Disorders of Brain Size

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Chapter 25 Disorders of Brain Size

Introduction

The two obvious disorders of brain size – microcephaly (too small) and macrocephaly (too large) – are very common or relatively common disorders, depending largely on how they are defined. Microcephaly (MIC) and macrocephaly are usually defined as head circumference – or more formally, “occipitofrontal circumference” (OFC) – that is more than 2 standard deviations (SD) below or above the mean for age and gender [Opitz and Holt, 1990; Roche et al., 1987]. However, because this criterion includes many developmentally normal individuals and a host of underlying causes, researchers studying both usually define severe MIC or macrocephaly as OFC more than 3 or 4 SD below or above the mean [Barkovich et al., 1998; Dobyns, 1996; Woods et al., 2005; Jackson et al., 2002].

When defined as OFC smaller than 2 SD below the mean, approximately 2.3 percent of the population would be expected to have MIC if OFC is truly a normally distributed measurement [Ashwal et al., 2009]. The published estimates for OFC below −2 SD at birth are 55.8 per 10,000 [Vargas et al., 2001] and 54 per 10,000 [Dolk, 1991]. Based on 2004 census data of 3.7 million live births in the United States [Dye, 2005], this would predict that 25,000 neonates are born each year with MIC, far less than 2.3 percent of the population, which would be about 85,100 children. The difference may be accounted for by a non-normal distribution of neonatal head size, postnatal MIC, or incomplete ascertainment. If MIC is defined as OFC smaller than 3 SD below the mean, this would be expected to apply to only approximately 0.1 percent of the population, which agrees well with the published estimate of approximately 14 per 10,000 [Dolk, 1991].

The same arguments apply for macrocephaly, but this criterion includes any cause of a large head size, including hydrocephalus, certain bone diseases, and many other causes. When considering specifically increased brain size, the term megalencephaly (MEG), or “large brain,” is preferred. Here we will consider the causes of MIC and macrocephaly or MEG separately.

Microcephaly

Microcephaly is a descriptive term that refers to a cranium that is significantly smaller than the standard for the individual’s age and sex. It should usually be considered as a neurologic sign rather than a disorder, as it may result from many different causes that affect several different stages of brain development [Ashwal et al., 2009]. MIC is a common neurological sign in isolation, and in association with other abnormalities. Across the literature and in practice, the definition of MIC and the approach to evaluation of affected individuals are not uniform [Leviton et al., 2002; Opitz and Holt, 1990]. About 1 percent of referrals to child neurologists are specifically for evaluation of MIC [Lalaguna-Mallada et al., 2004], and approximately 15 percent of children referred to child neurologists for evaluation of developmental disabilities have MIC [Watemberg et al., 2002].

Historically, a confusing plethora of terms have been used to describe and classify various types of MIC. When severe congenital MIC is seen without other major brain or somatic malformations it is known as primary microcephaly or microcephalia vera, a term first introduced by Giacomini in 1885 [Giacomini, 1885]. It is likely that primary MIC is not a distinct etiologic category, but a term that describes a group of disorders, many with etiologies not yet known. As MIC can conceivably result from any developmental defect or brain injury that disturbs prenatal or early postnatal brain growth, many different causes are known. Improvements in neuroimaging and genetic technologies have resulted in a better understanding of the types and causes of MIC, suggesting that a reappraisal of schemes for classification and diagnostic testing is warranted. We have chosen to separate MIC into two broad categories, congenital and postnatal onset.

Table 25-1 summarizes some of the common disorders associated with these two groups of microcephaly.

Table 25-1 Etiologies of Congenital and Postnatal Microcephaly

  Congenital Postnatal Onset
GENETIC
Isolated/Inborn errors of metabolism Autosomal-recessive microcephaly
Autosomal-dominant microcephaly
X-linked microcephaly (uncertain)
Chromosomal (rare: “apparently” balanced rearrangements and ring chromosomes)
Congenital disorders of glycosylation
Mitochondrial disorders
Peroxisomal disorders
Menkes’ disease
Amino acidopathies and organic acidurias
Glucose transporter defect
Syndromic
Chromosomal Trisomy 21, 13, 18
Unbalanced rearrangements
 
