Craniosynostosis

► [Premature closure of one or more cranial sutures with resultant deformity of the skull]

Cranial sutures have a critical role in calvarial morphogenesis, serving as growth centers during skull development. Patent sutures allow changes in the displacement and curvature of the skull bones in response to expansion of the brain (Cohen 1993a). Pre

Human Skull Supraorbital Groove

Fig. 1.3 a-f. Craniosynostosis. a The theoretical model for suture closure and the resultant compensation observed. b Premature closure of the sagittal suture, with predicted com-

cranial deformity. c Premature closure of the metopic suture. d Premature closure of unilateral coronal suture. e Premature closure of unilateral lambdoid suture. f Premature closure of

Fig. 1.3 a-f. Craniosynostosis. a The theoretical model for suture closure and the resultant compensation observed. b Premature closure of the sagittal suture, with predicted com-

cranial deformity. c Premature closure of the metopic suture. d Premature closure of unilateral coronal suture. e Premature closure of unilateral lambdoid suture. f Premature closure of pensation growth in the uninvolved sutures and resultant bilateral lambdoid sutures. (From Alden et al. 1999)

mature sutural fusion leads to abnormal growth patterns, which result in abnormal cranial and facial morphology. The extent and nature of head shape alterations depend on which sutures fuse prematurely and on the amount of compensatory overgrowth that occurs at the edges of the patent sutures. Changes take place in a predictable manner, closure of a given suture producing distinct asymmetry of the head shape (Virchow 1851). Specifically, (a) compensatory growth is greatest in sutures that are contiguous with the stenotic suture; and (b) growth occurs asymmet rically in sutures that are perpendicular to the involved suture, with increased bone deposition directed away from the bone plate, and symmetrically along both sides of a suture that runs parallel to the stenotic suture (Fig. 1.3a-f) (Delashaw et al. 1991; Alden et al. 1999). While compensatory sutural growth can be explained in terms of increased os-teoblastic differentiation and osteogenesis, the question of what abnormal molecular mechanisms underlie premature closure of a cranial suture remains unanswered. The central requirement for mainte nance of suture patency is normal tissue interaction with the underlying dura mater (Opperman et al. 1993). The biochemical nature of such interaction is substantiated by the identification of several soluble dural factors, which either promote or antagonize sutural fusion (Zimmerman et al. 1996). The human NELL-1 gene is preferentially expressed in the mesenchymal cells and osteoblasts at the osteogenic front along the parasutural bone margins and is up-regulated during unilateral premature closure of the coronal suture (Ting et al. 1999). Fibroblast growth factor receptors (FGFRs) 1,2, and 3 are expressed in preosteoblasts and osteoblasts involved in membranous ossification of the skull vault (Delezoide et al. 1998). Gain-of-function mutations in FGFRs are associated with syndromic forms of craniosynostosis (see further discussion) (Cohen 1995; Wilkie 1997). Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites, and skeleton patterning (Brunet et al. 1998) and is expressed postnatally in the sure mesenchyme of patent, but not fusing, cranial sutures (Warren et al. 2003). Since noggin expression is suppressed by FGF2 and syndromic FGFR signaling, it is likely that syndromic FGFR-mediated craniosynostoses result from inappropriate down-regulation of noggin expression (Warren et al. 2003).

The prevalence of craniosynostoses, including syndromic cases, in the general population has been estimated at 34-48 per 100,000 live births (Lajeunie et al. 1995). Males are affected more often than females (M : F ratio 4:1). Apart from the oxycephalic type of craniosynostosis, which is observed predominantly in North Africa and usually appears around 2 years of age, most craniosynostoses are recognizable at birth. The first and most obvious clinical sign is the abnormal shape of the skull. A palpable bony ridge may mark the obliterated suture. Although isolated craniosynostosis has traditionally been considered a benign condition, in which surgery is indicated mainly for cosmetic reasons, increased intracra-nial pressure has been observed in 17% of children with single suture closure (Thompson et al. 1995). Moreover, decreased cerebral blood flow has been reported in the brain of children with simple cran-iosynostosis (David et al. 1996). Premature fusion of multiple cranial sutures, on the other hand, has been consistently associated with increased intracranial pressure and the potential for mental and visual impairment (Renier et al. 2000) (Fig. 1.4). The risk of in-tracranial hypertension is considerably elevated in the syndromic forms of craniosynostosis, varying from 63 % in Crouzon syndrome through 45 % in

