Macrocephaly is confirmed when the head circumference is more than 2 standard deviations above the mean for age and sex. A large head may occur as an isolated anomaly, in association with several syndromes, or as a manifestation of hydrocephalus.

Isolated (Nonsyndromal) Macrocephaly. An excessive rate of head growth in otherwise normal infants aged 2-7 months is a relatively common, self-limiting condition devoid of any clinical significance. Features in clude bilateral enlargement of the subarachnoid spaces over the cerebral convexities, with normal brain size, normal to slightly enlarged ventricles, and absence of underlying brain anomalies or developmental delay (Hamza et al. 1987; Alper et al. 1999). Thus,macrocrania of this type is not associated with megalencephaly, unlike the familial forms discussed later in this section. The head circumference is in the high normal range at birth, and increases rapidly during the first few months of life, generally lying well above the 95th percentile at the time of presentation. The head growth curve tends to stabilize along the 95th percentile by the age of 18 months, and it usually becomes normal after the 2nd year of life. Based on the assumption that the cerebrospinal fluid (CSF) accumulates in the subarachnoid spaces,possi-bly as a result of diminished CSF resorption by immature arachnoid villi over the cerebral convexities (Briner and Bodensteiner 1981), the condition has been variously referred to as extra-axial fluid collections of infancy, benign subdural collections of infancy, and external hydrocephalus. However, since a more likely mechanism is a transitory imbalance in the rate of growth between the skull and the brain, resulting in relative expansion of the subarachnoid spaces, all the definitions in use are misnomers. It is worth noting that enlarged subarachnoid or subdur-al spaces can be caused by a variety of factors, including subdural hygroma, meningitis, shunt dysfunction, brain malformations, dehydration, malnutrition, total parental nutrition, and ACTH therapy (Bode and Strassburg 1987). Familial macrocephaly (megalencephaly, OMIM 248000, 155350) is characterized by increased head and brain size with no evidence of syndromic associations or hydrocephalus. Mild to severe mental deficiency has been described in all reported kindreds. The inheritance pattern is not known, both X-linked recessive (McKusick) and autosomal dominant (DeMyer 1972; Fryns et al. 1988) patterns having been implicated. A distinct form, with unremarkable neurological and mental development, benign familial macrocephaly (OMIM 153470), has been identified (Asch and Myers 1976; Day and Shutt 1979). Whether these two forms of nonsyndromic macrocephaly are distinct entities or different expressions of the same disorder is unknown (Arbour et al. 1996).

