Johns Hopkins Epidemiology of Cranio

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EPIDEMIOLOGY AND GENETICS OF CRANIOSYNOSTOSIS

The final shape of the mammalian skull is achieved through coordinated growth of the calvarial bones. These bones and the sites where their adjacent edges articulate are known as cranial sutures (Sadler, 1990; Cohen, 1993). These sutures are open during the prenatal and early postnatal developmental periods, which allows passage through the birth canal and accommodation of the rapidly growing brain. Early fusion of the sutures leads to significant functional and cosmetic defects. Craniosynostosis refers to abnormal shape of the skull as a result of premature closure of the cranial sutures. The particular defect depends on which of the sutures are closed (sagittal, coronal, metopic, lambdoidal or squamosal) and the amount of compensatory growth across the sutures that remain open. Craniosynostosis may occur prenatally or postnatally and may involve single suture, partially or completely, or multiple sutures. The earlier the onset the more severe the consequences are in both cosmetic and functional aspects. It is well known the human craniosynostosis is heterogeneous condition, both in its etiology and pathogenesis (Jabs, 1998). Several causative mechanisms are known: defects in mesenchymal blastema, premature maturation of the osseous matrix, or absence of growth across the suture. Craniosynostosis may occur as a primary defect or may be secondary to metabolic diseases (hyperthyroidism), maternal factors (uterine abnormalities), teratogenic exposure (valproic and retinoic acids) or other congenital defects (neural tube defects, hydrocephalus).

At least 100 syndromes with craniosynostosis are known, and more than half of them follows Mendelian patterns of inheritance (Cohen, 1993; 1997). Both autosomal dominant and recessive inheritance with significant interfamilial and intrafamilial phenotypic variability have been observed. Chromosome abnormalities involving more than 15 autosomes, as well as sex chromosomes are found in patients with craniosynostosis. Sagittal craniosynostosis is present in slightly over 50% of patients with non-syndromic craniosynostosis and male predominance occurs in this group (Cohen, 1986). Next most common defect is coronal craniosynostosis which represents up to 29% of the cases with 60-75% of affected being females. Metopic suture accounts for less than 10%, and the other sutures are affected even less common. Synostosis of one lambdoidal suture produces bulging of the forehead on the opposite side known as "compensational frontal plagiocephaly" (Brueton and Mulliken, 1992). Difficulties in precise classification of this malformation occur because of atypical defects, when the suture is open, but there is no growth across it, i.e. "functional" craniosynostosis. Radiologic and computerized tomographic data is helpful in distinguishing "true" from "functional" craniosynostosis.

Few epidemiologic studies of craniosynostosis have been performed. Reported incidence varies from 3-5 per 10,000 (Cohen, 1986) to as high as 10 per 10,000 (French et al., 1990). These discrepancies may be due to different methods of ascertainment, i.e., surgical (Lammer et al., 1997) vs. medical cases, or may result from different diagnostic criteria used to differentiate between isolated and syndromic cases. Prospective analysis of 29,235 births in a single hospital identified 18 cases over an 8 year period, yielding a birth prevalence of 6 per 10,000 for isolated non-syndromic cases (Shuper et al., 1985). Epidemiologic study conducted in Western Australia between 1980-1994 documented prevalence of 5.02 per 10,000 births (Singer et al., 1999).

Few risk factors and no consistent associations between unrelated medical conditions or pregnancy complications and craniosynostosis have been identified in these epidemiologic studies (Hunter and Rudd, 1976; 1977; Shuper et al., 1985). Singer et al. (1999) identified the following risk factors: male sex, prematurity (<37 weeks gestation), presentation other that vertex, and advanced paternal age (40 years or older) even after correction for known dominant syndromes. A case-control study of Zeiger et al. (1998) found that tobacco smoking during pregnancy increases the risk of non-syndromic sagittal craniosynostosis. Nitrosatable drugs used before or around birth have also been associated with increased risk of sagittal/lambdoidal craniosynostosis, indicating ischemia/reperfusion injury as a possible mechanism (Gardner et al., 1998)

Most commonly non-syndromic craniosynostosis occur sporadically. About 8-10% of coronal synostosis patients have a positive family history of the disorder, but only about 2% of sagittal synostosis present as familial forms (Hunter and Rudd, 1976; 1977; Shuper et al., 1985). However, some of the patients with coronal synostosis may have been misdiagnosed as non-syndromic, due to the extreme variability of some Mendelian syndromes.

Significant progress in understanding the genetic basis of some syndromic forms of craniosynostosis has occurred for the past several years. Mutations in fibroblast growth factor receptors (FGFRs) were found in Crouzon, (MIM 123500), Jackson-Weiss (MIM 123150), Pfeiffer (MIM 101600), Apert (MIM 101200), Beare-Stevenson (MIM 123790), and Saethre-Chotzen (MIM 10100) syndromes (Jabs, 1998; Park et al., 1995; Meyers et al., 1995; Przylepa et al., 1996; Wilkie et al., 1997). These syndromes are genetically heterogeneous. Mutations in more that one member of the FGFR family have been identified in cases of Crouzon and Pfeiffer syndromes. All FGFR mutations are activating on a cellular level and are associated with a significant phenotypic variability. Within a single family, affected members with the same mutation can be diagnosed with either Crouzon or with Pfeiffer syndrome (Rutland et al., 1995). Even an identical FGFR mutation has been found in unrelated patients with Pfeiffer and Apert syndromes (Passos-Bueno et al., 1997). This indicates that craniosynostosis syndromes thought to represent distinct clinical entities may actually be within the same phenotypic spectrum. This project will focus on identification of modifying factors, genetic or environmental, that may account for this variability. Loss of function mutations in TWIST, a basic helix-loop-helix transcription factor have been identified as a genetic cause of Saethre-Chotzen syndrome (Howard et al., 1997; El Ghouzzi et al., 1997). This may indicate that TWIST and FGFRs are involved in the same signaling pathway, a hypothesis supported by the findings that Drosophila twist gene regulates the expression of DFR1, which is the homologue of the human FGFR (Shishido et al., 1993). Craniosynostosis, Boston type, another autosomal dominant craniosynostosis syndrome, has been found to have a gain of function mutation in a homeobox gene, MSX2 (Jabs et al., 1993).

The genetic bases for some forms of non-syndromic craniosynostosis have been elucidated. The higher sibling recurrence risk observed in non-syndromic coronal craniosynostosis (Hunter and Rudd, 1997; Lajeunie et al., 1995) suggest that there is a greater genetic component to coronal than to sagittal synostosis. A group of patients with presumable non-syndromic coronal craniosynostosis, were screened for a mutation in the gene for FGFR3 Pro250Arg (749CG) (Moloney et al., l997). Thirty-one percent (eight probands) were found to be heterozygous for this mutation. In two cases, the mutation showed autosomal dominant transmission with evidence of variable expressivity; the remaining six cases were sporadic. By statistical analysis these authors demonstrate that this mutation may account for up to 52% of all cases. Their interpretation is that this mutation is a common cause of non-syndromic craniosynostosis. Therefore, it is likely that other mutations or polymorphisms in genes known to be involved in syndromic craniosynostosis and other genes involved in normal calvarial sutural development will account for the genetic basis for non-syndromic craniosynostosis.

Simeon Boyadjiev Boyd, MD

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