The bones of the cranial vault, face, and vomer are entirely of intramembra- nous origin

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The skull is conventionally divided into three inter- connected portions: the neurocranium or calvarium, the skull base, and the facial area. The calvarium is made up of the membranous portions of the occipital, parietal, frontal, and temporal bones and is bounded inferiorly by the base of the skull, which separates the calvarium from the facial area. The process of in- tramembranous bone formation, in which ossiﬁca- tion occurs directly in the membrane, is entirely re- sponsible for the development of the parietal, frontal, nasal, lacrimal, zygomatic, and palatal bones and of the vomer, inferior concha, maxilla, and mandible. In addition, it contributes parts of the occipital, sphenoid, and temporal bones, which are formed chieﬂy in cartilage. The ethmoid bone is the only craniofacial bone of entire cartilaginous origin.

Neurocranium. The developing brain is enveloped by a membranous cranium, and the sides and roof of the calvarium are initially formed from a connective tissue capsule in which membranous bones will appear.

At about 9 weeks of gestation, proliferation of mesenchymal cells in a meshwork of collagen fibers is followed by their transformation into osteoblasts that start to deposit osteoid matrix, which later un- dergoes mineralization. Thus, ossification occurs directly in the membrane, in the absence of an inter- vening cartilaginous model. The bones of the cranial vault, face, and vomer are entirely of intramembra- nous origin. At birth they are still in their incom- pletely mineralized membranous capsule, separated by broad strips of connective tissue, the sutures, and patches of connective tissue, the fontanels (Silver- man et al. 1993). Since the neurocranium reflects the growth of the brain and follows the neural growth curve, whereas the facial area follows the somatic growth curve, the neurocranium in the newborn is larger than the face in a proportion of 8:1, decreasing to 2.5:1 by the age of 6 years. Most of the postnatal growth and differentiation of the skull occur during the first 2 years of life, when most features of the adult skull have appeared, including the inner and outer tables, diploic space, vascular markings, and

grooves for the dural sinuses. During childhood, the skull grows at a significantly reduced pace, attaining its definitive size in about the 20th year of life. The sutures and fontanels are prominent in the newborn, progressively diminishing in width during the ensu- ing months. The fetal skull has six fontanels. The posterior fontanel may be closed at birth, while the anterior fontanel, which is the largest (about 2 cm) and most important for clinical evaluation, is usually reduced to fingertip size during the first half of the 2nd year (Silverman et al. 1993). Obliteration of the great sutures of the vault does not occur before the 2nd–

3rd decades, except for the metopic (frontal) and mendosal (occipital) sutures, which usually disap- pear during the ﬁrst 2–3 years of life.

Skull Base. The earliest evidence of skull formation is found during the 5th and 6th weeks of gestation, when dense mesenchymal tissue masses migrate anteriorly to regions that correspond to the primitive ethmoid, auditory, nasal, and optic centers, parallel- ing anterior migration of the notochord toward the oropharyngeal membrane (Lemire et al. 1975). The mesenchymal tissue extends anteriorly to create a ﬂoor for the developing brain, and during the 7th gestational week is transformed into cartilaginous tissue at the level of the basisphenoid and basioc- ciput, giving rise to the primitive base of the skull.

Cartilage also encircles the auditory and olfactory primary centers, whereas anterolateral migration of cartilaginous tissue from the occipital cartilage around the lower portion of the brain forms the early foramen magnum. Fusion of the various cartilaginous masses into a unique cartilaginous area, the chondrocranium, is followed by the appearance of various ossiﬁcation centers, with conversion of the chondrocranium into bone. The temporal bone de- velops from the pars branchialis, which radiates from the 1st and 2nd branchial arches, and from the pars otica, which originates from the auditory vesicle and adjacent mesenchyme. The development of the external and that of the middle ear are closely linked and are independent of development of the internal ear.

Skull

Alessandro Castriota-Scanderbeg, M.D.

Chapter 1

We acknowledge the contribution of Dr. Rodolfo Luna, Dept. of Radiology S. Camillo Hospital, Rome, to the preparation of this chapter.