Contiguous gene deletion 4p deletion (Wolf–Hirschhorn syndrome)
5p deletion (cri du chat syndrome)
7q11.23 deletion (Williams’ syndrome)
22q11 deletion (velocardiofacial syndrome)
17p13.3 deletion (Miller–Dieker syndrome)
Single-gene defects Cornelia de Lange syndrome
Holoprosencephaly (isolated or syndromic)
Smith–Lemli–Opitz syndrome
Seckel’s syndrome
Rett’s syndrome
Nijmegen breakage syndrome
Ataxia-telangiectasia
Cockayne’s syndrome
Aicardi–Goutières syndrome
XLAG syndrome
ACQUIRED
Disruptive injuries Fetal death of a twin
Ischemic stroke
Hemorrhagic stroke
Traumatic brain injury
Hypoxic-ischemic encephalopathy
Hemorrhagic and ischemic stroke
Infections TORCHES syndrome and HIV Meningitis and encephalitis
Congenital HIV encephalopathy
Teratogens/Toxins Alcohol, hydantoin, radiation
Maternal phenylketonuria
Poorly controlled maternal diabetes
Lead poisoning
Chronic renal failure
Deprivation Maternal hypothyroidism
Maternal folate deficiency
Maternal malnutrition
Placental insufficiency
Hypothyroidism
Anemia
Malnutrition
Congenital heart disease

HIV, human immunodeficiency virus; TORCHES, toxoplasmosis, rubella, cytomegalovirus, herpes simplex, syphilis; XLAG, X-linked lissencephaly with abnormal genitalia.

(Adapted from Ashwal S, et al. Practice parameter: Evaluation of the child with microcephaly [an evidence-based review]: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 73:887–897, 2009.)

Pathology

The embryology relevant to neuronal proliferation and microcephaly is reviewed in the following chapter describing malformations of cortical development (Chapter 26). The pathological changes described in different types of MIC are diverse, which is not surprising, given the large number of associated conditions. Here we will confine our comments to severe congenital microcephaly. The macroscopic changes described in most pathological reports are subtle, consisting of very small cerebral volume, normal or minimally altered pattern of convolutions, and normal size of the third and lateral ventricles [Robain and Lyon, 1972]. However, our brain imaging experience shows that this is not quite true, as, in many forms, the frontal lobes are disproportionately small, and the number and complexity of the gyri and the depth of sulci are generally reduced.

The microscopic changes, especially those involving the cerebral cortex, are heterogeneous. In one group, the cortex has normal thickness and lamination, but the number of neurons in the brain is dramatically reduced. We suppose these to be the less severely affected individuals, although the available data are not clear on this point. In probably several other types of MIC, the cortex appears abnormally thin, presumably resulting from premature exhaustion of the germinal zone [Barkovich et al., 1992; Evrard et al., 1989].

In the latter, abnormalities of cellular architecture predominate in the first two layers of the cortex, referred to as “type I familial MIC” by Robain [Robain and Lyon, 1972]. Layer two is almost devoid of granule neurons, and may be fragmented into small nests (sometimes called “glomeruli”) or small columns that protrude into the molecular layer. In a few individuals, the vertical bands of neurons arising in layer two cross the molecular layer to protrude into the meninges. Neurons may be seen in the molecular layer, either as scattered large pyramidal or stellate neurons, or as persistence of a fetal monolayer of granule neurons found just beneath the pia. The lower cortical layers were less affected, but with abnormal distribution of cells in some areas. In some brains, persistence of fetal wavy or “combed” monocellular bands in the middle of the cortex has been seen [Robain and Lyon, 1972]. In these types of MIC, the cerebellum is typically small but proportionate to the reduced size of the cerebrum or relatively larger.

Severe congenital MIC has been observed in combination with several other types of brain malformations, including holoprosencephaly, disproportionate brainstem and cerebellar hypoplasia, true lissencephaly with widespread malformation of neuronal migration, diffuse periventricular nodular heterotopia, and diffuse polymicrogyria (Table 25-2).

