , Qinghai province .Results The genotype frequencies of rs 2981582 CC ,CT and TT were 40 .48% ,39 .05% and 20 .47% among the breast cancer patients while 36 .09% ,48 .69% and 15 .22% among the controls .The genotype frequencies of rs 1219648 GG ,AG and AA were 24 .76% ,26 .19 % and 49 .05% among the patients while 23 .91% ,47 .39% and 28 .70% among the controls .The genotype frequencies of rs 2420946 CC ,CT and TT were 29 .05% ,45 .24% and 25 .71% among the patients while 30 .87% , 51 .74% and 17 .39% among the controls .The genotype frequencies of all genetic loci had no significant difference between rs 2981582 and rs 2420946 (P>0 .05) .But the genotype frequencies of rs 1219648 AA have statistical sense (P< 0 .05) ,compared with GG ,the incidence of breast cancer was remarkably increased with AA [OR=1 .65 ,95% CI= (1 .01 ,2 .69)] .Conclusion This study shows that FGFR2 rs1219648 AA is related to breast cancer risk among Tibetan population .

Two cases of Antley-Bixler syndrome caused by mutations in different genes, FGFR2 and POR

Antley-Bixler syndrome (ABS) is a rare form of syndromic craniosynostosis with additional systemic synostosis, including radiohumeral or radioulnar synostosis. Another characteristic feature of ABS is mid-facial hypoplasia that leads to airway narrowing after birth. ABS is associated with mutations in the FGFR2 and POR genes. Patients with POR mutations present with either skeletal manifestations or congenital adrenal hyperplasia with ambiguous genitalia. We report here two cases of ABS caused by mutations in FGFR2 and POR. Although the patients had craniosynostosis and radiohumeral synostosis in common and cranioplasty was performed in both cases, the male with POR mutations showed an elevated level of 17α-hydroxyprogesterone during newborn screening and was diagnosed with congenital adrenal hyperplasia by adrenocorticotropic hormone stimulation. This patient has been treated with hydrocortisone and fludrocortisone. He had no ambiguous genitalia but had bilateral cryptorchidism. On the other hand, the female with the FGFR2 mutation showed severe clinical manifestations: upper airway narrowing leading to tracheostomy, kyphosis of the cervical spine, and coccyx deformity. ABS shows locus heterogeneity, and mutations in two different genes can cause similar craniofacial and skeletal phenotypes. Because the long-term outcomes and inheritance patterns of the disease differ markedly, depending on the causative mutation, early molecular genetic testing is helpful.

Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome / Análisis molecular de los exones 8, 9 y 10 del gen del factor de crecimiento de fibroblastos (FGFR2) en dos familias con casos índice de síndrome de Apert

Introduction: Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. Methods: Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. Results: Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function.

Introducción: El síndrome Apert (SA) es un síndrome que cursa con craneosinostosis el cual es ocasionado por mutaciones en el gen del Receptor 2 del Factor de Crecimiento de Fibroblastos (FGFR2). Se caracteriza clínicamente por presentar sindactilias cutáneas y óseas en manos y pies de forma simétrica, cursa además con manifestaciones variables esqueléticas, cerebrales, en piel y otros órganos internos. Métodos: Miembros de dos familias con caso índice de Síndrome Apert fueron evaluados con el objetivo de describir las características clínicas relevantes y el análisis molecular (secuenciación y amplificación) de los exones 8, 9 y 10 del gen FGFR2. Resultados: La familia 1 está constituida por la madre, el caso índice y un medio hermano que presenta labio y paladar hendido. En esta familia solo se encontró la mutación S252W en la secuencia del exón 8 del gen FGFR2 del caso índice. A pesar no encontrarse mutaciones dentro del estudio realizado al paciente afectado con labio y paladar hendido, se conoce que estas patologías comparten vías de señalización, lo que permite sospechar alteraciones en genes compartidos. En la familia 2, el resultado molecular del caso índice reportó la variante T78.501A en la secuencia del intrón 8, la cual se sitúa cercana al sitio de splicing, pudiendo alterar este proceso con una consecuente alteración de la función de la proteína.

The study of the mechanism in the endochondral ossification of bone mesenchymal stem cells in mice by continued enhanced function of fibroblast growth factor type Ⅱ receptor mutation / 重庆医学