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This explains why congenital anomalies involving the external ear are often associated with deformities of the middle ear, while the inner ear is not affected and vice versa. However, because mesenchyme is in- volved in the development of all portions of the ear, a combination of malformation may be observed in certain situations, including maternal thalidomide ingestion or certain oto-cranio-facial dysplasias. In the newborn, the sphenoid bone consists of a single central mass (body and lesser wings) and paired lateral masses, the greater wing and pterygoid process.

The pituitary fossa is round and shallow, the dorsum sellae is short, and the clinoid processes are rudi- mentary. The synchondrosis between exoccipital and supraoccipital portions of the occipital bone usually disappears during the 2nd or 3rd year, whereas the spheno-occipital synchondrosis begins to close near the time of puberty but may remain open until adulthood. The cranial half of the ﬁrst sclerotome is incor- porated into the occipital condyles, and only the tip of the odontoid retains a contribution from this seg- ment. The caudal half of the ﬁrst sclerotome forms the anterior, lateral, and posterior masses and arches of the atlas, as well as the odontoid. The second cervical sclerotome gives rise to the body, lateral masses, and posterior arch of the axis.

Facial Area. The face has a dual embryonic origin. The medial facial structures derive from the frontonasal prominence, while the lateral facial structures derive from the branchial arches. Therefore, anomalies tend to affect either medial or lateral structures separate- ly. At 4 weeks of gestation the frontal prominence is an unpaired, median accumulation of tissue com- posed of ectoderm and mesenchyme that overlies the stomodeum superiorly. The stomodeum is also bor- dered laterally by the paired maxillary and inferiorly by the paired mandibular processes, both derived from the ﬁrst branchial arch. On both sides of the frontal prominence, an epithelial thickening gives rise to the nasal placode, which appears to be separated into a medial and a lateral process by 5 weeks of gestation. At this time, the mandibular arches merge together in the midline to form the lower lip and underlying structures. By 6 weeks of gestation the medial nasal processes are displaced toward the midline by the enlarging maxillary processes located lateral to them, and they merge with the frontal prominence to form the frontonasal prominence. This structure will give rise to the nasal and frontal bones, cartilaginous nasal capsule, central one-third of the upper lip, central one-third of the superior alveolar ridge including the incisors, and primary palate (Naidich et

al. 1996). At 8 weeks of gestation, the nasomedial processes merge with the ipsilateral maxillary processes and with each other in the midline, form- ing the upper lip, including the columella and nasal philtrum. In addition, the cheeks and corners of the mouth are formed by the merging of the maxillary and mandibular processes on each side. This merging process is coupled with descent of the nose and with medial migration of the orbits over the nose.

The maxillary processes form the lateral portions of the upper jaw and contribute all of the upper teeth behind the incisors (Naidich et al. 1996). They also give rise medially to paired palatal shelves, which merge with each other in the midline and with the primary palate anteriorly to form the definitive palate at about 10 weeks of gestation. At this time, the nasal septum grows downward and fuses with its cephalic surface and the palate, thus leading to sepa- ration of the right and left nasal chambers and the nasal and oral cavities (Naidich et al. 1996). Develop- ment of the nasal cavity is complete by the 2nd month of fetal life, with membranous ossification of the lower nasal cavity and vomer, and with endo- chondral ossification of the upper nasal cavity and ethmoidal plate. The latter is still cartilaginous at birth and does not ossify until after birth. The maxillary sinuses are the largest and most developed sinuses at birth. Pneumatization proceeds from the in- fundibulum in an inferolateral direction and is complete when the permanent teeth have erupted, allowing the sinus floor to extend below the level of the hard palate into the maxillary ridge. The ethmoid air cells also are present at birth. Development then proceeds from medial to lateral and from anterior to posterior, until complete formation is attained in late puberty. The frontal sinuses develop as a superolater- al extension of the anterior ethmoid sinus into the frontal bone. They are not present at birth and are the last sinuses to reach their full size, usually well after puberty. In the sphenoid sinus, aeration begins at about 3 years of life and proceeds from anterior to posterior underneath the sella turcica until complete pneumatization is attained in early adulthood.