Mammary Digital Nail Syndrome
Fig. 1.4. Microcephalic type of craniosynostosis in a 7-year-old girl. Note diminished head size, with shortening of all cranial diameters. All sutures are obliterated. Prominence of the convolutional markings indicates long-standing increased intracranial pressure

Apert syndrome to 29% in the other disorders (Renier et al. 2000). In these patients the risk of mental impairment is related to both the hydrocephalus and the extent and nature of the associated brain malformations.

Craniosynostosis can be classified as primary or secondary. Primary craniosynostosis can occur as an isolated anomaly,either sporadic or familial, or in association with certain syndromes. Secondary cran-iosynostosis may be related to a metabolic disorder such as rickets, hypophosphatasia, thyroid dysfunction, and hypercalcemia, or occur in response to primary brain atrophy. Restraint of the fetal head leads to decreased intracranial pressure and, in turn, to progressive narrowing of the sutures, thickening of the calvarium with loss of the convolutional markings, and overgrowth of the air-filled paranasal sinuses and mastoid cells (Graham 1981). Accurate assessment of the type of craniosynostosis has important therapeutic implications, since re-opening of a prematurely closed suture in an otherwise normal child allows for residual brain growth and reconfiguration of the cranial shape (Fernbach 1998).

The terminology of craniosynostosis is complex and sometimes confusing. Scaphocephaly, or dolichocephaly, defines a narrow and elongated head resulting from premature closure of the longitudinal

Dolichocephaly

Fig. 1.5 a-e. Scaphocephaly. a, b In an 18-month-old boy sagittal synostosis is seen. Note elongation of the skull, with prominent occipital and frontal regions. (From Renier et al. 2000) c, d In a female newborn the skull is dolichocephalic, with markedly increased AP diameter. The sagittal suture is completely obliterated, except for its most caudal segment, which appears as a thin, sharply marginated vertical line of radiolu-cency (d). All the other sutures are wide open. A small, receding mandible is an additional finding in this child. e In a 7-year-old boy typical cranial deformity and prominence of the convolutional markings are observed

Fig. 1.5 a-e. Scaphocephaly. a, b In an 18-month-old boy sagittal synostosis is seen. Note elongation of the skull, with prominent occipital and frontal regions. (From Renier et al. 2000) c, d In a female newborn the skull is dolichocephalic, with markedly increased AP diameter. The sagittal suture is completely obliterated, except for its most caudal segment, which appears as a thin, sharply marginated vertical line of radiolu-cency (d). All the other sutures are wide open. A small, receding mandible is an additional finding in this child. e In a 7-year-old boy typical cranial deformity and prominence of the convolutional markings are observed suture (Fig. 1.5a-e). It is the most frequent type of craniosynostosis, accounting for about 55% of all cases, and occurs most commonly as an isolated anomaly, without ocular or neurological defects. Brachycephaly refers to a short wide skull, with small posterior fossa and retrusion of the supraorbital rim, root of the nose, and lower part of the forehead. The upper part of the forehead bulges over this retrusion (Fig. 1.6a,b). It is due to bilateral coronal synostosis and occurs with a frequency of about 15-20% of all cases. Hypertelorism and proptosis are associated features. This type of craniosynostosis occurs in several syndromes as a result of mutations involving the FGFR receptors. Oxycephaly is caused by the premature closure of both the coronal and the sagittal sutures and is characterized by a receding forehead, which is tilted backward in continuity with the nasal dorsum, and a receding supraorbital rim, giving rise to the false impression of exophthalmos (Fig. 1.7a,b). Plagiocephaly indicates the asymmetrical, oblique skull resulting from unilateral synostosis of the coro nal suture (anterior plagiocephaly) or the lambdoid suture (posterior plagiocephaly). With anterior plagiocephaly, ipsilateral frontal flattening, uptilting of the orbit, and distortion of the root of the nose combine to give the head and face a typical Harlequin appearance (Fig. 1.8a,b). Posterior plagiocephaly is associated with ipsilateral occipital flattening, compensatory overgrowth of the contralateral parietal and occipital region, and anteroinferior displacement of the ear. Overall, the cosmetic deformity is less severe than that accompanying coronal or metopic synosto-sis, and the dense bony bridge is not usually palpable. Absence of this clinical sign and paucity of the radiological findings make the diagnosis of posterior plagiocephaly difficult. It is assumed that bone growth may be restricted at the level of the lambdoid suture even though it appears to be open both radiographi-cally and intraoperatively. Definitions such as 'lazy' or 'blocked' suture, or 'functional synostosis' have been applied to these situations. The diagnosis, however, is important, since posterior plagiocephaly may

