Facial skeleton dysmorphology in syndromic craniosynostosis: differences between FGFR2 and no-FGFR2-related syndromes and relationship with skull base and facial sutural patterns.

PURPOSE: To assess the role of FGFR2 mutations and sutural synostotic patterns on facial skeleton dysmorphology in children with syndromic craniosynostosis. METHODS: Preoperative high-resolution CT images in 39 infants with syndromic craniosynostosis were evaluated. Patients were divided into infants with and without FGFR2 mutations; each group was split according to synostotic involvement of minor sutures/synchondroses: isolated or combined involvement of middle (MCF) and posterior cranial fossae (PCF). Quantitative analysis of the midface and mandible measures was performed. Each subgroup was compared with a group of age-matched healthy subjects. RESULTS: Twenty-four patients with FGFR2 related syndromes were clustered in 3 subgroups: MCF + PCF (8 patients, 5.4 ± 1.75 months), MCF (8 patients, 3.62 ± 1.68 months), and PCF (8 patients, 2.75 ± 0.46 months). Fifteen no-FGFR2 patients were clustered in 2 subgroups: MCF + PCF (7 patients, 9.42 ± 0.78 months) and PCF (8 patients, 7.37 ± 2.92 months). Both FGFR2 and no-FGFR2 groups with involvement of minor sutures coursing in MCF showed more facial sutural synostoses. Children with minor suture/synchondrosis synostosis of MCF (MCF-PCF and MCF subgroups) showed altered position of glenoid fossa and mandibular inclination ([Formula: see text]), but children in the FGFR2 group had also reduced midfacial depth and maxillary length ([Formula: see text]). Children with minor suture/synchondrosis synostosis of PCF (PCF subgroups) had reduced posterior mandibular height, but those children in the FGFR2 group also showed reduced intergonion distance ([Formula: see text]). CONCLUSIONS: In children with syndromic craniosynostosis, both skull base and facial suture synostosis affect facial dysmorphology/hypoplasia. FGFR2 mutations may worsen facial hypoplasia both acting on bone development and causing an earlier premature closure of facial sutures.

Exceptional Response to Erdafitinib in FGFR2-Mutated Metastatic Pancreatic Ductal Adenocarcinoma.

Despite advances in cancer therapeutics, pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, with a poor prognosis at time of diagnosis. Research in PDAC has suggested that adaptive signaling in the tumor microenvironment may promote tumor proliferation and survival. Several FGFR fusion genes-specifically FGFR2-are involved with the creation and progression of cancer. These mutations are found in a variety of cancer types. This report presents a unique case of a young patient with stage IV PDAC with a known FGFR2 fusion. This molecular alteration afforded a remarkable response to FGFR inhibitor therapy, erdafitinib, after the patient experienced disease progression on multiple chemotherapy regimens.

Molecular characterization of fast-growing melanomas.

BACKGROUND: The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM) and the potential to stratify patients at high risk of death has not been comprehensively studied. OBJECTIVE: To investigate the epidemiologic, clinical, and mutational profile of primary cutaneous melanomas with a thickness ≥ 1 mm, stratified by rate of growth. METHODS: Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin-embedded primary melanoma samples. Comparison of FGMM (rate of growth > 0.5 mm/month) and nonFGMM (rate of growth ≤ 0.5 mm/month). RESULTS: Two hundred patients were enrolled, among wom 70 had FGMM. The relapse-free survival was lower in the FGMM group (P = .014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than nonFGMM (P = .033). Ulceration (P = .032), thickness (P = .006), lower sun exposure (P = .049), and fibroblast growth factor receptor 2 (FGFR2) mutations (P = .037) were significantly associated with fast growth. LIMITATIONS: Single-center study, cohort size, potential memory bias, number of investigated genes. CONCLUSION: Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness, and FGFR2 mutations are associated with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM, which are probably good candidates for adjuvant therapies.

Derazantinib: an investigational drug for the treatment of cholangiocarcinoma.

INTRODUCTION: This review evaluates the clinical role of fibroblast growth factor receptor 2 (FGFR2) inhibition with derazantinib in patients with intrahepatic cholangiocarcinoma (iCCA) harboring actionable oncogenic FGFR2 fusions/rearrangements, mutations and amplifications. FGFR inhibitors such as derazantinib are currently being evaluated to address the unmet medical need of patients with previously treated, locally advanced or metastatic iCCA harboring such genetic aberrations. AREAS COVERED: We summarize the pharmacokinetics, and the emerging safety and efficacy data of the investigational FGFR inhibitor derazantinib. We discuss the future directions of this novel therapeutic agent for iCCA. EXPERT OPINION: Derazantinib is a potent FGFR1‒3 kinase inhibitor which also has activity against colony stimulating factor-1‒receptor (CSF1R) and vascular endothelial growfth factor receptor‒2 (VEGFR2), suggesting a potentially differentiated role in the treatment of patients with iCCA. Derazantinib has shown clinically meaningful efficacy with durable objective responses, supporting the therapeutic potential of derazantinib in previously treated patients with iCCA harboring FGFR2 fusions/rearrangements, mutations and amplifications. The clinical safety profile of derazantinib was well manageable and compared favorably to the FGFR inhibitor class, particularly with a low incidence of drug-related hand-foot syndrome, stomatitis, retinal and nail toxicity. These findings support the need for increased molecular profiling of cholangiocarcinoma patients.

FGFR-associated craniosynostosis syndromes and gastrointestinal defects.

Craniosynostosis is a relatively common birth defect characterized by the premature fusion of one or more cranial sutures. Examples of craniosynostosis syndromes include Crouzon (CS), Pfeiffer (PS), and Apert (AS) syndrome, with clinical characteristics such as midface hypoplasia, hypertelorism, and in some cases, limb defects. Mutations in Fibroblast Growth Factor Receptor-2 comprise the majority of known mutations in syndromic forms of craniosynostosis. A number of clinical reports of FGFR-associated craniosynostosis patients and mouse mutants have been linked to gastrointestinal tract (GIT) disorders, leading to the hypothesis of a direct link between FGFR-associated craniosynostosis syndromes and GIT malformations. We conducted an investigation to determine GIT symptoms in a sample of FGFR-associated craniosynostosis syndrome patients and a mouse model of CS containing a mutation (W290R) in Fgfr2. We found that, compared to the general population, the incidence of intestinal/bowel malrotation (IM) was present at a higher level in our sample population of patients with FGFR-associated craniosynostosis syndromes. We also showed that the mouse model of CS had an increased incidence of cecal displacement, suggestive of IM. These findings suggest a direct relationship between FGFR-related craniosynostosis syndromes and GIT malformations. Our study may shed further light on the potential widespread impact FGFR mutations on different developmental systems. Based on reports of GIT malformations in children with craniosynostosis syndromes and substantiation with our animal model, GIT malformations should be considered in any child with an FGFR2-associated craniosynostosis syndrome. © 2016 Wiley Periodicals, Inc.

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.