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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 ultimate 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 polymi-crogyria, agyria/pachygyria and arrhinencephaly, and intrapartum or neonatal brain hypoxia (Plummer 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 contamination of various tissues and organs by the infectious 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). Cytomegalovirus 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 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 exposed 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, hepato-splenomegaly, obstructive jaundice, and osteolytic metaphyseal bone lesions. Fetal death may occur. Delayed manifestations of the congenital rubella syndrome include growth deficiency, hearing loss, congenital heart disease, mental retardation, and cataract or glaucoma (Peckham et al. 1979). Microcephaly is relatively uncommon. The virus may remain in the tissues and cause a pathology e.g., diabetes mellitus, years after birth. Congenital toxo-plasmosis may manifest at birth with fever, macu-lopapular rash, thrombocytopenia, lymphade-nomegaly, hepatosplenomegaly, microcephaly, mi-crophthalmia, 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. Hydrocephalus 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 syndrome, which occurs in the offspring of women infected 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 simplex virus infection, manifestations include microcephaly, periventricular and cortical brain calcifications, retinal dysplasia and, in severe cases, encephalitis characterized by widespread cystic brain lesions (multicystic leukoencephalopathy). Microcephaly is seen in fetuses exposed to several terato-genic agents. The fetal alcohol syndrome is characterized by growth deficiency of prenatal onset, mild to moderate microcephaly, short palpebral fissures, mental deficiency, and fine motor dysfunction. Additional 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 significant 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 (Sampson 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 hy-poplasia 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 hypopla-sia, 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 offspring 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 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 abnormally 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 importance that the phenylalanine levels be controlled prior to conception (Jones 1997).

Isolated (Nonsyndromal) Microcephaly. Primary microcephaly (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 distinctively different from microcephaly caused by early-onset degenerative brain diseases characterized by progressive loss of previously formed brain structures and of previously acquired neurological functions (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 dysmor-phic 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 heterogeneous: one form, MCPH1, is caused by mutation in the gene encoding microcephalin, and another, MCPH5, is caused by mutation in the ASPM gene. Additional loci include MCPH2 (OMIM 604317) at chromosomal 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 callo-sum 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, epi-physeal maturation delay), hands and feet (large hands and feet, brachydactyly and clinodactyly), spine (cleft vertebral arches, platyspondyly), and pelvis (hypoplastic iliac wings and acetabuli, horizontal 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

Radiographics Primordial Dwarfism

Fig. 1.1 a, b. Osteodysplastic primordial dwarfism type I (ce-phaloskeletal 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 narrow and the anterior fontanel is small. b At 11 months microcephaly is still present, but the occipital protuberance is no longer appreciable and the skull looks more nearly round. (From Vichi et al. 2000)

Fig. 1.1 a, b. Osteodysplastic primordial dwarfism type I (ce-phaloskeletal 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 narrow and the anterior fontanel is small. b At 11 months microcephaly is still present, but the occipital protuberance is no longer appreciable and the skull looks more nearly round. (From Vichi et al. 2000)

156590) (Alzial et al. 1980; Tenconi et al. 1981). The autosomal dominant form of microcephaly-chori-oretinopathy may be identical to lymphedema, microcephaly, 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. Microcephaly, mental retardation, and cerebral calcifications 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 chorioretinopa-thy 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). Microcephaly is of postnatal onset. Points of difference from intrauterine infection are that thrombocytope-nia with purpuric rash does not occur and viral studies 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 disorder 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 presenting symptoms in the infant. Severe mental retardation is almost invariably present. Skeletal features may include hemivertebrae, butterfly and fused vertebrae, 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 Aicardi 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-

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

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  • murrin
    What is automisal recesive microcephaly?
    9 years ago
    Can arsenic cause microcephely?
    7 years ago

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