Saethre Chotzen Syndrome

Fig. 1.6 a, b. Brachycephaly in a 6-month-old baby girl with bi- seen, as is retrusion of the supraorbital rim, root of the nose, lateral coronal synostosis. The anteroposterior diameter of the and lower part of the forehead. (From Renier et al. 2000) skull is decreased, and vertical occipital and frontal bones are

Fig. 1.6 a, b. Brachycephaly in a 6-month-old baby girl with bi- seen, as is retrusion of the supraorbital rim, root of the nose, lateral coronal synostosis. The anteroposterior diameter of the and lower part of the forehead. (From Renier et al. 2000) skull is decreased, and vertical occipital and frontal bones are require a surgical intervention, whereas positional occipital flattening, a nonsynostotic condition due to simple skull molding, does not. A sixfold increase in the number of children with postural flattening happened to occur roughly contemporaneously with publication of recommendations made by the American Academy of Pediatrics that infants be placed on their backs for sleep to prevent them from dying of the 'sudden infant death syndrome' (Fernbach 1998; American Academy of Pediatrics Task Force on Infant Positioning and SIDS 1992). Trigonocephaly refers to the triangular shape of the forehead when viewed from above that is caused by premature closure of the frontal metopic suture (Fig. 1.9a-d). Reduced expansion of the frontal and facial bones results in hypotelorism of varying degree. A prominent midline ridge, corresponding to the fused metopic suture, is usually observed. Trigonocephaly occurs most commonly as an isolated defect, but can also be part of several chromosomal (9p-, 11q-, 13q+) and mendelian (Frydman trigonocephaly syndrome, Say-Meyer trigonocephaly syndrome) disorders, some craniosynostotic syndromes, and the C syndrome, as well as occurring in association with a number of cerebral, cardiac, genital, and limb defects (see fur ther discussion) (Cohen 2000a). Cloverleaf skull designates the severe skull deformity characterized by a flattened, trilobular appearance of the cranial vault (Fig. 1.10). This anomaly is caused by congenital synostosis of the coronal and lambdoidal sutures in combination with hydrocephalus (Holtermuller and Wiedemann 1960). Severe exophthalmos with corneal ulcerations is commonly observed. Clover-leaf skull can occur as an isolated defect, as a component of several syndromes, or in nonrandom association with other malformations. All cases of the isolated variety (kleeblattschaedel syndrome, OMIM 148800) have been sporadic and of unknown etiology. The syndromic associations include some cran-iosynostotic syndromes, such as Crouzon, Pfeiffer, Carpenter, Beare-Stevenson cutis gyrata, and cran-iosynostosis, Boston type, syndromes; one form of thanatophoric dwarfism (thanatophoric dysplasia with kleeblattschaedel, OMIM 187601) featuring straight, relatively long femurs (curved, short femurs in the common type) and taller vertebral bodies (severely flattened vertebrae in the common type), which is due to mutations in the extracellular domain of the FGFR3 tyrosine kinase (instead of the FGFR3 tyrosine kinase domain of the common form)

