Craniosynostoses: Genetic Considerations
by Beth A. Pletcher, MD, May 1999

Craniosynostoses represent a heterogeneous group of disorders with both sporadic and syndromic occurrences as well as single and multiple sutural involvement. While the precise cause of premature fusion of cranial sutures has not been elucidated it is clear that, in many of the syndromic craniosynostoses, fibroblast growth factor receptor (FGFR) genes are in some way involved in the pathogenesis. About 1 in 3000 infants are noted to have craniosynostosis although the actual numbers may be a bit higher because some subtle (and not so subtle) sutural alterations and cranial asymmetries may be missed on clinical examination. Sagittal synostosis is most commonly diagnosed and represents over 50% of the synostoses. This type of synostosis results in a dolicocephalic head shape (football configuration) and for unknown reason occurs much more often in males than females. About 2% of sagittal synostoses are felt to be familial. Coronal synostosis, on the other hand affects females a little more often than males and represents 1/5 to 1/3 of the cases of synostosis. Bilateral coronal synostosis results in a brachycephalic head shape (basketball configuration) and about 8% of these are felt to be familial. Less common forms of synostosis involve the metopic suture, lambdoid suture or even combinations of sutures. In familial, non-syndromic craniosynostosis, autosomal dominant inheritance is most likely and bilateral coronal suture synostosis increases one's concern about a possible familial form.

In addition to simple synostosis, there are over 75 syndromes described where craniosynostosis is a feature. When craniosynostosis occurs in the context of growth retardation, multiple congenital anomalies and/or mental retardation, one should always consider a cytogenetic cause. For example, metopic suture synostosis is quite common in deletion 9p which is also associated with dysmorphic facial features and developmental delay. A cloverleaf cranial deformity is a severe defect resulting in a trilobular head shape and is seen in both thanatophoric dysplasia and two subtypes of Pfeiffer syndrome.

From a diagnostic standpoint there are several areas of investigation that may be helpful when a child presents with cranial asymmetry or abnormal head shape. Examination should include palpation of the cranium for obvious ridging and scrutiny for limb, ear or cardiac defects since these are the most often associated additional findings. A complete family history should be taken asking specific questions about individuals with an unusual head shape, proptosis, midface flattening, nasal depression or deviation as well as broad thumbs or toes. Family photos may also prove helpful when looking for subtle craniofacial changes in less affected family members. Diagnostic testing might include plain skull films to examine sutural fusion and, in some cases, CT or even 3D CT may be employed to clarify the presence or absence of fusion and extent of the cranial deformity including alterations in the base of the skull.

Recent advances in molecular genetics have greatly expanded our understanding of some of the more well known syndromic craniofacial syndromes. While in the past patients have been categorized by clinical features alone, the discovery of several "craniofacial genes" in recent years has forced clinicians to rethink their diagnostic approach. It has been shown that mutations (genetic typos) within the same gene can result in several different craniofacial syndromes. Furthermore, mutations in different genes can also result in the same collection of clinical features and identical diagnoses. In order to put this in perspective, it may be useful to review some of the more common craniofacial disorders and their clinical descriptions.

• Crouzon syndrome is the prototype of craniosynostoses and usually involves variable degrees of bilateral coronal synostosis resulting in ocular proptosis, frontal bossing, maxillary hypoplasia and conductive hearing loss. Proptosis can lead in some cases to exposure keratitis, conjunctivitis, divergent strabismus or even optic nerve atrophy. Unlike most other similar syndromes, individuals with Crouzon syndrome do not generally have any hand, feet, finger or toe findings. About 3/4 of affected individuals are noted to have an affected parent.

• Pfeiffer syndrome is described as an acrocephalosyndactyly which includes mild cutaneous syndactyly as well as broad thumbs and broad great toes. The classic (type 1) form of Pfeiffer syndrome is associated with coronal synostosis with or without sagittal suture synostosis. Facially these patients often have a high forehead, hypertelorism, depressed nasal bridge and narrow palate. Types 2 and 3 are much more severe and present with a cloverleaf (Kleeblattschadel anomaly), significant proptosis and a variety of other anomalies resulting in poor survival. Type 1 patients may or may not be found to have an affected parent whereas all type 2 and 3 patients represent new dominant mutations.

• Apert syndrome is the craniosynostosis syndrome most associated with variable and often significant degrees of syndactyly. Sutural involvement with this condition may be irregular, but frequently involves the coronal sutures. Clinical features often found include: shallow orbits, strabismus, hypertelorism, down-slanting palpebrae, high/narrow palate as well as partial or complete, osseous or cutaneous, finger and/or toe syndactyly. Unlike the other syndromes, mental retardation is more common in Apert syndrome and a variety of intracranial anomalies have been reported as well as cleft palate and C5-C6 vertebral fusion. Most cases of Apert syndrome represent new dominant mutations.

• Saethre-Chotzen syndrome is probably one of the most variable of the craniosynostosis disorders and can include fusion of any combination of coronal, lambdoid or metopic sutures. In addition to the familiar features of a high forehead, maxillary hypoplasia and a narrow palate, these individuals frequently have facial asymmetry, ptosis, lacrimal duct abnormalities and an unusual finding described as a prominent ear crus. Mild cutaneous syndactyly of the second and third finger and/or third and fourth toes is not uncommon as are broad great toes with valgus deviation or finger-like thumbs.

• Jackson-Weiss syndrome is a more recently described and often under recognized craniosynostosis syndrome associated with specific hand and foot findings including some well described radiographic changes in the feet. There appears to be great variability in this condition as well with some unaffected obligate carriers identified in a number of families. In addition to the sutural synostosis, the unique radiographic and clinical findings in the feet include: a short/broad first metatarsal, abnormally shaped tarsal bone and calcaneocuboid fusion. Many individuals now recognized to have Jackson-Weiss syndrome had previously been suspected to have Saethre-Chotzen or Pfeiffer syndromes.

Although there are many other craniofacial syndromes, those listed above are the most commonly diagnosed and most genetically well-defined. Below is a table outlining the recent molecular discoveries that are expanding our understanding of these conditions that impact cranial growth.

In light of these incredible advances in the molecular characterization of these and other craniofacial disorders, we are now at a point where many patients can be identified to have a specific gene mutation rather than a particular syndrome. Research into the molecular causes of craniofacial disorders has helped us to understand why there is significant clinical overlap with these conditions and could potentially lead to a more complete understanding of the pathogenesis of disorders of bone growth. This will not only impact our understanding of conditions involving the head and face, but could also shed light on a number of skeletal dysplasias with more widespread abnormalities of bone growth. Already mutations in the FGFR3 gene have been linked to achondroplasia/hypochondroplasia and thanatophoric dysplasia. While these discoveries in the past few years have been truly exciting, this is surely just the beginning of a long and fruitful journey.