Table 25-2 Severe Congenital Microcephaly Types by Imaging or Pathology

Microcephaly Type References
MIC WITH SIMPLIFIED GYRAL PATTERN ONLY (PRIMARY MIC)
MIC with normal six-layer cortex (probably high-functioning) Barkovich et al. [1992]
MIC with layer two cortical dysplasia Robain and Lyon [1972]
MIC with simplified gyri and enlarged extra-axial space (may also be associated with postnatal MIC) Basel-Vanagaite and Dobyns [2010]
MIC WITH DISPROPORTIONATE PONTOCEREBELLAR HYPOPLASIA (MIC-PCH)
MIC with simplified gyri and pontocerebellar hypoplasia, NOS Basel-Vanagaite and Dobyns [2010]
MIC with simplified gyri and pontocerebellar hypoplasia and enlarged extra-axial space Basel-Vanagaite and Dobyns [2010]
Von Monakow type MIC-PCH Thurel and Gruner [1960]
MICROLISSENCEPHALY (MLIS) WITH TRUE AGYRIA-PACHYGYRIA
Barth MLIS syndrome Barth et al. [1982]
Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) Juric-Sekhar et al. [2010]
Norman–Roberts MLIS syndrome Dobyns et al. [1984]
MIC WITH DIFFUSE PERIVENTRICULAR NODULAR HETEROTOPIA (MIC-PNH)
MIC-PNH Robain and Lyon [1972]
MIC WITH DIFFUSE POLYMICROGYRIA (MDP)
MDP isolated Barkovich et al. [1992]
MDP with other congenital anomalies (somatic) Pavone et al. [2000]
MIC WITH OTHER CORTICAL MALFORMATIONS
MIC with cortical malformations, NOS (not well defined)  

MIC, microcephaly; NOS, not otherwise specified.

The authors have seen agenesis of the corpus callosum in most different types of MIC, and suspect that, in most, it is a nonspecific feature of slowed brain growth. (The growing cerebral hemispheres must be closely enough apposed for the precallosal sling to cross the gap, which requires growth.) We have therefore not included MIC and agenesis as a classification in its own right at this time, although this may need to be added in the future.

Brain Imaging

In most patients with primary MIC, brain imaging reveals characteristic abnormalities that we designated “microcephaly with simplified gyral pattern” [Barkovich et al., 1998; Dobyns and Barkovich, 1999]. This pattern consists of a reduced number of gyri separated by abnormally shallow sulci. Common associated abnormalities include foreshortened frontal lobes, mildly enlarged lateral ventricles, and sometimes a thin corpus callosum or even partial agenesis of the corpus callosum.

While interpretation of brain imaging studies in MIC would seem to be straightforward, this has proved challenging in practice, primarily for severe congenital MIC. First, scans of children with MIC are often interpreted as normal, other than for the small size, if this is recognized on the imaging study, but close inspection will show the features noted above. While these changes can be subtle, they are not normal. Further, brain imaging in individuals with more severe forms of MIC may show fewer convolutions, with some broader than 2 cm, leading to interpretation as “pachygyria.” But imaging in the large majority of these patients shows a normal or an especially thin cortex, while true lissencephaly (agyria and pachygyria) is always associated with an abnormally thick cortex. Clinicians often respond to such reports by ordering tests that are appropriate for children with true lissencephaly, which are always negative. With the rare exception of mutations of TUBA1A, no genes associated with microlissencephaly (MLIS) have been reported.

While the first several genes associated with severe congenital MIC were associated with nonspecific brain imaging patterns (as described above), several recently identified MIC genes are associated with recognizable patterns of abnormalities. Focusing on children with severe congenital MIC, the authors recently reviewed brain imaging in approximately 250 children with MIC, most of whom (230 of 247) had MIC without associated somatic anomalies [Basel-Vanagaite et al., 2010]. Among this group of patients, four relatively common brain imaging patterns were found, which involved abnormalities in the gyral pattern, size of extra-axial space, and relative size of the brainstem and cerebellum in comparison to the cerebrum. The four groups were:

Examples are shown in Figure 25-1. Rare forms of severe MIC are associated with additional brain malformations, as listed in Table 25-2.

Clinical Features

The clinical manifestations associated with MIC are remarkably heterogeneous. In most individuals with severe congenital MIC, examination reveals obvious small head size, often with a low, sloping forehead and a flat occiput. The face and ears are normal, but because of the small head size, may appear disproportionately large. Cognitive impairment is moderate in some types, but severe to profound in others. In moderately affected patients, hyperactivity may dominate the patient’s behavior, while tone is typically normal. In severely affected children, spasticity and epilepsy predominate. In children with milder forms of MIC, a variety of subtle dysmorphic features may be present and may be helpful in identifying a specific syndrome causing MIC. Features of some of these syndromes are outlined in the different tables in this chapter.

For children with the most common, relatively high-functioning forms of primary MIC, survival far into adult life is typical. For more severely handicapped children unable to walk or feed by mouth, the mortality rate is higher, with survival often limited to 10–20 years, although no formal studies have been done. Children with MIC and other severe brain malformations, especially those with cortical malformations such as lissencephaly, heterotopias, and polymicrogyria, are likely to have much shorter survival.