Oxycephaly

Fig. 1.7 a, b. Oxycephaly. a In a 7-year-old girl bilateral coronal and sagittal synostosis are present.Note the receding forehead, which appears continuous with dorsum of the nose. (From Renier et al. 2000) b In a 70-year-old woman note decreased anteroposterior diameter of the skull,with pronounced convo-lutional markings on the frontal bones. There are no discernible coronal sutures

Fig. 1.7 a, b. Oxycephaly. a In a 7-year-old girl bilateral coronal and sagittal synostosis are present.Note the receding forehead, which appears continuous with dorsum of the nose. (From Renier et al. 2000) b In a 70-year-old woman note decreased anteroposterior diameter of the skull,with pronounced convo-lutional markings on the frontal bones. There are no discernible coronal sutures

(Langer et al. 1987; Tavormina et al. 1995); a short-limbed form of campomelic syndrome (OMIM 211990) (Khajavi et al. 1976); and a group of miscellaneous disorders, including osteoglophonic dwarfism, Antley-Bixler syndrome, amniotic band sequence, chromosomal trisomies 13 and 15, and maternal use of cocaine (Cohen 1973;Esmer et al. 2000). In addition, the cloverleaf anomaly has been described in association with a micromelic form of bone dysplasia (OMIM 156830) (Andersen 1989) and with a lethal disorder involving multiple anomalies, which mimics gracile bone dysplasia (OMIM 607161) (Sharony et al. 2002).

Nonsyndromic Craniosynostosis. Craniosynostosis is a highly heterogeneous feature. Isolated craniosynostosis (OMIM 123100) has been described in several families with an autosomal dominant inheritance pattern with variable expression (Gordon 1959; Nance and Engel 1967). Significant inter- and intrafa-milial variability exists in the type and number of sutures involved, and hence in the resultant skull deformity. However, bilateral coronal synostosis and multiple synostoses are particularly common (Shillito and Matson 1968). Familial isolated scaphocephaly has been shown to segregate as a dominant trait with 38% penetrance (Lajeunie et al. 1996). This type of craniosynostosis is caused by deletion in the short arm of chromosome 7, specifically at 7p21.3-7p21.2 (McPherson et al. 1976; Motegi et al. 1985; Garcia-Esquivel et al. 1986). An autosomal recessive form of isolated craniosynostosis (OMIM 218500) has also been recognized (Cross and Opitz 1969; Armendares 1970). In addition, familial cases of lambdoid craniosynostosis (posterior plagiocephaly, OMIM 600775) have been reported (Fryburg et al. 1995). A single lambdoid suture or both sutures may close prematurely. Isolated trigonocephaly (OMIM 190440) can be familial with an autosomal dominant inheritance and instances of male-to-male transmission (Frydman et al. 1984; Hennekam et al. 1990). A form associated with agenesis of the olfactory bulbs and tracts (OMIM 275600) has been recognized (McKusick).

Fig. 1.9 a-d. Trigonocephaly. a, b In a 4-month-old boy with ► metopic synostosis. Observe the triangular forehead and hy-potelorism. (From Renier et al. 2000) c, d In a 21-month-old infant girl. The prematurely closed metopic suture is seen as a vertical band of hyperdensity in the midline. Observe narrowing of the forehead, decreased width of the ethmoid bone, and orbital hypotelorism. Superior lifting of the orbital roofs suggests associated closure of the caudal segment of the coronal sutures

Synostosis Syndrome
Fig. 1.8 a,b. Anterior plagiocephaly in a 4-year-old girl. Uni- side of the synostosis with uptilting of the orbit and frontal lateral coronal synostosis. There is frontal flattening on the prominence at the opposite side. (From Renier et al. 2000)
Holtermuller WiedemannKleeblattschaedel
Fig. 1.10. Cloverleaf skull in a 6-month-old girl born to a cocaine-addicted mother. Note typical trilobed head deformity. Also note microphthalmos, short palpebral fissures, small mouth, micrognathia, and low-set malformed ears. (From Esmer et al. 2000)