References

Lemire RJ, Loeser JD, Leech RW, Alvord EC. Normal and abnormal development of the human nervous system. Harper &

Row, New York, 1975

Naidich TP, Zimmerman RA, Bauer BS, Altman NR, Bilaniuk LT. Midface: embryology and congenital lesions. In: Som PM, Curtin HD (eds.) Head and neck imaging. C.V. Mosby Company, St. Louis, 1996 (3rd ed.), pp. 3–60

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Silverman FN, Byrd SE, Fitz CR. The skull, spine, and central nervous system. In: Silverman FN, Kuhn JP (eds.) Caffey’s pediatric X-rays diagnosis. An integrated imaging ap- proach. C.V. Mosby Company, St. Louis, 1993 (9th ed.), pp.

4–8

Abnormalities of the Shape and/or Size of the Skull

The skull is the single anatomical area of the body in which most of the dramatic diagnostic improve- ments have occurred in parallel with the increasing sophistication of imaging modalities. The speciﬁc abilities of computed tomography (CT), magnetic resonance imaging (MRI) and, with reference to the infantile skull, of ultrasound (US) to display the brain, ventricles, and meninges and their diseases have expanded the number of reachable diagnoses enormously, resulting in a substantial change in therapeutic strategies. Moreover, the superb tissue con- trast of MRI has made the diagnosis of several entities involving the facial area possible. Nevertheless, the role of conventional radiography in the diagnosis of congenital skull lesions is still remarkable.

Roentgenograms display the skull as a whole, allowing perception of its overall shape, the interrelation- ships between the constitutive portions, its degree of symmetry, the appropriateness of bone mineralization, and the presence of multiple anomalies and their distribution. Skull radiograms can also identify intracranial calcifications, skull fractures, bony defects, and anomalies of the craniocervical junction and first cervical vertebra. It is currently believed that conventional radiography serves as the first imaging modality in most congenital skull defects and that it needs to be complemented by other tech- niques in specific situations.

In this chapter, the possible variations in the size and shape of the skull have been lumped in three large categories, namely, microcephaly, macrocephaly, and craniosynostosis. The ﬁrst two of these are clinical diagnoses, while the third is now best achieved by CT scanning. In the following pages, an attempt has been made to highlight the contribution of skull roentgenology to the proper assessment of these entities. It may be worth noting, however, that several other entities, such as encephaloceles and holoprosencephalic disorders, are discussed elsewhere in the chapter even though they are associated with an abnormal craniofacial contour.

Microcephaly

䉴 [Small head]

Microcephaly is a clinical diagnosis established when the head circumference is found to be more than 3 standard deviations below the normal mean. The head circumference is measured by applying the tape ﬁrmly over the glabella and supraorbital ridges anteriorly and that part of the occiput that gives the maximal circumference. If the head has an unusual or abnormal shape, serial measurements of the changing size of the head can best be made by positioning the tape over whatever points on the forehead and occiput give maximal circumference. Children with familial small stature or growth retardation from any cause have a proportionally small head, and not microcephaly. Thus, the term ‘microcephaly’ implies a disproportion between the head and the remainder of the body. Microcephaly is usually associated with microencephaly, the reduced brain size being the ul- timate cause of skull underdevelopment in most cases. Microcephaly occurs in association with several developmental disorders and destructive processes involving the brain during the fetal period and early infancy. In addition, it can occur as an isolated anomaly and in the context of various malformation syndromes and chromosomal abnormalities.

Microcephaly Associated with Brain Maldevelopment and/

or Destruction. This category includes fetal infections, fetal exposure to teratogenic agents, fetal irradiation, several developmental brain defects, such as polymicrogyria, agyria/pachygyria and arrhinencephaly, and intrapartum or neonatal brain hypoxia (Plum- mer 1952). A discussion of the various forms of brain maldevelopment is beyond the scope of this book. In- trauterine infection with cytomegalovirus, rubella, and toxoplasmosis are important causes of microcephaly of prenatal onset. Symptoms in these disorders, including microcephaly, result from direct con- tamination of various tissues and organs by the in- fectious agent. Thus, intrauterine infections do not produce the multiple major and minor structural malformations that are seen, for example, in association with chromosomal abnormalities, single mutant genes, and teratogenic agents (Holmes 1987). Cyto- megalovirus is the most common fetal infection and can occur in fetuses of mothers with either primary or recurrent infection. However, only 15% of the infants born to mothers with primary infection have clinical evidence of disease during the neonatal period. Microcephaly, deafness, and impaired mental