In general, all forms of MIC are associated with below-average intelligence [Dolk, 1991; Nelson and Deutschberger, 1970]. However, mild MIC with OFC between −2 and −3 SD is not inevitably linked with mental retardation; 7.5 percent of a large group of microcephalic children had normal intelligence [Martin, 1970; Sells, 1977]. However, some patients with mild MIC have severe or profound mental retardation. Their intellectual disability may be partly explained by associated brain abnormalities, whether developmental or destructive, as brain imaging frequently reveals additional abnormalities [Sugimoto et al., 1993].

Several coexistent conditions, such as varying degrees of cognitive impairment, epilepsy, cerebral palsy, and ophthalmological and audiological disorders, occur commonly in children with microcephaly and are reviewed in the sections below.

Cognitive Impairment

A correlation between MIC and mental retardation has been recognized since studies in the late 1800s, and subsequent research has explored the strength of this correlation in a number of ways, although rarely in a prospective manner among a broad sample of subjects. In reported studies, the incidence of MIC has varied, depending on the population studied. Prevalence estimates of MIC in institutionalized patients have reported a rate of MIC ranging from 6.5 percent [Krishnan et al., 1989] to 53 percent [Roboz, 1973]. In contrast, for children seen in neurodevelopmental clinics, the prevalence of microcephaly averages 24.7 percent (range 6–40.4 percent) [Smith, 1981; Martin, 1970; Desch et al., 1990].

Other studies have looked at the incidence and significance of MIC in children who were functioning normally or had normal intelligence. In one report of 1006 students in mainstream classrooms it was found that 1.9 percent had mild microcephaly (−2–3 SD) and none had severe microcephaly (below −3 SD) [Sells, 1977]. The microcephalic subjects had a similar mean IQ (99.5) to the normocephalic group (105), but lower mean academic achievement scores (49 vs. 70). Another report, looking at the records of 1775 normally intelligent patients aged 11–21 years, followed in adolescent medicine clinics, found 11 (0.6 percent) with severe MIC (below −3 SD) [Barmeyer, 1971]. Among a separate sample of 106 retarded adolescents, the incidence of severe MIC was 11 percent.

A related issue concerns the incidence of developmental disability in individuals with MIC. Several investigations based on the United States National Collaborative Perinatal Project (1959–1974) have data regarding the degree of developmental disability in children with MIC. In an early report, OFC measurements of less than 43 cm (−2.3 SD) for males and 42 cm (−2.4 SD) for females at 1 year of age were associated with IQ <80 at 4 years in half the individuals [Nelson and Deutschberger, 1970]. A second study using these data found congenital MIC (<2 SD) in 1.3 percent that was associated with a greater risk of mental retardation at 7 years (15.3 vs. 7 percent) in selected populations [Camp et al., 1998]. A third study found that, of normocephalic children, 2.6 percent were mentally retarded (IQ ≤70) and 7.4 percent had borderline IQ scores (71–80). Of the 114 (0.4 percent) children with mild microcephaly (2–3 SD), 10.5 percent were mentally retarded and 28 percent had borderline IQ scores [Dolk, 1991]. Severe MIC (below −3 SD) was found in 41 (0.14 percent) children, and 51.2 percent were mentally retarded and 17 percent had borderline IQ scores. These reports have been supported by findings in several other studies [O’Connell et al., 1965; Watemberg et al., 2002].

A number of additional studies of microcephalic children have examined other clinical factors. Available data are conflicting as to whether having proportionate MIC is less predictive of developmental and learning disabilities [Sells, 1977] or not [Nelson and Deutschberger, 1970]. Other studies have shown that early severe medical illness or acquired brain injury can be associated with MIC and a future risk of retardation [Avery et al., 1972]. The pattern of head growth can also be a significant predictor of outcome. Infants whose birth OFCs were normal but who acquired MIC by age 1 year were likely to be severely delayed. On the other hand, when MIC and developmental delay were acquired as a consequence of the combined deprivations of early childhood malnutrition, poverty, and lack of stimulation, as frequently occurs in emerging countries [Grantham-McGregor et al., 2007], significant potential for physical and cognitive recovery exists [Rutter, 1998].

There is also some evidence to support the generally held belief that there is a correlation between the severity of MIC and degree of developmental disability. One study of 212 children with MIC, seen in either a birth defects or a child development clinic, found a significant correlation between the degree of MIC and severity of mental retardation. Among the 113 subjects with mild MIC (2–3 SD below the mean), mental retardation was found in just 11 percent. The mean IQ of the children with the most normal OFC, between 2.0 and 2.1 SD below the mean, was 63. Mental retardation was diagnosed in 50 percent of the 99 subjects with more severe MIC (≥3 SD), and in all of those with an OFC more than 7 SD below the mean. The mean IQ of the children with an OFC between 5 and 7 SD below the mean was 20 [Pryor and Thelander, 1968].