Syndromal Macrocephaly. Macrocephaly is a feature of several well-recognized disorders, including achon-droplasia, thanatophoric dysplasia, Robinow syndrome, Kenny-Caffey disease, gargoylism, Sotos syndrome, and other overgrowth syndromes. Many of these disorders have been discussed elsewhere in this book. Further rarer or less well-defined entities are briefly outlined here. Macrocephaly of postnatal onset with prominent forehead occurs in FG syndrome (Opitz-Kaveggia syndrome, OMIM 305450), a genetically heterogeneous, X-linked recessive disorder with one gene locus, FGS1, located at Xq12-q21 (Briault et al. 1997; Graham et al. 1998); a second gene locus, FGS2 (OMIM 300321), located at Xq11.2-q28 (Briault et al. 2000); a third locus, FGS3 (OMIM 300406), which may be located at Xp22.3 (Dessay et al. 2002); and a fourth gene locus,FGS4 (OMIM 300422),corre-sponding to the Xp11.4-p11.3 region (Piluso et al. 2003). Major clinical features of the syndrome are mental retardation, congenital hypotonia, and imper-forate anus (Opitz and Kaveggia 1974; Dallapiccola et al. 1984; Zwamborn-Hanssen et al. 1995). Additional manifestations include short stature, joint hyperlaxi-ty progressing to contractures with spasticity and unsteady gait in later life, peculiar facies (prominent forehead with frontal hair upsweep, hypertelorism, epicanthal folds, prominent lower lip, small ears), anal anomalies (anteriorly placed anus, anal stenosis), and a characteristic, extroverted personality similar to that of Williams syndrome, with occasional aggressive outbursts (Romano et al. 1994; Graham et al. 1999). Skeletal abnormalities include broad thumbs and great toes, clinodactyly, camptodactyly, foramina parietalia permagna, and vertebral and sternal defects (Kato et al. 1994; Chrzanowska et al. 1998). Occasionally,craniosynostosis,absence of corpus callosum, hydrocephalus, cryptorchidism, and cardiac defects are present (Keller et al. 1976; Riccar-di et al. 1977). Greig cephalopolysyndactyly syndrome (OMIM 175700) is characterized by craniofacial dys-morphism (macrocephaly with high forehead and bregma, frontal bossing, mild hypertelorism, and broad nasal root) and digital malformations, with postaxial polydactyly of the hands and preaxial poly-dactyly of the feet and syndactyly (Greig 1928; Mer-lob et al. 1981). Greig syndrome is different from the craniosynostosis syndromes in that there is no evidence of premature closure of cranial sutures. The thumbs and great toes are broad, with bifid terminal phalanges. The disorder is caused by disruption of the GLI3 gene,which is assigned to 7p13 (Pettigrew et al. 1991; Vortkamp et al. 1991), and is inherited as an autosomal dominant trait with variable expression (Temtamy and McKusick 1978; Fryns 1982). Interestingly, at least one type of craniosynostosis (OMIM 123100) is caused by mutation in a gene located at 7p. Phenotypic overlap is recognized between Greig syndrome and acrocallosal syndrome (OMIM 200990)