Abnormalities of the Shape and/or Size of the Skull 5

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functioning may not become apparent for several months (Kumar et al. 1973). When fully expressed, the disease is characterized by intrauterine growth retardation, hepatosplenomegaly, jaundice, petechial rash, chorioretinitis, microcephaly, intracranial calcifications, seizures, and mental retardation (Stagno et al. 1977). Permanent severe neurological disability is found in 55% of affected individuals. Encephalo- clastic lesions (hydranencephaly, porencephaly) and cortical dysplasia (micropolygyria) may occur as a result of brain infection during the stage of neuronal migration. The cerebral calcifications are typically periventricular in distribution, whereas in congenital toxoplasmosis infection may have a more widespread pattern (neither pattern is specific, however). Eye manifestations occur less commonly than in rubella and toxoplasmosis. From 50% to 80% of fetuses ex- posed to maternal rubella prior to the 8th week of gestation become infected. In the 2nd trimester, the percentage of infected fetuses falls to 10–20%. The earlier in pregnancy infection occurs, the higher the likelihood of severe clinical manifestations at birth, including marked thrombocytopenia, congenital heart defect, viral interstitial pneumonia, hepatosplenomegaly, obstructive jaundice, and osteolytic metaphyseal bone lesions. Fetal death may occur. De- layed manifestations of the congenital rubella syndrome include growth deficiency, hearing loss, congenital heart disease, mental retardation, and cataract or glaucoma (Peckham et al. 1979). Micro- cephaly is relatively uncommon. The virus may remain in the tissues and cause a pathology e.g., dia- betes mellitus, years after birth. Congenital toxo- plasmosis may manifest at birth with fever, macu- lopapular rash, thrombocytopenia, lymphade- nomegaly, hepatosplenomegaly, microcephaly, microphthalmia, and convulsions. Cerebral calcifications and chorioretinitis may be present at birth or appear later. The disease can have a fatal course within days after birth. Involvement of the central nervous system occurs in 50% of the infected fetuses. Hy- drocephalus may result from aqueductal stenosis caused by meningoencephalitis and ependymitis (McCabe and Remington 1988; Daffos et al. 1988).

Toxoplasma gondii has a worldwide distribution. The vast majority of infected adult individuals are asymptomatic, but toxoplasmic encephalitis is a frequent complication in patients with AIDS or other forms of immunodeﬁciency. The fetal varicella syn- drome, which occurs in the offspring of women in- fected with varicella prior to the 20th week of gestation, involves microcephaly in association with mental deﬁciency and cortical brain atrophy, with or

without seizures. Prenatal growth deficiency of variable degree, chorioretinitis, cutaneous scars, and limb defects are additional features (Laforet and Lynch 1947). In newborns with perinatal herpes sim- plex virus infection, manifestations include micro- cephaly, periventricular and cortical brain calcifications, retinal dysplasia and, in severe cases, encephalitis characterized by widespread cystic brain lesions (multicystic leukoencephalopathy). Micro- cephaly is seen in fetuses exposed to several terato- genic agents. The fetal alcohol syndrome is character- ized by growth deficiency of prenatal onset, mild to moderate microcephaly, short palpebral fissures, mental deficiency, and fine motor dysfunction. Addi- tional manifestations include maxillary hypoplasia, micrognathia, epicanthal folds, thin upper lip, altered joint position and/or function, small fingernails, and cardiac septal defects (Jones et al. 1973; Jones and Smith 1973). While the effect of daily ingestion of a small amount of alcohol by the mother is usually negligible for the developing fetus, the intake of moderate to high levels is associated with a signifi- cant fetal risk of developing serious problems, the most frequent of which is mental retardation (Lemoine and Lemoine 1992). Congenital anomalies are found in 30–50% of infants born to heavy drinkers, and the greater the intake the more severe the signs. Approximately 1 in 300 babies is born showing prenatal effects of alcohol, and 1 in 600 has fetal alcohol syndrome. Thus, the teratogenic effects of alcohol are a major public health concern (Samp- son et al. 1997). In the fetal aminopterin/methotrexate syndrome, which is caused by maternal exposure to the folic acid antagonist, aminopterin, and its methyl derivative, methotrexate, during the first trimester of pregnancy, microcephaly is associated with a severe form of cranial dysplasia, consisting in marked hypoplasia of the calvarial bones, wide fontanels, and premature synostosis of lambdoid or coronal sutures. Features in the face include a broad nasal bridge, shallow supraorbital ridges, prominent eyes, epicanthal folds, maxillary and mandibular hypoplasia, and low-set ears. Additional manifestations include growth retardation of prenatal onset persisting postnatally, mesomelic limb shortening, clubfoot, syndactyly, and normal mental development (Thier- sch 1952; Shaw and Steinback 1968). Maternal phenylketonuria fetal syndrome involves the off- spring of mothers affected by phenylketonuria (OMIM 261600), a metabolic disorder inherited as an autosomal recessive trait. Major manifestations are mental deficiency, growth retardation, mild neurological impairment (increased muscular tone, stra-