Objective To study the role of ERK signal pathway in the endochondral ossification of bone mesenchymal stem cells ,and to explore the mechanism of ERK signal pathway in persistent enhanced FGFR2 function on development of mice BMSCs by a knock‐in mouse model with the FGFR2S252W/+ .Methods Mice with neo‐FGFR2 gain‐of‐function mutation were mated with EII‐Cre mice .The genotype of generation mice were identified by PCR and divided into wild type group and mutant type group ac‐cording to their genotype .6 week‐old mice were sacrificed to receive bone mesenchymal stem cells .The western blot was used to compare the level of P‐ERK and ERK and the RT‐PCR was applied to detect the genes of Col2 ,Col10 ,OC ,OP in chondrogenic dif‐ferentiation medium of BMSCs .Then ,treatment of cultured BMSCs with PD98059 ,compare the changes of genes and utilize the in vitro culture of long bones detect the role of ERK signal pathway in the endochondral ossification by FGFR2 mutant .Results We successfully derive BMSCs from FGFR2S252W/+ mutant mice and found the activity of ERK signal pathway of FGFR2S252W/+ was en‐hanced .After been cultured in chondrogenic differentiation medium ,the expressions of the BMSCs mRNA of Col2 ,Col10 from mu‐tant group were decreased ,while the expressions of OC ,OP were increased .Those OC ,OP genes levels showed an increased treated by PD98059 .Using in vitro culture of long bones ,we found the retardation of total length growth of long bones has been rescued by PD98059 treatment ,suggesting that ERK signal pathways was responsible for the retarded long bone development in FGFRS252W/+mice .Conclusion The results indicate these effects are mediated by the ERK signal pathway .Furthermore ,the retardation of long bones has been recued by PD98059 treatment ,suggesting that ERK signal pathway is responsible for the retarded long bone devel‐opment in FGFR2S252W/+ mice .

Shape analysis of the sphenoid bone in Apert syndrome using 3D CT scans

Apert syndrome is a rare acrocephalosyndactyly syndrome characterised by craniosynostosis, midface hypoplasia and syndactyly of the hands and feet. The majority of cases arise as the result of one of two mutations of the fibroblast growth factor receptor 2 gene (FGFR2). Due to the involvement of both the cranial and the facial sutures, the keystone of the craniofacial skeleton, the sphenoid bone, is affected by the disease process and as a result is dysmorphic. This may significantly affect craniofacial morphology but it is recognised that there are marked variations in this between different affected individuals. This is a retrospective study examining the morphology of the sphenoid bone using three dimensional reconstructions of computed tomography (CT) scan data. Shape analysis was performed using generalised Procrustes analysis and principal component analysis (GPA/PCA). Comparisons were made between the individuals with Apert syndrome and a group of normal individuals, and between the two genotypic groups. The sphenoid bone in those with Apert syndrome showed marked differences in morphology compared to the normal individuals with a restriction in height and increased angulation of the lesser wings; however, there were no consistent differences between the two genotypic groups. It is possible that fronto-orbital advancement (FOA) surgery indirectly releases the sphenoid bone and allows compensatory growth in this direction.

Análisis genotípico de 11 pacientes colombianos con Síndrome de Apert / Genotypic analysis of 11 Colombian Apert syndrome patients

Antecedentes. El síndrome de Apert (SA) es una de las craneosinostosis sindrómicas más severas que afecta el neuro y viscerocraneo y además presenta alteraciones multisistémicas con repercusiones en aspectos físicos (aspecto general y talla baja), sensoriales (hipoacusia y trastornos visuales), cognoscitivos (retardo mental o trastornos del aprendizaje) y de inclusión laboral (sindactilia severa en manos y pies). Su etiología es la mutación del receptor 2 del factor de crecimiento fibroblástico (FGFR2) y se hereda de forma autosómica dominante. Materiales y métodos. Se analizaron clínica y molecularmente 11 pacientes con sospecha de SA. Se realizó estudio mutacional mediante RFLP para el gen FGFR2. Resultados. Se confirmaron molecularmente los 11 pacientes con SA, cuyas edades oscilaron desde los 0 a 32 años. Todos los pacientes presentaron el fenotipo clásico. Se encontró un 63.6% de pacientes con la mutación S252W y 36.4% con P253R. Discusión. De los pacientes analizados, llamo la atención la presencia de talla baja y RM/RGD en algunos de ellos. Desde el punto de vista genotípico, las frecuencias mutacionales para S252W y P253R no mostraron diferencias con relación a lo reportado mundialmente. Aunque no se disponen de datos de la incidencia de esta patología a nivel local, este estudio podría ser el primer acercamiento para fines epidemiológicos en Colombia.

Background. Apert Syndrome (AS) is one of the most severe syndromic craniosynostosis affecting neuro and viscerocranium and presenting with multisystemic anomalies altering physical aspects (general looks and short stature), sensorineural aspects (deafness and visual problems), cognitive development (mental retardation or trouble learning) and work inclusion (severe syndactyly in hands and feet). Its aetiology relies on mutation of the Fibroblast Growth Factor Receptor type 2 (FGFR2) gene, inherited by an autosomal dominant path. Materials and methods. 11 patients with suspicion of AS were clinically evaluated and molecularly tested for mutations in FGFR2 by RFLP. Results. Patients with AS from 0 to 32 years old were analized for mutations in FGFR2 gene. All of them had the classical phenotype of the disease. 63.6% of the patients had the S252W mutation while 36.4% had the P253R mutation. Discussion. Of all patients enrolled in this study it is notwworthy that some of them had short stature, while others had mental retardation or global development delay. Mutational frequencies for S252W and P253R did not show difference according to what has been reported worldwide. Although there is no data about the incidence of this disease locally, this study could be a first approach to its epidemiology in Colombia.

Craniosynostosis genetics: The mystery unfolds.

Craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity. Sagittal synostosis is common form of isolated craniosynostosis. The sutures involved, the shape of the skull and associated malformations give a clue to the specific diagnosis. Crouzon syndrome is one of the most common of the craniosynostosis syndromes. Apert syndrome accounts for 4.5% of all craniosynostoses and is one of the most serious of these syndromes. Most syndromic craniosynostosis require multidisciplinary management. The following review provides a brief appraisal of the various genes involved in craniosynostosis syndromes, and an approach to diagnosis and genetic counseling.

Síndrome de Apert, una aproximación para un diagnóstico clínico. Reporte de caso / Apert syndrome, an approach to a clinical diagnosis. Case report

Introducción: El síndrome de Apert, o acrocefalosindactilia tipo I, es un síndrome caracterizado por craneosinostosis, acompañada de sindactilia simétrica en las cuatro extremidades, alteraciones maxilofaciales, cutáneas y retardo mental variable. Este síndrome se debe a una mutación en el gen del receptor 2 del factor del crecimiento fibroblástico (FGFR2), el cual se expresa de manera autosómica dominante (AD) Caso clínico: Se presenta caso de recién nacido femenino, de 36 semanas de edad gesta-cional, con las características fenotípicas clásicas de este síndrome como la acrocefalia y la sindactilia en manos y pies. Discusión: El síndrome de Apert hace parte de lo que hoy se denomina un espectro de enfermedades causadas por la mutación en el gen FGFR2 que se caracterizan por anormalidades en el cráneo y las extremidades. Este gen es necesario para la osificación normal y también está implicado en la diferenciación neural. Sus mutaciones producen un receptor anormal que funciona aun sin la unión de su ligando "ganancia de función", lo que se traduce en una osificación temprana de los huesos, en grados variables, dependiendo del sitio exacto de la mutación.

Introduction: Apert's syndrome or acrocefalosindactyly tipe I, is a syndrome characterized by craniosynostosis, symmetric syndactylia in hands and feet's, maxillofacial and cutaneous disorders, and variable mental retardation. This syndrome is due to a mutation in the gene that encode the fibroblast growth factor Receptor 2 (FGFR2), which has an autosomal dominant inheritance (AD). Case report: We report a female newborn of 36 weeks gestational age, with the classical phenotypic characteristics of this syndrome, as acrocefalia and syndactyly of hands and feet. Discussion: Apert's syndrome is part of what today is called a spectrum of disease caused by a mutation in the FGFR2 gene, which is characterized by abnormalities in the skull and extremities. This gene is required for normal ossification and is also involved in neural differentiation. Mutations cause an abnormal receptor that functions even without the binding of its ligand "gain of function", which translates into an early ossification of the bones, in varying degrees, depending on the exact site of the mutation.

Cutis Verticis Gyrata and Alopecia Areata: A Synchronous Coincidence?

Cutis verticis gyrata (CVG) is a descriptive term for a scalp condition that is convoluted folds and deep furrows that resemble the surface of the cerebral cortex. It is categorized by the underlying etiology, as primary essential, primary non-essential and secondary. Alopecia areata (AA) is a common, organ specific autoimmune disease, and most AA cases are sporadic. There is clearly a strong genetic component. There is no established relationship between CVG and AA. We report one case which was affected with essential primary CVG and alopecia areata, and suggest a possibility of genetic association between CVG and AA, possibly both being related to mutations in the fibroblast growth factor receptor 2 (FGFR2).

A Case of Apert Syndrome with a P253R Mutation on FGFR2 Exon VIII

Apert syndrome is a rare congenital anomaly characterized by craniofacial malformations and severe symmetrical syndactyly of fingers and toes. This syndrome is caused by a genetic mutation; the S253 mutation is common, though the P253R mutation is not as frequent. Common symptoms include skeletal malformations, poor joint mobility, eye and ear problems, cleft palate, and orthodontic and other dental problems. We report a case of an infant with the common morphological features of Apert syndrome. Interestingly, she was found to have the P253R mutation in FGFR2 exon VIII, which has been less commonly observed in Korea. A brief review of the literature is included.

The expression and clinical significance of FGFR2, and c-Cbl in gastric carcinoma / 中国癌症杂志

Background and purpose: FGFR2 is a receptor tyrosine kinase and c-Cbl is a new RING finger type of ubiquitin ligase in the ubiquitin-proteasomes path. The purpose of this study was to evaluate the expression and significance of FGFR2 and c-Cbl in gastric carcinoma. Methods: The expression of FGFR2 and c-Cbl were detected by immunohistochemical method of SP. Results: The positive expression rates of FGFR2 and c-Cbl were 77.4%,71.0% in gastric carcinoma, respectively, both were higher than those normal tissue (P<0.05);The expression of FGFR2 and c-Cbl were positively correlated with depth of invasion and TNM staging, and there was a positive relationship between the expressions of FGFR2 and c-Cbl. Conclusion. The expressions of FGFR2 and c-Cbi were associated with some clinicopathologic features in gastric carcinoma, indicating that their expression may be the prognostic factors for gastric carcinoma.