Crouzon syndrome is a rare autosomal dominant genetic disorder, which causes the premature fusion of the cranial suture. Fibroblast growth factor receptor 2 (FGFR2) mutations are well-known causatives of Crouzon syndrome. The current study aimed to assess the FGFR2 gene associated with Crouzon syndrome in a Vietnamese family of three generations and to characterize their associated clinical features. The family included in the present study underwent complete clinical examination. A patient was clinically examined and presented with typical features of Crouzon syndrome including craniosynostosis, shallow orbits, ocular proptosis and midface hypoplasia. However the patient had normal hands and feet, a normal hearing ability and normal intelligence. Genomic DNA collected from all family members (except from a 16 week-old-foetus) and 200 unrelated control subjects from the same population was extracted from leukocytes obtained from peripheral blood samples. Genomic DNA was extracted from the 16-week-old foetus via the amniotic fluid of the mother. All coding sequences of FGFR2 were amplified via polymerase chain reaction and directly sequenced. A heterozygous FGFR2 missense mutation (c.1012G>C, p.G338R) in exon 10 was identified in the patient with Crouzon but not in other family members, the 16 week-old-foetus or the controls. This mutation was therefore determined to be the causative agent of Crouzon syndrome. In addition, a novel heterozygous silent mutation (c.1164C>T, p.I388I) in exon 11 of the FGFR2 gene was identified in the patient with Crouzon, his mother and the 16-week-old fetus, but not in other family members. The mutation in exon 10 of FGRF2 was confirmed via restriction-enzyme digestion. The gain of the BsoBI site confirmed the FGFR2 mutation in exon 10 of the patient with Crouzon. This molecular finding may provide useful information to aid clinicians in the diagnosis of Crouzon syndrome and may also aid early prenatal diagnoses.

Background: Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia that is characterized by variable degrees of epiphyseal abnormality primarily involving the hip and knee joints. Mutations in a gene encoding matrilin-3 (MATN3) have been reported as disease causing of autosomal dominant MED. The current study identified a novel c.572 C > A variant (p.A191D) in exon 2 of MATN3 in a Vietnamese family with MED. Case presentation: A standard clinical tests and radiological examination were performed in an 8-year-old Vietnamese girl patient. The clinical examination showed that patient height was under average, with bent lower limbs, limited mobility and dislocation of the joints at both knees. Radiological documentation revealed abnormal cartilage development at the epiphysis of the femur and patella. The patient has a varus deformity of the lower limbs. The patient was diagnosed with autosomal dominant MED using molecular testing in the order of the coding sequences and flanking sequences of five genes: COMP (exons 8-19), MATN3 (exon 2), COL9A2 (exon 3), COL9A3 (exon 3), COL9A1 (exon 8) by Sanger sequencing. A novel heterozygous missense variant (c.572 C > A, p.A191D) in MATN3 was identified in this family, which were not inherited from parents. The p.A191D was predicted and classified as a pathogenic variant. When the two predicted structures of the wild type and mutant matrilin-3 were compared, the p.A191D substitution caused conformational changes near the substitution site, resulting in deformity of the β-sheet of the single A domain of matrilin-3. Conclusions: This is the first Vietnamese MED family attributed to p.A191D matrilin-3 variant, and our clinical, radiological and molecular data suggest that the novel de novo missense variant in MATN3 contributed to MED.