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bismus), microcephaly, and a characteristic facies, with prominent glabella, long philtrum, upturned nasal tip, thin upper lip, maxillary hypoplasia, and micrognathia. Cardiac defects occur in 15% of the patients. The disorder is due to the toxic effect of ab- normally high levels of phenylalanine in the mother, which accumulates on the fetal side of the placenta and interferes with normal central nervous system development. The severity of the manifestations in the fetus is directly related to the levels of phenylalanine in the maternal blood (Lipson et al. 1984; Levy and Waisbren 1983). It is therefore of the utmost im- portance that the phenylalanine levels be controlled prior to conception (Jones 1997).

Isolated (Nonsyndromal) Microcephaly. Primary micro- cephaly (OMIM 251200) is a genetic disorder in which microcephaly is associated with a small but apparently normally formed brain and mental retardation. Smallness of the brain is caused by a defect in neuronal proliferation at about 2–4 weeks of gestation, resulting in the presence of too few neuronal cells in the germinal matrix. The disorder is distinc- tively different from microcephaly caused by early- onset degenerative brain diseases characterized by progressive loss of previously formed brain structures and of previously acquired neurological func- tions (Qazi and Reed 1973). In primary microcephaly, other neurological, visceral, or skeletal defects are usually not associated, although short stature (Mikati et al. 1985), neurological symptoms such as quadri- plegia and seizures (Tolmie et al. 1987), and dysmorphic features such as small ears, protruding midface, and retrognathia (Rizzo and Pavone 1995) have all been described in some pedigrees. Most cases are autosomal recessive. The disorder is genetically hetero- geneous: one form, MCPH1, is caused by mutation in the gene encoding microcephalin, and another, MCPH5, is caused by mutation in the ASPM gene. Ad- ditional loci include MCPH2 (OMIM 604317) at chro- mosomal location 19q13; MCPH3 (OMIM 604804) at 9q34; and MCPH4 (OMIM 604321) at 15q15-q21 (Roberts et al. 1999; Moynihan et al. 2000; Jamieson et al. 1999). Instances of microcephaly with autosomal dominant transmission (OMIM 156580) have also been recognized (Haslam and Smith 1979). Unlike autosomal recessive microcephaly, intellectual impairment is less severe and additional anomalies are either less pronounced or absent (Ramirez et al. 1983;

Rossi et al. 1987; Evans 1991; Hennekam et al. 1992).

The frequency of true microcephaly has been reported to be about 1 in 250,000 in The Netherlands (van den Bosch 1959).

Syndromal Microcephaly. Microcephaly is particularly frequent in several syndromes of growth deﬁciency, including Seckel syndrome, 3 M syndrome, fetal alcohol syndrome, and Dubowitz syndrome, and in a number of chromosomal imbalances, some of which are discussed elsewhere in this book. Osteodysplastic primordial dwarﬁsm type I (cephaloskeletal dysplasia of Taybi-Linder type, OMIM 210710) is characterized by marked microcephaly, with dolichocephaly, small receding forehead, and prominent occiput (Fig. 1.1);

brain malformations such as brain dysgenesis, pachygyria, heterotopias, agenesis of corpus callosum or cerebellar vermis, and hypoplasia of frontal lobes; unusual facies with large protruding eyes, ﬂat bridge of nose, low-set ears, and absent hair; and skeletal abnormalities of the long bones (short long bones with enlarged and irregular metaphyses, epiphyseal maturation delay), hands and feet (large hands and feet, brachydactyly and clinodactyly), spine (cleft vertebral arches, platyspondyly), and pelvis (hypoplastic iliac wings and acetabuli, hori- zontal acetabular roofs) (Taybi and Linder 1968;

