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.

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.

Síndrome de Saethre-Chotzen: suas alterações dismórficas. Relato de caso / Saethre-Chotzen syndrome: facial dysmorphic features. A case report

Introdução: A síndrome de Saethre-Chotzen é um distúrbio raro de herança autossômica dominante causada por mutações no gene TWIST, localizado no lócus 7p21; os pacientes apresentam defeitos na cabeça (plagiocefalia e assimetría facial) e na parte distal das extremidades, dedos encurtados e ligados pela persistência de uma membrana entre eles (sindactilia). Objetivo: Apresentar um relato de caso da síndrome de Saethre-Chotzen, discutindo as características diagnósticas que diferenciam essa síndrome dos outros tipos de craniossinostoses e o diagnóstico diferencial. Descrição: Estudante de 11 anos apresentando os seguintes sinais clínicos: plagiocefalia decorrente de craniossinostose, acrobraquicefalia, assimetria facial e hemimelia, com ausência da porção distal do antebraço direito. Comentários: Apresentamos um caso ilustrativo da síndrome de Saethre-Chotzen, que constitui a mais frequente das doenças com craniossinostoses e descrevemos as importantes alterações faciais dismórficas da síndrome.

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.

S252W mutation in Indian patients of Apert syndrome.

Two common mutations in the exon IIIa of fibroblast growth factor receptor 2 account for majority of the cases of Apert syndrome. They can be analyzed by amplifying the segment followed by testing for the abolition of restriction sites. We evaluated two children with typical features of Apert syndrome. A segment of FGFR2 exon IIIa was amplified by polymerase chain reaction. Restriction fragment length polymorphism was analyzed using enzymes MboI and BglI respectively for S252W and P253R mutations. The DNA segment was sequenced using ABI 310 automated DNA fragment analyzer. Both the patients showed S252W mutations. DNA sequencing confirmed the results of the restriction fragment length polymorphism. Our study is the first report from Indian subcontinent to show the prevalence of S252W mutation among Apert syndrome patients from Indian origin.

Pfeiffer type acrocephalosyndactyly with hydrocephalus and tracheomalacia

Pfeiffer syndrome is a rare form of acrocephalosyndactyly It is characterized by craniosynostosis involving one or more sutures resulting in abnormal skull shape and facial dysmorphism. Broad medially deviated distal phalanges of thumbs and big toes with soft tissue syndactyly are typical. Various multisystem anomalies have been reported as infrequent associations of this syndrome. A case of an infant with the typical features along with the uncommon associations of hydrocephalus and tracheomalacia is reported. The literature is briefly reviewed for clinical features, classification, genetic basis and management

A case of Pfeiffer syndrome type 1 with an A344P mutation in the FGFR2 gene.

Pfeiffer syndrome, an autosomal dominant disorder, consists of craniosynostosis, broadening of the thumbs and great toes, and partial soft tissue syndactyly of the hands and feet. Three clinical subtypes have been classified mainly for the purpose of genetic counseling. Mutations in FGFR1 and FGFR2 are known to be associated with the syndrome. However, the correlation between genotype and phenotype is not well defined. Only one patient with Pfeiffer syndrome with no other clinical information has been reported to have had an A344P mutation of the FGFR2. Here we report a Thai male patient with sporadic Pfeiffer syndrome type 1 with impaired intelligence (IQ = 77). Mutation analysis revealed A344P in FGFR2. Identification of the clinical features and molecular defects in more patients is required to better correlate the genotype and phenotype of this complex syndrome.