The above studies all underscore the fact that MIC is common in developmentally disabled children, with the incidence greater in those more severely affected. Even in low-risk populations (e.g., children with normal school placements), 1.9 percent have MIC, and in many of these children, subtle cognitive deficits are detected. In addition, there is a 50 percent increased risk for being developmentally delayed in children with MIC compared to children without MIC (e.g., 15.3 vs. 7 percent), and a strong correlation between the severity of MIC and developmental outcome (i.e., mental retardation occurs in 10.5 percent of children with mild MIC [<2 SD] and in 51.2 percent of children with severe microcephaly [below −3 SD]). Because of these observations, it is important for serial developmental screening to be done in children with MIC to detect developmental disorders.

Epilepsy

The relation between MIC and epilepsy is of great clinical importance for several reasons:

One study involving 66 children with MIC (<−2 SD) found an overall prevalence of epilepsy of 40.9 percent [Abdel-Salam et al., 2000]. It has also been suggested that epilepsy is more common in postnatal-onset than in congenital MIC. In one study, epilepsy occurred in 50 percent of children with postnatal-onset microcephaly compared to only 35.7 percent of those with congenital MIC [Abdel-Salam et al., 2000]. A second study found that epilepsy was four times more common in postnatal-onset MIC [Qazi and Reed, 1973].

MIC also is a significant risk factor for medically refractory epilepsy [Berg et al., 1996; Chawla et al., 2002; Aneja et al., 2001]. In one study of 30 children, MIC was found in 58 percent of those with medically refractory epilepsy compared to 2 percent in whom seizures were controlled [Chawla et al., 2002].

Although children with MIC are at greater risk for epilepsy, many do not have epilepsy. There are, however, certain MIC syndromes in which epilepsy is a prominent feature. Knowledge of these disorders and their genetic basis can help establish a diagnosis and determine prognosis. Some of the more commonly recognized entities are summarized in Table 25-3.

Table 25-3 Severe Epilepsy and Microcephaly Associated Genetic Syndromes*

Disorder Gene(s) or Locus
STRUCTURAL MALFORMATIONS
Classic lissencephaly (isolated LIS sequence) LIS1, DCX, TUBA1A
Lissencephaly: X-linked with abnormal genitalia ARX
Lissencephaly: autosomal-recessive with cerebellar hypoplasia RELN, VLDLR
Bilateral frontoparietal polymicrogyria (COB) GPR56
Periventricular heterotopia with microcephaly ARFGEF2
Holoprosencephaly-associated genes SHH, SIX3, GLI2, TDGF1, PTCH1, FOXH1, ZIC2, TFIF1, SMAD2
Holoprosencephaly phenotypes-associated loci HPE1 21q22.3
HPE2 2p21
HPE3 7q36
HPE4 18p11.3
HPE5 13q32
HPE 6 2q37.1
HPE7 9q22.3
HPE 8 14q13
HPE9 2q14
SYNDROMES
Wolf–Hirschhorn syndrome 4p16
Angelman’s syndrome UBE3A, 15q11–q13
Rett’s syndrome Xp22, Xq28
MEHMO (mental retardation, epilepsy, hypogonadism, microcephaly, obesity) Xp22.13–p21.1
Mowat–Wilson syndrome (microcephaly, mental retardation, distinct facial features with/without Hirschsprung’s disease) ZFHX1B, 2q22

* Adapted from Ashwal S, et al. Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 73:887–897, 2009. Data extracted from OMIM (www.ncbi.nlm.nih.gov/omim); the reader is referred to that source for updated information as new entries are added and data are revised. The reader can also go directly to GeneTests (www.genetests.org), to which OMIM links, for updated information regarding the availability of genetic testing on a clinical or research basis.

Studies have not examined the role of obtaining a routine electroencephalography (EEG) in children with MIC to determine their risk for developing epilepsy. In one study of children with MIC, EEG abnormalities were found in 51 percent of 39 children who either had no seizures or occasional febrile seizures [Abdel-Salam et al., 2000]. EEG abnormalities (focal, generalized, or mixed epileptiform discharges) were present in 78 percent of 18 children with medically refractory epilepsy.

Overall, it is important to be aware that epilepsy is more common in children with MIC, and when it occurs, it is more difficult to treat. Certain MIC syndromes are associated with a much higher incidence of epilepsy, and increasingly, genetic etiologies defining the relation between MIC and epilepsy are being reported. In addition, there are no systematic studies regarding EEG findings in children with MIC who have or do not have epilepsy.

