Competencias, facultades y coordinación entre la

Craniosynostosis was the term introduced by Rudolf Virchow in 1851 to describe the premature fusion of the calvarial bones (Virchow, 1851). In 1791, Sommering had previously observed that skull growth occurred along calvarial sutures and that failure of growth at a particular suture resulted in cranial deformity, although without naming the condition (Delashaw et al. 1989; Sommering, 1839). Technically speaking, craniosynostosis is the process of premature sutural fusion and craniostenosis the effect, although the former term is now used to describe both processes.

To date, more than 100 causally related syndromic forms of craniosynostosis have been identified and still more which are non-syndromic combining in an incidence of approximately 1 in 2500 births; in 10-20% of these cases there is evidence of Mendelian inheritance (Cohen Jr, 1993; Hockley, 1993; Reardon and Winter, 1995). The causes of craniosynostosis are numerous, ranging from monogenic disorders to metabolic diseases and hence the pathology of the disease is highly heterogeneous (Table 1.4). Although it is caused mainly by primary congenital disorders it can also be secondary to inadequate brain growth

as in microcephaly or appear after shunt operations for hydrocephalus (Cohen Jr, 1993; Hockley, 1993). Teratogenic exposure during pregnancy is known to cause craniosynostosis in humans with substances such as retinoic acid, aminopterin and phenytoin identified as key teratogens (Cohen Jr, 1993;

Hockley, 1993). Animal models of craniosynostosis have been produced by an excess dose of vitamins A and D, and ethanol administration maternally

(Hockley, 1993).

CAUSES EXAMPLES

Monogenic Conditions Syndromic - Crouzon, Pfeiffer, Isolated Craniosynostoses Chromosomal Disorders del (Iq), dup (3q), del (7p), dup (7p),

triploidy, tetrasomy 14q Metabolic Disorders Hyperthyroidism, Rickets Mucopolysaccharidoses Mucolipidosis III

Haematological Disorders Thalassaemias, Sickle Cell Anaemia, Congenital Haemolytic Icterus,

Polycythemia Vera.

Teratogens Aminopterin, Diphenylhydantoin, Retinoic Acid, Valproic Acid Malformations Microcephaly, Encephalocele,

Holoprosencephaly

Table 1.4 Known Causes of Craniosynostosis

Adapted from Cohen Jr (1993)

It was originally thought that calvarial sutures did not play a major role in the determination of skull shape (Cohen Jr, 1993; Delashaw et al. 1989; Moss,

1959). Instead it was suggested by Moss that the deformation of the cranial base is the primary cause of craniofacial abnormalities resulting in secondary fusion of the cranial sutures. The evidence for this line of thought was based on several observations. First, cranial vault abnormalities can occur in the absence of a fused suture and second, skull growth in the rat is unaffected by removal of a

cranial vault suture. In addition, cranial base abnormalities have been associated with craniosynostoses particularly in patients with sagittal or bicoronal

synostosis (Cohen Jr, 1993; Delashaw et al. 1989; Moss, 1959; Persing et al. 1991). This theory held great weight for several years until a number of

experimental studies disproved it. Albright and Byrd concluded in a histological survey of craniosynostotic sutures that in sagittal craniosynostosis, skull base changes are secondary to the fusion along the sagittal suture (Albright and Byrd,

1981). In addition, there are many documented cases where familial, isolated, non-syndromic craniosynostoses have been observed (Cohen Jr, 1993; Cohen,

1977). In some families the degree of fusion in individuals is variable and it is difficult to explain why dramatically different abnormalities of the cranial base are seen in the same family as a dominant trait. Obviously a different mechanism must be operating in such cases.

As the pathogenesis of the craniosynostosis is so variable, even within the same syndrome, the extent to which the skull is deformed and associated problems arise must be individually assessed. Generally speaking, however, the severity of the skull deformity rises with an increase in the number of sutures prematurely synostosed. Early synostosis invariably results in raised intracranial pressure as the growing brain puts pressure on the fixed skull and there is some evidence that chronic raised intracranial pressure may result in mental retardation.

Hydrocephalus is common in cases where more than one suture has closed and usually presents within 5 years of birth. Blindness may result if papilloedema caused by optic atrophy is not detected quickly. Many of the syndromes which have been identified exhibit additional deformities particularly involving the digits and facial region with the latter often resulting in airway obstruction. These patients present significant problems to clinicians despite important advances in surgical techniques over the past 20 years (Wilkie, 1997).

The most common craniosynostosis syndromes are Apert (incidence 1 in 10,000), Crouzon (1 in 60,000); Pfeiffer and Saethre-Chotzen (incidence unknown) and Jackson-Weiss (1 in 26,000). Achondroplasia (1 in 26,000) and Thanatophoric Dysplasia (1 in 20,000) are skeletal dysplasias but are included because of their close relationship with craniosynostoses, a point which will be discussed later.

Apert, Crouzon, Pfeiffer, Saethre Chotzen and Jackson-Weiss syndromes are primarily inherited in an autosomal dominant pattern with sporadic cases

appearing from novel mutations. A number of features are shared between these syndromes as summarised in Table 1.5; a tower shaped skull, widely spaced protruding eyes, a hooked nose and underdeveloped midface are characteristic of these craniosynostoses (Muenke and Schell, 1995; Reardon and Winter, 1995). However, although these dominant conditions are fully penetrant, the degree to which the features are expressed remains highly variable (Lewanda et al. 1994) and consequently it is often the case that clinical diagnoses are made on the basis of hand and foot malformations.

Apert syndrome sufferers present with severe syndactyly (cutaneous and bony fusion of the digits) whilst the facial features show some similarity in Crouzon syndrome but the digits remain unaffected (Hockley, 1993; Wilkie et al. 1995). Pfeiffer syndrome is distinguished from other craniosynostoses by broad thumbs and great toes whereas the lack of hand abnormalities is diagnostic of Jackson- Weiss patients (Muenke and Schell, 1995; Reardon and Winter, 1995). Indeed, the true birth prevalence of the craniosynostoses is probably much higher as patients who are mildly affected may never come to medical attention (Lewanda et al. 1994).

Phenotype HCH ACH TD PS AS JWS CS

Short limb dwarfism + + + - - - -

Cloverleaf skull - - + + - - - Underdeveloped midface - + + + + + + Craniosynostosis - - - + + + + Foot anomalies - - - + + + - Hand anomalies - - - + + - -

Table 1.5 Phenotypes in skeletal disorders

HCH, hypochondroplasia; ACH, achondroplasia; TD, thanatophoric dysplasia; PS, Pfeiffer syndrome; AS, Apert syndrome; JWS, Jackson-Weiss syndrome; CS, Crouzon syndrome. Adapted from Muenke and Schell (1995).

In 1994, the first report emerged linking mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) with Crouzon syndrome (Reardon et al. 1994).

Subsequently, six of the major craniosynostosis syndromes

(Apert, Beare Stevenson, Crouzon, Jackson-Weiss, Muenke and Pfeiffer) have now been associated with mutations in FGFR 1, 2 and 2 (reviewed Burke et al.

1998; Muenke and Schell, 1995; Wilkie, 1997).