Sigaudy et al. 1998). Cephaloskeletal dysplasia differs from Seckel bird-headed dwarfism (OMIM 210600) in that it has abnormal body proportions with short limbs and large hands and feet, sparse or absent scalp hair, short neck, and hyperkeratosis. Bloom syndrome (OMIM 210900) is an autosomal recessive disorder most commonly affecting Ashkenazi Jews and caused by mutations in the gene encoding DNA helicase RecQ protein-like-3, which maps to 15q26.1 (German et al. 1994). The features are proportionate, pre- and postnatal growth deficiency resulting in adult short stature, microcephaly with malar hypoplasia, and skin lesions, including a butterfly erythema of the midface usually developing during the 1st year, and areas of hypo- and hyperpigmentation (Bloom 1954, 1966). Skeletal features are not always present and include syndactyly, polydactyly, clinodactyly of the 5th finger, short lower limbs, and clubfoot. Neoplasms, including leukemia and solid tumors, occur at a significantly higher frequency than in the general population (Sawitsky et al. 1966). Chromosomal instability is a characteristic feature of the disorder (Cohen and Levy 1989). Microcephaly-chorioretinopathy is a familial disorder distinct from simple microcephaly (OMIM 251200). Mental retardation is a constant feature. Chorioretinopathy is remarkably similar to that seen in fetal toxoplasmosis (McKusick et al. 1966;

Schmidt et al. 1968). The disorder is transmitted as an autosomal recessive trait (OMIM 251270) (Cantu et al. 1977; Abdel-Salam et al. 2000) or as an autosomal dominant with variable expressivity (OMIM

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156590) (Alzial et al. 1980; Tenconi et al. 1981). The autosomal dominant form of microcephaly-chori- oretinopathy may be identical to lymphedema, mi- crocephaly, chorioretinopathy syndrome (OMIM 152950), another autosomal dominant condition with variable expression (Limwongse et al. 1999). The pseudo-TORCH syndrome (pseudotoxoplasmosis syndrome, OMIM 251290) is a familial disorder whose clinical course closely mimics that of TORCH

(toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) infection. Micro- cephaly, mental retardation, and cerebral calciﬁca- tions are the chief features, whereas hepatomegaly, liver dysfunction, petechial rash, and thrombocytopenia are occasionally present (Reardon et al.

1994). Unlike toxoplasmosis and the other TORCH infections, serology is negative and chorioretinopathy is absent. This trait can be either autosomal or X- linked recessive (Ishitsu et al. 1985). Another genetic disease mimicking TORCH infection is Aicardi- Goutières syndrome (OMIM 225750). This disorder is a form of progressive familial encephalopathy with onset in infancy to early childhood, manifesting with extensive calcification of the basal ganglia, brain tissue loss (especially gray matter), and cerebrospinal fluid pleocytosis, leading to death in early childhood (Aicardi and Goutières 1984; Mehta et al. 1986). Mi- crocephaly is of postnatal onset. Points of difference from intrauterine infection are that thrombocytopenia with purpuric rash does not occur and viral stud- ies are unrewarded. The disorder is genetically heterogeneous, with one locus on chromosome 3p21 (Crow et al. 2000). Locus heterogeneity accounts for the potential difficulties in the differentiation of this condition from pseudo-TORCH syndrome. The dis- order must be distinguished from Aicardi syndrome (OMIM 304050), a condition characterized by infantile spasms, severe brain defects with microcephaly (agenesis of corpus callosum, cerebral ventricular enlargement, gray matter heterotopias, pachygyria, hypoplasia of cerebellar vermis), microphthalmia, and chorioretinopathy with multiple lacunae (Aicar- di et al. 1969). Flexion spasms are the usual present- ing symptoms in the infant. Severe mental retardation is almost invariably present. Skeletal features may include hemivertebrae, butterfly and fused ver- tebrae, spina bifida, scoliosis, and rib anomalies, including absent, extra, fused, or bifid ribs (Dennis and Bower 1972). Patients commonly die before or during adolescence, usually of pneumonia. The inheritance is probably X-linked dominant, with lethality in the hemizygous male. Chromosome breakpoints at Xp22 have been reported, pointing to location of the Aicar- di gene in this area (Ropers et al. 1982; Naidich et al.