Cerebral Palsy

Not unexpectedly, many children with MIC are diagnosed later in infancy with cerebral palsy, and likewise, children with cerebral palsy are frequently found to be microcephalic. Data from one study of 216 children with MIC and developmental disabilities found a rate of cerebral palsy of 21.4 percent compared to 8.8 percent in a population of normocephalic developmentally disabled children (p <0.001) [Watemberg et al., 2002]. In contrast, several studies have examined the incidence of MIC in children with cerebral palsy. Three studies of children with cerebral palsy found congenital MIC in 1.8 percent of cases [Croen et al., 2001; Pharoah, 2007; Laisram et al., 1992]. In three other studies, the combined incidence of congenital and postnatal-onset MIC ranged between 32.5 percent and 81 percent, and averaged 47.9 percent [Edebol-Tysk, 1989; Lubis et al., 1990; Suzuki et al., 1999]. In one of these studies, 68 percent were diagnosed with secondary (i.e., acquired microcephaly) and 13 percent had congenital MIC [Edebol-Tysk, 1989]. Others have shown that the yield of determining the etiology of cerebral palsy is improved if MIC is present [Shevell et al., 2003]. These data suggest that it is important for physicians and others caring for children with MIC to monitor for the development of cerebral palsy, so that appropriate physical and occupational therapeutic interventions can be initiated.

Ophthalmological Disorders

No studies have surveyed the incidence of vision loss or specific ophthalmological disorders in children with MIC. One study found an incidence of 145 cases of congenital eye malformations (microphthalmia, anophthalmia, cataracts, coloboma, etc.) in 212,479 consecutive births [Stoll et al., 1997]. MIC was among the malformations in 56 percent of these children. Another study (n = 360) with severe MIC (below −3 SD) found eye abnormalities in 6.4 percent, but in only 0.2 percent of 3600 age-matched normocephalic controls [Kraus et al., 2003]. Other reported eye abnormalities in children with MIC that have been reported when searching the OMIM database for MIC have found associations with anophthalmia, blindness or visual loss, cataracts, colobomas, microphthalmia, nystagmus, optic atrophy, ptosis, and retinal disorders. Table 25-4 lists some of the more common MIC syndromes associated with ophthalmological disorders.