(Chudley and Houston 1982), an autosomal recessive disorder characterized by postaxial Polydactyly, hallux duplication, macrocephaly with protruding forehead and occiput, hypertelorism, hypoplastic or absent corpus callosum, and severe mental retardation (Schinzel and Schmid 1980; Schinzel 1982). Specifically, the digital changes are similar to those of Greig cephalopolysyndactyly syndrome. However, mental retardation, agenesis of the corpus callosum, and in-tracerebral cysts are distinctive features of acrocal-losal syndrome (Baraitser et al. 1983). Moreover, the genetics is different, the acrocallosal syndrome being related to a gene locus at 12p13.3-p11.2 (Pfeiffer et al. 1992). The combination of agenesis of the corpus callosum and polydactyly is also found in hydro-lethalus (see further discussion below) (Schinzel and Kaufmann 1986). Bannayan-Riley-Ruvalcaba syndrome (macrocephaly/multiple lipomas/hemangioma-ta, OMIM 153480) displays macrocephaly, multiple lipomas and hemangiomata, intestinal polyposis, and pigmentary changes of the penis (Bannayan 1971). Overlap is recognized with the syndrome of cutis marmorata telangiectatica congenita (CMTC, OMIM 219250) (Halal and Silver 1989), a disorder manifesting with livedo reticularis, telangiectases, and superficial ulceration (Andreev and Pratarov 1979). A significant proportion of patients have associated anomalies or syndromes, including congenital hypothyroidism (Pehr and Moroz 1993),phlebectasia (Lingier et al. 1992), leg-length discrepancy (Dut-kowsky et al. 1993), hypospadias (Ben-Amitai et al. 2001), Sturge-Weber syndrome (OMIM 185300), Adams-Oliver syndrome (OMIM 100300),Bannayan-Riley-Ruvalcaba syndrome (OMIM 153480), and patent ductus arteriosus (OMIM 607411) (Petrozzi et al. 1970). In addition, cutis marmorata telangiectati-ca congenita may occur in association with megalen-cephaly and macrocephaly, central nervous system malformations (Chiari I malformation, spinal cord syrinx, hydrops of the optic nerves), body asymmetry, macrosomia, nevus flammeus, and visceral and subcutaneous cavernous hemangiomas. The latter association, referred to as megalencephaly-cutis marmorata telangiectatica congenita (M-CMTC, OMIM 602501), is considered a distinct entity of central nervous system and vascular dysgenesis (Moore et al. 1997; Carcao et al. 1998). The diagnosis is based on the association of macrocephaly with at least two of the other manifestations listed (Franceschini et al. 2000). Craniometadiaphyseal dysplasia, wormian bone type (Schwarz-Lelek syndrome, OMIM 269300) encompasses macrocrania, genu varum or valgum, widening of the long bones and metaphyses, and in creased levels of serum alkaline phosphatase (Gorlin et al. 1969). Macrocephaly with multiple epiphyseal dysplasia and distinctive facies (OMIM 607131) is an association of macrocrania, dysmorphic facies (frontal bossing, hypertelorism, maxillary hypopla-sia, low-set ears), genu valgum, and prominent joints, particularly wrists, knees, and ankles. Additional features include epiphyseal dysplasia of the long bones, short neck, pectus excavatum, spindle-shaped fingers with soft-tissue syndactyly, clinodactyly, agenesis of the corpus callosum, and frontotemporal brain atrophy (Al-Gazali and Bakalinova 1998). The inheritance is autosomal recessive, the gene locus having been located at 15q26 (Bayoumi et al. 2001). Several leukodystrophies exhibit megalencephaly as a prominent feature. Canavan disease (cerebral spongy degeneration, OMIM 271900), a common disorder in the Ashkenazi Jewish population, is caused by deficiency of aspartoacylase, the enzyme that hydrolyzes N-acetylaspartic acid (NAA) to aspartate and acetate, resulting in increased amounts of NAA in the CSF, urine, and plasma (Matalon et al. 1988). The defect is due to mutations in the gene encoding aspartoacy-lase,which is mapped to 17pter-p13 (Kaul et al. 1994). Major clinical features include early-onset severe muscle hypotonia, severe mental defect, megalo-cephaly, blindness, extrapyramidal cerebral palsy, and death in infancy. Neuropathologic findings are nonspecific and include spongy degeneration of the brain white matter and astrocytic swelling with normal neurons (Matalon et al. 1989). Megalencephaly associated with progressive spasticity and dementia similar to those seen in Canavan disease also occur in Alexander disease (OMIM 203450), another form of leukodystrophy caused by mutation in the gene encoding glial fibrillary acidic protein (GFAP), which has been mapped to 17q21 and 11q13 (Alexander 1949; Brenner et al. 2001). On brain imaging, the combination of megalencephaly with diffuse white matter abnormalities is common to Canavan disease and GM1 gangliosidosis (OMIM 230500) (Gorospe et al. 2002). The differential diagnosis is based on the laboratory findings (deficiency of aspartoacylase in Canavan disease, deficiency of beta galactosidase in GM1 gangliosidosis) and distinct pathological features (spongy changes in Canavan disease and Rosenthal fibers, the result of astrocytic degeneration, in Alexander disease) (Herndon et al. 1970). Megalencephaly with dysmyelination (OMIM 249240) is a rare disorder manifesting with spasticity, hyper-reflexia, ataxia, and white matter abnormalities on brain imaging (Harbord et al. 1990). Complete lack of motor and speech development, distinctive facies