Syndromic Craniosynostosis. One well-recognized group of genetic disorders with craniosynostosis, including Crouzon craniofacial dysostosis, Crouzon syndrome with acanthosis nigricans, Apert syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome, Beare-Steven-son syndrome, and Saethre-Chotzen syndrome, are inherited in an autosomal dominant fashion with high penetrance and variable expressivity. All these disorders, except Saethre-Chotzen syndrome, are caused by mutations in one of the FGFR genes. Crouzon craniofacial dysostosis (OMIM 123500) involves only the face and skull. The distinguishing dysmorphism consists in underdevelopment of the midfacial bones, resulting in shallow orbits with ex-ophthalmos, and prognathism with inverted dental occlusion (Fig. 1.11 a, b). The skull manifests bilateral closure of the coronal sutures (brachycephaly), although other types of craniosynostosis, including scaphocephaly, plagiocephaly, and trigonocephaly, occasionally occur (Tartaglia et al. 1999). Coronal synostosis causes elevation of the orbital roofs, displacement of the greater wings of the sphenoid bone into a more vertical orientation ('frontalization' of the sphenoid), and ballooning of the ethmoid, contributing to exotropia. A striking harlequinesque appearance of the orbits and prominent digital markings in the frontal area (in more than 90 % of cases) are typically found. Cranial deformity usually becomes evident by the age of 3 years, but the degree of craniofacial abnormalities, like the age of onset, is variable. Severe exophthalmos may be complicated by exposure conjunctivitis and keratitis, whereas maxillary hypoplasia may produce upper airway ob struction resulting in obligatory mouth breathing (Renier et al. 2000). Occasional manifestations include mental retardation, hydrocephalus, seizures, conductive hearing loss, spinal anomalies (fusion between the 2nd and 3rd cervical vertebrae), and subluxation of the radial head with limited elbow extension. Family history is negative in about one quarter of cases, which presumably represent fresh new mutations. Mutations involving the FGFR2 gene, which maps to 10q26, cause Crouzon syndrome (Reardon et al. 1994). An identical mutation in the same gene may cause Pfeiffer syndrome,whereas different mutations in the same gene cause Apert syndrome and Jackson-Weiss syndrome. A variant form of Crouzon syndrome is associated with acanthosis nigricans and is caused by mutation in the FGFR3 gene (Meyers et al. 1996). Apert syndrome (OMIM 101200) includes severe craniofacial anomalies and osseous and/or cutaneous syndactyly of hands and feet, often with complete fusion of the 2nd to 4th fingers (Cohen and Kreiborg 1995). Irregular synostosis of cranial sutures, especially coronal sutures, results in a small an-teroposterior skull diameter with high, full forehead and flat occiput. Midface hypoplasia with flat face, shallow orbits, horizontal supraorbital groove, hy-pertelorism, strabismus, small nose, narrow palate, malocclusion, and dental anomalies are major facial abnormalities. In contrast to Crouzon syndrome, craniofacial involvement is apparent at birth. Additional manifestations include stunted growth,mental deficiency, central nervous system anomalies (agenesis of corpus callosum, hydrocephalus, gyral anomalies), acne, vertebral defects and, occasionally, visceral anomalies involving the gastrointestinal, respiratory, cardiovascular, and genitourinary systems. Mutations in the FGFR2 gene cause Apert syndrome (Wilkie et al. 1995). Most cases are sporadic, caused by de novo mutation favored by high paternal age at conception. Thus, the risk of recurrence is negligible for the unaffected parents and 50 % for the affected individual. Pfeiffer syndrome (OMIM 101600) displays brachycephaly with craniosynostosis of coronal sutures, with or without sagittal suture, in combination with anomalies of hands and feet. Three clinical subtypes are recognized (Cohen 1993b). Type 1 corresponds to the classic phenotype characterized by brachycephaly, broad thumb and great toe, variable degrees of syndactyly, and normal intelligence. Type 2 is marked by cloverleaf skull, severe proptosis, severe central nervous system involvement, elbow ankylosis, broad thumbs and great toes, variable visceral anomalies, and early death. Type 3 is similar to type 2, but does not include cloverleaf skull. Pfeiffer