1990). It has been suggested that Aicardi syndrome and focal dermal hypoplasia syndrome (Goltz-Gorlin syndrome, OMIM 305600) are allelic disorders, the different phenotypes resulting from different patterns of X-inactivation (Lindsay et al. 1994). The genes for short stature (OMIM 312865), X-linked recessive chondrodysplasia punctata (OMIM 302950), mental retardation (OMIM 300428), X-linked ichthyo-

Fig. 1.1 a, b. Osteodysplastic primordial dwarﬁsm type I (cephaloskeletal dysplasia or Taybi-Linder syndrome) in a baby boy. a In the newborn phase microcephaly is observed, with prominent occiput and receding forehead. The sutures are nar- row and the anterior fontanel is small. b At 11 months micro- cephaly is still present, but the occipital protuberance is no longer appreciable and the skull looks more nearly round.

(From Vichi et al. 2000) a

b

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sis (OMIM 308100), and Kallmann syndrome (OMIM 308700) (Ballabio and Andria 1992) are also mapped within the Xp22.3-p22.2 region.

Radiographic Synopsis

AP and LL projections. Because the clinical measure- ment of the head circumference is reliable, conventional radiography plays a marginal role in the diagnosis of microcephaly. Nevertheless, the intracranial volume can be inferred from the cranial diameters taken on plain radiographs (Cronqvist 1968; Erasmie et al. 1982; Nellhaus 1968; Haack and Meihoff 1971).

Prenatal ultrasound allows for accurate assessment of the size of the fetal head and may provide insights into associated brain anomalies. CT and MRI may be used to estimate the cranial area (Hahn et al. 1984), but are especially suited for displaying brain abnormalities and malformations that are eventually asso- ciated with microcephaly (Jaworski et al. 1986).

1. Microcephaly; intracranial calciﬁcations (TORCH infections, pseudo-TORCH syndrome, Aicardi- Goutières syndrome)

2. Microcephaly; maxillary hypoplasia; microg- nathia (fetal alcohol syndrome, maternal phenyl- ketonuria fetal syndrome)

3. Microcephaly; severe hypoplasia of calvarial bones, with wide fontanels; premature synostosis of lambdoid or coronal sutures; maxillary and mandibular hypoplasia (fetal aminopterin/metho- trexate syndrome)

4. Severe microcephaly, with small receding forehead and prominent occiput; narrow sutures; small fon- tanels (osteodysplastic primordial dwarﬁsm type I) 5. Mild microcephaly; mild maxillary hypoplasia

(Bloom syndrome) Associations

• Adams-Oliver syndrome

• Adducted thumb syndrome

• Aicardi syndrome

• Aicardi-Goutières syndrome

• Angelman syndrome

• Aniridia-Wilms tumor association

• Beckwith-Wiedemann syndrome

• Bloom syndrome

• Börjeson-Forssman-Lehmann syndrome

• Brain atrophy or maldevelopment (prenatal or perinatal hypoxia and irradiation, agyria/pachygyria, polymicrogyria, arrhinencephaly)

• Branchio-oculo-facial syndrome

• C syndrome (Opitz trigonocephaly syndrome)

• Caudal dysplasia sequence

• Cephaloskeletal dysplasia (Taybi-Linder syndrome)

• Cerebro-costo-mandibular syndrome

• Cerebro-oculo-facio-skeletal (COFS) syndrome

• Chondrodysplasia punctata, Conradi-Hünermann

• Chromosome syndromes (3p–, 4p–, 5p–, 11q–, 13q–, 18p–, 18q–, 4p+, 10q+, 15q+, trisomy 13 and 18, XXXXX, XXXXY)

