Craniosynostosis and cancer

Related conditions: Craniofacial syndromes

Definition: Craniosynostosis is a process resulting in premature closure or fusion of the cranial sutures. The most common site is the sagittal suture, followed by the coronal, lambdoidal, and metopic. This condition results in an abnormally shaped skull and occurs with a male-to-female ratio of 3:1. Approximately 10 percent are familial, resulting from an autosomal dominant inheritance. Other cases are the result of chromosome deletions, duplications, translocations, breaks, missense, or splice-site abnormalities. Prenatal head constraint is hypothesized as a causative factor in some cases. In utero human development proceeds in a normal fashion, with abnormalities becoming apparent at birth or shortly thereafter. The phenotypic presentation is variable. More than one hundred syndromes have been associated with craniosynostosis.

Risk factors: Primary cases of craniosynostosis, in the majority of cases, is the result of spontaneous genetic mutations, although it can also be transmitted genetically from a parent. Children with microcephaly (poor brain growth) are at risk of developing craniosynostosis. Normal brain growth pushes the cranial bones apart at the sutures, but with impaired brain growth, sutures may prematurely fuse.

Etiology and the disease process: Mutations in fibroblast growth factor receptor (FGFR1, FGFR2, FGFR3), TWIST, and MSX2 genes are associated with craniosynostosis development. Fibroblast growth factor receptors affect animal growth, development, and homeostasis. They regulate cell growth, differentiation, migration, and survival. They exert direct influence on the formation of various tissues, organs, and blood vessels and are responsible for wound healing. FGFR mutations are directly associated with specific growth and development abnormalities, including the inability to control cell growth leading to tumor formation.

Currently, four FGFR mutations have been identified. These mutations produce a variety of results. Germline mutations cause skeletal dysplasia (hypochondroplasia, achondroplasia) and craniosynostosis syndromes (Apert, Beare-Stevenson, Crouzon, Pfeiffer, Jackson-Weiss), while somatic mutations cause a variety of cancers.

Oncogenes and tumor-suppressor genes are located near recombination sites on chromosomes. Thus, when breaks, translocations, deletions, and amplifications occur in these regions, tumor-suppressor genes can be excluded or oncogenes can be amplified. These processes lead to the development of various cancers. FGFR mutations have been identified in endometrial, breast, gastric, colorectal, bladder (urothelial), cervical, endometrial, and glial tumors and multiple myeloma. In addition, FGFR mutations are implicated in the formation of benign skin lesions such as epidermal nevi and seborrheic keratoses.

Saethre-Chotzen syndrome, an autosomal dominantly inherited form of craniosynostosis, is caused by the mutation of the transcription factor gene TWIST1. The protein encoded by this gene is a transcription factor that regulates metastasis and is overexpressed in Saethre-Chotzen syndrome. This abnormality is highly associated with early breast cancer development.

An autosomal dominant MSX2 defect has been identified as the causative agent in Boston-type craniosynostosis.

Incidence: Craniosynostosis occurs in 1 in 3,000 live births. The association with different syndromes varies from 1 in 25,000 to 1 in 150,000.

Symptoms: Normally, bone growth in the skull occurs at its edges, where the initial skull bones are approximated by fibrous connective tissue. When premature fusion of approximated skull bones occurs, the skull assumes an abnormal shape. Palpation of the sutures, fontanels, and skull bones; measurement of the skull circumference; and observation of the skull shape are performed by the care provider during a physical examination of the individual. Premature suture closure may result in additional symptoms, such as increased intracranial pressure and developmental delay. The individual may exhibit bulging eyes, wide-spaced eyes, a beaked nose, low-set ears, and a small jaw. Certain syndromes may also be associated with hand and limb abnormalities.

Screening and diagnosis: Detection is through physical examination and radiographic techniques including X rays and three-dimensional computed tomography (CT) scans. A CT scan not only can detect suture fusion but also can evaluate the brain for underlying structural abnormalities, thereby assisting the surgeon in planning corrective surgery.

Individuals with craniosynostosis are at risk for having an associated syndrome and for developing various cancers. Because of the high incidence of chromosomal defects, duplications, deletions, and substitutions associated with craniosynostosis, affected individuals are candidates for genetic counseling and chromosomal analysis. In addition to the underlying chromosomal issues, research suggests that undergoing multiple CT scans at a young age also increases the risk of cancer for people with craniosynostosis. Early and consistent screening for cancer leads to diagnosis and treatment in earlier stages of the disease, making a cure more possible.

Treatment and therapy: Surgery is performed to reopen closed sutures and provide a more normal-appearing skull. An open surgical technique is used with multiple suture fusions or if the surgery is performed after the first year of life. This method involves an ear-to-ear incision, removing, reshaping, replacing, and securing the affected bones. For a single fused suture or if surgery is done in the first few months of life, surgical instruments called endoscopes are inserted through small scalp incisions, and small pieces of bone are removed, releasing the suture fusion. These patients then wear a custom-molded helmet for several months. The helmet provides a template for normal skull growth and shape. For other cosmetic issues, the individual may require orthodontic and orthognathic (jaw) surgery to restore normal facial features.

Prognosis, prevention, and outcomes: The prognosis for craniosynostosis is good and improves with early detection and treatment. The morbidity and mortality depend on associated defects as part of a syndrome. Currently, there is no method to prevent autosomal dominant transmission to offspring or to prevent new mutations.

FGFR mutations produce a variety of results. Research is necessary to determine how mutations result in different consequences. If it can be determined how mutations affect outcomes, definitive targeted therapies can be developed. One such proposal is anti-FGFR therapy, designed to target the upregulated FGFR genes. Because of the associated risk for a variety of cancers, the individual will require ongoing evaluation and screening for carcinogenesis.

Bibliography

Cohen, M. Michael. “Malformations of the Craniofacial Region: Evolutionary, Embryonic, Genetic, and Clinical Perspectives. American Journal of Medical Genetics 115 (2002):245–68.

Coumoul, Xavier, and Chu-Xia Deng. “Roles of FGF Receptors in Mammalian Development and Congenital Diseases.” Birth Defects Research 69 (2003): 286–304.

Hansen, Ruth, et al. “Fibroblast Growth Factor Receptor 2, Gain-of-Function Mutations, and Tumourigenesis: Investigating a Potential Link.” Journal of Pathology 207 (2005): 27–31.

Matthews, David J., and Mary E. Gerritsen. Targeting Protein Kinases for Cancer Therapy. Hoboken: Wiley, 2010. Print.

Muenke, Maximilian, Wolfram Kress, Hartmut Collmann, and Benjamin Solomon. Craniosynostoses: Molecular Genetics, Principles of Diagnosis and Treatment. Basel: Karger, 2011. Print.

Ridgway, E. B. “Skull Deformities.” Pediatric Clinics of North America 5.2 (2004): 359–87.

Schweitzer, T., et al. “Avoiding CT Scans in Children with Single-Suture Craniosynostosis.” Child's Nervous System 28.7 (2012): 1077–082. Print.