Gorlin Cohen Syndrom
Fig. 1.11 a,b. Crouzon craniofacial syndrome in a 4-year-old divergent strabismus, narrow palate with open mouth, and girl. Note maxillary hypoplasia, ocular proptosis with mild relative prognathism. (From Renier et al. 2000)

syndrome is genetically heterogeneous. All cases of types 2 and 3 have been sporadic, whereas autosomal dominant inheritance and sporadic cases probably due to fresh new mutations have been seen in type 1. Some cases of Pfeiffer syndrome are due to mutations in the FGFR1 gene, which maps to 8p11.22-p12 (Muenke et al. 1994). In addition, mutations in the FGFR2 gene at chromosomal location 10q25-q26, identical to those causing Crouzon syndrome, have been reported (Rutland et al. 1995). Jackson-Weiss syndrome (OMIM 123150) is characterized by cran-iosynostosis, midfacial hypoplasia, and foot anomalies (Jackson et al. 1976). An extremely wide variability of phenotypic expression is characteristic. The disorder is caused by mutation in the gene encoding FGFR2 and is allelic to Crouzon syndrome (Li et al. 1994; Jabs et al. 1994). Beare-Stevenson cutis gyrata syndrome (OMIM 123790) is characterized by cutis gyrata (involving the scalp, forehead, face, neck, trunk, palms, and soles), acanthosis nigricans, cran-iofacial anomalies with various types of craniosynos-tosis including cloverleaf skull, ear defects, geni-toanal anomalies, skin tags, and prominent umbilical stump (Beare et al. 1969; Stevenson et al. 1978). This syndrome results from mutations in the FGFR2 gene (Przylepa et al. 1996). All cases have been sporadic, and increased paternal age supports the possibility of fresh autosomal dominant mutations. Saethre-Chotzen syndrome (OMIM 101400) is characterized by brachycephaly with high forehead, maxillary hypoplasia, ear anomalies (small ears, prominent ear crus), and cutaneous syndactyly of hands and feet. Cranial maldevelopment consists in premature coronal synostosis (sometimes lambdoid and/or metopic sutures are involved),irregular ossification of the cal-varium, facial asymmetry with deviation of the nasal septum, narrow palate,shallow orbits,hypertelorism, and lacrimal duct abnormalities. In addition to partial cutaneous syndactyly, mild brachydactyly and clinodactyly of the 5th fingers are features in the hand and foot. Most patients have mutations in the TWIST gene at chromosomal location 7p21 (El Ghouzzi et al. 1997). Some patients with an overlapping phenotype have mutations in the FGFR3 and FGFR2 genes (Paznekas et al. 1998). Shprintzen-Gold-berg syndrome (marfanoid craniosynostosis syndrome, OMIM 182212) is marked by craniosynostosis associated with malar and mandibular hypopla-sia, shallow orbits with severe proptosis, soft tissue palatal hypertrophy, and clinical features typical of Marfan syndrome, including multiple abdominal hernias, arachnodactyly, camptodactyly, dolicho-stenomelia, pectus carinatum, kyphoscoliosis, ptosis, hypospadias, and dilated aortic root with aortic dissection (Shprintzen and Goldberg 1979; Furlong et al. 1987). A point of difference from Marfan syndrome is that ectopia lentis does not occur. Skeletal manifestations include bowed long bones, metaphy-