• Cockayne syndrome

• Cofﬁn-Lowry syndrome

• Cofﬁn-Siris syndrome

• Cohen syndrome

• Craniosynostosis syndromes

• De Lange syndrome

• Deprivation dwarﬁsm

• Dubowitz syndrome

• Dyggve-Melchior-Clausen syndrome

• Fanconi pancytopenia syndrome

• Fetal exposure to teratogens (alcohol, aminopterin/methotrexate, maternal phenylketonuria, lead mercury)

• Fetal infections (cytomegalovirus, toxoplasmosis, rubella, herpes simplex, varicella, syphilis)

• Focal dermal hypoplasia syndrome (Goltz-Gorlin syndrome)

• Freeman-Sheldon syndrome

• Hallermann-Streiff syndrome

• Homocystinuria

• Incontinentia pigmenti

• Johanson-Blizzard syndrome

• Killian/Teschler-Nicola syndrome

• Klippel-Trenaunay-Weber syndrome

• Lenz microphthalmia syndrome

• Lesch-Nyhan syndrome

• Lymphedema/microcephaly/chorioretinopathy syndrome

• Marden-Walker syndrome

• Meckel syndrome

• Meningitis, encephalitis

• Microcephaly, primary

• Microcephaly-chorioretinopathy syndrome

• Microphthalmia-linear skin defects syndrome

• Miller-Dieker syndrome

• Neu-Laxova syndrome

• Noonan syndrome

• Oculo-dento-digital syndrome

• Oro-facio-digital syndrome type I

• Oto-palato-digital syndrome type II

• Peters’ plus syndrome

• Prader-Willi syndrome

• Pseudo-TORCH syndrome

• Raine syndrome

• Restrictive dermopathy

• Riley-Day syndrome

• Roberts syndrome

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• Rothmund-Thomson syndrome

• Rubinstein-Taybi syndrome

• Seckel syndrome

• Shprintzen syndrome

• Smith-Lemli-Opitz syndrome

• Steinert myotonic dystrophy syndrome

• Thanatophoric dysplasia

• Townes-Brocks syndrome

• Tricho-rhino-phalangeal syndrome (Langer-Giedion syndrome)

• Walker-Warburg syndrome

• Williams syndrome

• Xeroderma pigmentosa syndrome

• X-linked a-thalassemia/mental retardation syn- drome

• Yunis-Varon syndrome

References

Abdel-Salam GMH, Czeizel AE, Vogt G, Imre L. Microcephaly with chorioretinal dysplasia: characteristic facial features.

Am J Med Genet 2000; 95: 513–5

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Macrocephaly

䉴 [Large head]

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-

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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 presenta- tion. 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 im- mature 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 subdural spaces can be caused by a variety of factors, including subdural hygroma, meningitis, shunt dysfunction, brain malformations, dehydration, malnutri- tion, 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 un- known (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 on- set 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 occasion- al 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 polydactyly 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). Interest- ingly, at least one type of craniosynostosis (OMIM 123100) is caused by mutation in a gene located at 7p.

Phenotypic overlap is recognized between Greig syn- drome and acrocallosal syndrome (OMIM 200990)

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(Chudley and Houston 1982), an autosomal recessive disorder characterized by postaxial polydactyly, hal- lux duplication, macrocephaly with protruding forehead and occiput, hypertelorism, hypoplastic or absent corpus callosum, and severe mental retardation (Schinzel and Schmid 1980; Schinzel 1982). Speciﬁ- cally, 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 acrocallosal 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 syn- drome (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 telangiectatica congenita may occur in association with megalencephaly and macrocephaly, central nervous system malformations (Chiari I malformation, spinal cord syrinx, hydrops of the optic nerves), body asymme- try, macrosomia, nevus ﬂammeus, and visceral and subcutaneous cavernous hemangiomas. The latter association, referred to as megalencephaly-cutis mar- morata 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-Lélek 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 hypoplasia, 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 pro- minent feature. Canavan disease (cerebral spongy degeneration, OMIM 271900), a common disorder in the Ashkenazi Jewish population, is caused by deﬁ- ciency 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 aspartoacylase, 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