Familial Megalencephaly

Fig. 1.2. a Anteroposterior and b lateral projections depicting congenital hydrocephalus in a boy aged 2 years and 6 months. Note abnormally enlarged neurocranium and relatively small splanchnocranium. Delay in shunting for the hydrocephalus had resulted in massive dilatation of the lateral and third ventricles, with severe compression and distortion of the cerebral mantle. The child was able to walk, but his heavy head had to be held upright by his mother

Fig. 1.2. a Anteroposterior and b lateral projections depicting congenital hydrocephalus in a boy aged 2 years and 6 months. Note abnormally enlarged neurocranium and relatively small splanchnocranium. Delay in shunting for the hydrocephalus had resulted in massive dilatation of the lateral and third ventricles, with severe compression and distortion of the cerebral mantle. The child was able to walk, but his heavy head had to be held upright by his mother

(frontal bossing, low nasal bridge, large eyes), broad corpus callosum, enlarged volume of white matter, and pachygyria are features of megalencephaly/mega corpus callosum/lack of motor development (OMIM 603387) (Gkohlich-Ratmann et al. 1998). Megalen-cephalic leukoencephalopathy with subcortical cysts (OMIM 604004), probably an autosomal recessive disorder, is characterized by onset in infancy, slowly progressive ataxia and spasticity, and brain abnormalities consisting in megalencephaly, diffuse swelling of the white matter, and large subcortical cysts (van der Knaap et al. 1995; Topcu et al. 1998). Macrocephaly/autism syndrome (OMIM 605309) is an association of macrocephaly, macrosomia, obesity, peculiar facies (frontal bossing, 'dished-out' mid-face, biparietal narrowing, and long philtrum), and autism, sharing features of both Sotos syndrome and benign familial macrocephaly (Cole and Hughes 1991; Naqvi et al. 2000). MOMO syndrome (OMIM 157980), an acronym for macrosomia, obesity, macrocephaly, and ocular abnormalities, is an overgrowth syndrome caused by an autosomal mutation (Moretti-Ferreira et al. 1993).

Macrocephaly and Hydrocephalus. Hydrocephalus is the most common cause of macrocrania in infants and children, accounting for about 75% of all cases (Do-nat 1981). Prior to the age of 2 years,hydrocephalus is almost always accompanied by progressive enlargement of the head (Fig. 1.2). Approximately 70% of infants with hydrocephalus diagnosed either in utero or perinatally have associated malformations, 2040% of which are extracranial while the rest affects the central nervous system (neural tube defects, Dandy-Walker malformation, Chiari malformation). In about 25% of cases congenital hydrocephalus is caused by a chromosomal imbalance. Intrauterine infections, particularly toxoplasmosis, are a major cause of prenatal hydrocephalus, whereas brain hemorrhage accounts for a large proportion of the cases developing peri- and/or postnatally (Fernell et al. 1986). Neonatal meningoencephalitis, congenital midline tumors, choroid plexus papillomas, and vein of Galen malformations are additional causes of hydrocephalus in infancy and childhood (Barkovich 1996). Obstructive hydrocephalus in infants is most commonly the result of aqueductal stenosis, which in turn may be caused by intrauterine infections, hemorrhage, trauma, posterior fossa neoplasms and, in about 5% of cases, by an X-linked mutation (see sub sequent discussion). Communicating hydrocephalus occurs most commonly in association with sub-arachnoid hemorrhage, a frequent complication in premature infants (Schrander-Stumpel and Fryns 1998). As for macrocephaly, syndromic and nonsyn-dromic forms of hydrocephalus have been recognized. In all types, macrocephaly is due to an increased rate of head growth within the first few months of life, resulting in a disproportionately large forehead, frontal bossing, thinning of the calvarium, widening of the sutures, bulging of fontanels, and dilatation of the scalp veins. Ocular disturbances and spasticity of the lower limbs are common.