Ocular Hypertelorism
Fig. 1.12. Craniofrontonasal dysplasia in a 3-year-old girl. Note craniosynostosis with frontal bossing, hypertelorism, divergent strabismus, facial asymmetry, broad nasal bridge, and bifid nose. (From Renier et al. 2000)

seal flaring, persistently large anterior fontanel, 13 pairs of ribs,vertebral anomalies, and progressive osteopenia (Ades et al. 1995). The suggestion that this disorder may be caused by mutations in the same gene as is involved in Marfan syndrome, fibrillin-1, which maps to 15q21.1 (Dietz et al. 1995), has not been confirmed (Cohen 2000b). Craniosynostosis, Boston type (OMIM 604757) is caused by mutation in the gene encoding for transcription factor MSX2, which is located on 5q34 (Jabs et al. 1993; Muller et al. 1993). The phenotype is dominated by the craniosyn-ostosis, which ranges in severity from recession of the supraorbital region to cloverleaf skull anomaly. Severely affected individuals may be myopic or hy-peropic and may suffer from severe headaches (War-man et al. 1993). Intelligence is normal, and there are no abnormalities of hand or foot. Carpenter syndrome (acrocephalopolysyndactyly type II, OMIM 201000) is inherited as an autosomal recessive trait (Temtamy 1966). Major manifestations of the disorder are brachycephaly with variable synostosis of coronal, sagittal, and lambdoid sutures; malar hy-poplasia; shallow supraorbital ridges; flat nasal bridge; lateral displacement of inner canthi; ocular and ear defects; and limb anomalies including brachydactyly with partial syndactyly in the hands and preaxial polydactyly with partial syndactyly in the feet. Cardiovascular defects, mental retardation, hypogenitalism, and umbilical hernias are additional findings (Owen 1952; Robinson et al. 1985). Craniofrontonasal syndrome (OMIM 304110) is characterized by craniosynostosis (with brachycephaly and frontal bossing) and finger syndactyly in females (Fig. 1.12); and by hypertelorism, facial asymmetry, broad nasal root and bifid nasal tip, splitting of nails, broad 1st toe, and toe syndactyly in both sexes (Grutzner and Gorlin 1988). Although most cases are sporadic, several familial instances have been reported (Saavedra et al. 1996). The inheritance pattern is likely to be X-linked dominant. However, it is puzzling that the expression is much more severe in females than in males, a highly unusual characteristic for an X-linked disorder. Baller-Gerold syndrome (craniosynostosis-radial aplasia syndrome, OMIM 218600) is characterized by craniosynostosis and radial defects (Anyane-Yeboa et al. 1980). A wide range of additional malformations may occur. Wide overlap is recognized with several other entities, most notably Fanconi anemia and Saethre-Chotzen syndrome, raising the question of whether such an entity as the Baller-Gerold syndrome really exists (Cohen and Toreillo 1996). SCARF syndrome (OMIM 312830) is the acronym for skeletal abnormalities, cutis laxa, craniosynostosis, ambiguous genitalia, retardation of mental development, and facial abnormalities (Koppe et al. 1989). Joint hyperextensibility, abnormally shaped vertebrae, pectus carinatum, enamel hypoplasia with hypocalcification of the teeth, and multiple nodular liver tumors are additional manifestations. In Muenke syndrome (OMIM 602849), a disorder caused by a distinct mutation in the FGFR3 gene, which maps to 4p16.3, the most frequent and distinctive feature is synostosis of coronal suture(s) (Muenke et al. 1997). Occasional abnormalities include thimble-like middle phalanges, coned epiphy-ses, carpotarsal fusion, brachydactyly, sensorineural hearing loss, and developmental delay. Considerable phenotypic variability exists among individuals with the same mutation (Golla et al. 1997). C syndrome (Opitz trigonocephaly syndrome, OMIM 211750), presumably an autosomal recessive disorder, is characterized by trigonocephaly, unusual facies (up-slanting palpebral fissures, epicanthal folds, strabismus, hypoplastic nasal root), wide alveolar ridges, deep midline palatal furrow, multiple buccal frenula, limb defects, visceral anomalies involving the genitalia, heart, and intestine, redundant skin, joint contractures and dislocations, hemangiomas, mental deficiency, and hypotonia. The head is a normal size at birth, but becomes microcephalic in subsequent months. Many affected children die within the 1st year of life. The karyotype is normal (Opitz et al. 1969; Antley et al. 1981; Camera et al. 1990). Trigonocephaly has been described in association with short stature and developmental delay (OMIM 314320) in a family pattern consistent with X-linked recessive inheritance (Say and Meyer 1981).

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