Nonsyndromic hydrocephalus includes the isolated forms (X-linked hydrocephalus, autosomal recessive hydrocephalus due to aqueductal stenosis, autosomal recessive hydrocephalus),the forms associated with central nervous system malformations (Arnold-Chiari, Dandy-Walker, holoprosencephaly, hydranen-cephaly, vein of Galen malformation, neural tube defect, midline anomalies), and the communicating form, which is caused by subarachnoid hemorrhage (Schrander-Stumpel and Fryns 1998). X-linked recessive hydrocephalus due to congenital stenosis of the aqueduct of Sylvius (X-linked hydrocephalus, OMIM 307000) is the most common form of inherited hydrocephalus, with an estimated prevalence of about 1 in 30,000 newborns. The disorder is caused by mutation in the gene encoding the L1 cell adhesion molecule, L1CAM, mapped to chromosome Xq28 (Willems et al. 1990; Rosenthal et al. 1992). Human L1 is involved in neuronal cell migration, fascic-ulation, outgrowth, and regeneration and apparently has a prominent role in the formation of the pyramids and corticospinal tracts (Hlavin and Lemmon 1991; Lemmon et al. 1989; Williams et al. 1994). Approximately one-third of cases of congenital hydro-cephalus are due to aqueductal stenosis, and about 25% of those occurring in males are due to an X-linked recessive disorder (there may be a distinct form of X-linked hydrocephalus unrelated to the L1CAM gene) (Howard et al. 1981; Burton 1979; Strain et al. 1994). Enlarged cerebral ventricles, macrocrania, and mental retardation are prime manifestations. Spastic paraparesis and hypoplastic, ad-ducted thumbs are often associated (Edward et al. 1961). Death in the perinatal period is common (So-vik et al. 1977). Ventricular dilatation can be moderate, ensuring long survival with little or no macro-cephaly (Serville et al. 1992). Bilateral absence of the pyramidal tracts is an important finding in autopsies and MRI studies (Chow et al. 1985). Whether aque-ductal stenosis is primary or secondary to a commu nicating form of hydrocephalus is still debated (Lan-drieu et al. 1979; Willems et al. 1987). MASA syndrome (spastic paraplegia type 1, OMIM 303350), an acronym for mental retardation, aphasia, shuffling gait, and adducted thumbs, is allelic to X-linked aqueductal stenosis (Fryns et al. 1991). In addition, an autosomal recessive form of congenital hydro-cephalus due to stenosis of the aqueduct of Sylvius (OMIM 236635) has been suggested (Barros-Nunes and Rivas 1993; Haverkamp et al. 1999). Another autosomal recessive form of isolated hydrocephalus (OMIM 236600), which is not associated with aque-ductal stenosis, has also been recognized (Abdul-Karim et al. 1964; Halliday et al. 1986). This form appears to be common among Palestinian Arabs (Zlo-togora et al. 1994). A dominant form (OMIM 600256) due to deletion of 8q12.2-q21.2 occurs in the context of a contiguous gene syndrome in combination with branchio-oto-renal syndrome (OMIM 113650), Du-ane syndrome (OMIM 126800), and aplasia of the trapezius muscle (Vincent et al. 1994).

The syndromic forms of hydrocephalus encompass many different conditions, including chromosome abnormalities, mendelian disorders (WalkerWarburg syndrome, hydrolethalus, Meckel syndrome, Smith-Lemli-Opitz syndrome, Hurler disease, Crouzon craniofacial dysostosis, Apert syndrome, etc.), and malformations or disruption sequences (hydranencephaly, porencephaly, oculo-auriculo-vertebral spectrum, VACTERL association) (Schrander-Stumpel and Fryns 1998). Hydro-lethalus (OMIM 236680) is a lethal condition characterized by polydactyly (postaxial in the hands and preaxial in the feet) and external hydrocephalus (dilated ventricles communicating with the sub-arachnoid space). Meckel-Gruber syndrome (dys-encephalia splanchnocystica, OMIM 249000), another disorder with polydactyly and central nervous system malformation, exhibits kidney and liver cystic dysplasia and encephalocele, without hydro-cephalus (Fraser and Lytwyn 1981). Polyhydramnios, often massive, is invariably present in the hydro-lethalus syndrome. Additional manifestations include macrocephaly with frontal and occipital protuberances, keyhole-shaped foramen magnum, mi-crognathia, poorly formed nose and eyes, cleft lip and palate, heart defects, clubfoot, and lung and upper airway hypoplasia (Anyane-Yeboa et al. 1987; Sa-lonen and Herva 1990). Affected babies are stillborn or die soon after birth (Salonen et al. 1981). However, milder cases allowing survival for up to several months have been described (Aughton and Cassidy 1987; de Ravel et al. 1999) and can perhaps be ex plained in terms of allelic variability. In WalkerWarburg syndrome (OMIM 236670) hydrocephalus, ocular anomalies (microphthalmia), and sometimes encephalocele are found. Familial occurrence of VAC-TERL with hydrocephalus (OMIM 276950) is well established (Sujansky and Leonard 1983; Briard et al. 1984).VACTERL is the acronym for vertebral defects, anal atresia, cardiovascular defects, tracheo-eso-phageal fistula, renal malformations, and limb defects. Autosomal recessive inheritance is likely. In one patient, mutation in the PTEN gene was probably responsible for the phenotype (Reardon et al. 2001). Pedigrees consistent with X-linked inheritance (OMIM 314390) have also been reported (Wang et al. 1993; Froster et al. 1996; Lomas et al. 1998).

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