Table 25-4 Microcephaly Disorders with Prominent Ophthalmologic Involvement*

Syndrome (OMIM Number) Ophthalmologic Abnormality
Aicardi–Goutières syndrome (225750) Visual inattention, abnormal eye movements
Allan–Herndon–Dudley syndrome (300523) Rotary nystagmus, disconjugate eye movements
Alpers’ syndrome (203700) Blindness, visual disturbances; microcephaly occasional
Borjeson–Forssman–Lehmann syndrome (301900) Deep-set eyes, nystagmus, ptosis, poor vision, narrow palpebral fissures
Branchial clefts with characteristic facies, growth retardation, imperforate nasolacrimal duct, and premature aging (113620) Upslanting palpebral fissures, telecanthus, hypertelorism, ptosis, lacrimal duct obstruction, coloboma
Coloboma, microphthalmia, cataract
Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (609528) Downslanting palpebral fissures, hypertelorism, hypoplastic optic discs; described in two families
Cerebro-oculofacioskeletal syndrome (214150) Cataracts, blepharophimosis
Microphthalmia, deep-set eyes, nystagmus
**CHARGE syndrome (214800) Colobomas, anophthalmia, ptosis, hypertelorism, downslanting palpebral fissures
Cockayne’s syndrome (216400) Pigmentary retinopathy, optic atrophy, corneal opacity, decreased lacrimation, nystagmus, cataracts
Cohen’s syndrome (216550) Downslanting palpebral fissures, chorioretinal dystrophy, myopia, decreased visual acuity, optic atrophy
Down syndrome (190685) Upslanting palpebral fissures, epicanthal folds, iris Brushfield spots
Fraser’s syndrome (219000) Cryptophthalmos, malformed lacrimal ducts, hypertelorism, blindness
Glucose transport defect (606777) Abnormal paroxysmal eye movements; eye findings rare
Holoprosencephaly (236100) Cyclopia, ethmocephaly, cebocephaly, hypotelorism
Incontinentia pigmenti (308300) Microphthalmia, cataract, optic atrophy, retinal vascular proliferation, retinal fibrosis, retinal detachment, uveitis, keratitis
Jacobsen’s syndrome (147791) Epicanthal folds, hypertelorism
Ptosis, strabismus, coloboma, optic atrophy
Kabuki syndrome (147920) Long palpebral fissures, eversion of lateral third of lower eyelids, ptosis, blue sclerae, broad/arched/sparse eyebrows
Mental retardation with optic atrophy, deafness, and seizures (309555) Optic atrophy, severe visual impairment
Mental retardation, microcephaly, growth retardation, and joint contractures (606240) Ptosis; single case report of two sisters
Microcephaly, hiatus hernia, and nephrotic syndrome (251300) Absent cleavage of eye anterior chamber; described in one case report
Microphthalmia, syndromic (309800) Microphthalmia, optic nerve hypoplasia, coloboma, pigmentary retinopathy
Mitochondrial DNA depletion syndrome (251880) Nystagmus, disconjugate eye movements, optic dysplasia; microcephaly occasional
Mosaic variegated aneuploidy syndrome (257300) Hypertelorism, upslanting palpebral fissures, epicanthal folds, cataracts, nystagmus
Mucolipidosis IV (252650) Corneal clouding, corneal opacities, fibrous dysplasia of the cornea, progressive retinal degeneration, optic atrophy, strabismus, decreased electroretinogram
Neuronal ceroid-lipofuscinosis (256730) Progressive visual loss, optic atrophy, retinal degeneration, macular degeneration, abnormal electroretinogram
Norrie’s disease (310600) Blindness, retinal dysgenesis/dysplasia/detachment, cataracts, optic atrophy, other ocular abnormalities
Oculodentodigital dysplasia (164200) Microcornea, short palpebral fissures, epicanthal folds, glaucoma, cataract, iris anomalies
Oculopalatocerebral syndrome (257910) Persistent hypertrophic primary vitreous
Microphthalmos, leukocoria, retrolental fibrovascular membrane; rarely reported
Oculopalatoskeletal syndrome (257920) Blepharophimosis, blepharoptosis, epicanthus inversus, hypertelorism, conjunctival telangiectasia, glaucoma, anterior chamber anomalies, abnormal eye motility; rare
Osteoporosis-pseudoglioma syndrome (259770) Pseudoglioma, blindness, microphthalmia, vitreoretinal abnormalities, cataract, iris atrophy
Pelizaeus–Merzbacher disease (312080) Rotary nystagmus, optic atrophy
Peters plus syndrome (261540) Hypertelorism, Peters anomaly, anterior chamber cleavage disorder, nystagmus, ptosis, glaucoma, cataract, myopia, coloboma
Pyridoxamine 5′-phosphate oxidase deficiency (610090) Rotary eye movements; rare disorder
Pyruvate decarboxylase deficiency (312170) Episodic ptosis, abnormal eye movements
Pyruvate dehydrogenase deficiency (312170) Nystagmus, ptosis, saccade initiation failure, oculomotor apraxia
Rhizomelic chondrodysplasia punctata (215100) Cataract
Roberts’ syndrome (268300) Hypertelorism, shallow orbits, prominent eyes, bluish sclerae, corneal clouding, microphthalmia, cataract, lid coloboma
Smith–Lemli–Opitz syndrome (270400) Ptosis, epicanthal folds, cataracts, hypertelorism, strabismus
Spastic paraplegia, optic atrophy, microcephaly, and XY sex reversal (603117) Optic atrophy and poor vision; single case report
Syndactyly with microcephaly and mental retardation (272440) One family of several described had optic atrophy and poor vision
Townes–Brocks syndrome (107480) Chorioretinal coloboma, Duane anomaly; both of these are rare
Velocardiofacial syndrome (192430) Narrow palpebral fissures, small optic discs, tortuous retinal vessels, posterior embryotoxon
Walker-Warburg syndrome (236670) Multiple ocular findings including retinal detachment, cataracts, microphthalmia, hyperplastic primary vitreous, optic nerve hypoplasia, colobomata, glaucoma
Warburg micro syndrome (600118) Multiple ocular findings, including microphthalmia, microcornea, congenital cataracts, optic atrophy, ptosis
Wolf–Hirschhorn syndrome (194190) Hypertelorism, exophthalmos, ptosis, Rieger anomaly, nystagmus, iris coloboma

* Adapted from Ashwal S, et al. Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 73:887–897, 2009. From OMIM (www.ncbi.nlm.nih.gov/sites/entrez). Gene map loci are listed in each OMIM entry. Disorders are listed alphabetically; prevalence data are not known.

** CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and deafness.

Audiological Disorders

No studies have surveyed the incidence of hearing loss or audiological disorders in children with MIC. One study of 100 children with complex ear anomalies recorded that 85 had neurological involvement and 13 children had MIC [Wiznitzer et al., 1987]. Hearing loss is likely the most common audiological disorder associated with MIC, and Table 25-5 summarizes some of the common MIC syndromes listed in OMIM in which prominent audiological involvement is reported.

Table 25-5 Microcephaly Syndromes with Prominent Ear or Auditory Impairments*

Syndrome (OMIM Number) Ear or Audiologic Abnormality
Allan–Herndon–Dudley syndrome (300523) Large ears, simple ears, pinna modeling anomalies, prominent antihelix, flattened antihelix
Alpha-thalassemia/mental retardation syndrome (309580) Small ears, low-set ears, posteriorly rotated ears, sensorineural hearing loss
Brachyphalangy, polydactyly, tibial aplasia/hypoplasia (609945) Overfolded helices, hearing loss, cleft lobules, preauricular tags, cup-shaped ears
Branchial arch syndrome (301950) Hearing loss and external ear anomalies
Branchial clefts with characteristic facies, growth retardation, imperforate nasolacrimal duct, and premature aging (113610) Low-set ears, posteriorly rotated ears, hypoplastic superior helix, microtia, ear pits, overfolded ears, supra-auricular sinuses, conductive hearing loss
Camptodactyly, tall stature, and hearing loss syndrome (610474) Microcephaly occurs occasionally
Cerebrocostomandibular syndrome (117650) Low-set ears, conductive hearing loss, posteriorly rotated ears
Cerebro-oculofacioskeletal syndrome 1 (214150) Large ear pinnae
CHARGE syndrome (214800) Small ears, lop ears, deafness (sensorineural ± conductive), Mondini defect
Chondrodysplasia punctata (215100) Hearing loss
Chromosome 18 deletion syndrome (601808) External ear abnormalities
Chromosome 9q subtelomeric deletion syndrome (610253) Malformed ears, hearing loss
Cockayne’s syndrome (216400) Malformed ears, sensorineural hearing loss
Coffin–Lowry syndrome (303600) Prominent ears, sensorineural hearing loss
Cornelia de Lange syndrome (122470) Low-set ears, hearing loss
Cutis verticis gyrate, retinitis pigmentosa, and sensorineural deafness (605685) Sensorineural hearing loss; only one case report
Deafness, conductive, with malformed external ear (221300) Conductive hearing loss, malformed external ears, low-set external ears, malformed ossicles
Deafness, congenital, and onychodystrophy (220500) Sensorineural hearing loss
Dislocated elbows, bowed tibias, scoliosis, deafness, cataracts, microcephaly, and mental retardation (603133) Single case report of 4 siblings in consanguineous family
Ear, patella, and short stature syndrome (24690) Bilateral microtia, hearing loss, Mondini malformation, low-set ears, atretic auditory canal
Feingold’s syndrome (164280) “Ear abnormalities” common in one description
Focal dermal hypoplasia (305600) Protruding, simple ears, low-set ears, narrow auditory canals, mixed hearing loss
Genitopatellar syndrome (606170) One case report with hearing loss as an associated finding
***GOMBO syndrome (233270) One case report with conductive hearing loss
Iris coloboma with ptosis, hypertelorism, and mental retardation (243310) Low-set ears, overfolded helices, sensorineural hearing loss
Johanson–Blizzard syndrome (243800) Sensorineural hearing loss, cystic dilatation of cochlea and vestibular structures
Kabuki syndrome (147920) Large prominent ears, recurrent otitis media in infancy, posteriorly rotated ears, hearing loss, preauricular pit
Kearns–Sayre syndrome (530000) Sensorineural hearing loss
Klippel–Feil syndrome (118100) One case reported with microcephaly; hearing loss of any type common; external ear abnormalities occasional
Lathosterolosis (607330) Conductive hearing loss
Mental retardation, with optic atrophy, deafness and seizures (309555) Hearing loss; described in one family
Mental retardation–hypotonic facies syndrome, X-linked (309580) Deafness
Microphthalmia, syndromic (601186) Simple anteverted ears, hearing loss
Monosomy 1p36 syndrome (607872) Sensorineural hearing loss, external ear abnormalities
Oculodentodigital dysplasia (164200) Conductive hearing loss
Oculopalatoskeletal syndrome (257920) Conductive hearing loss
Otopalatodigital syndrome (311300) Low-set ears, conductive hearing loss, posteriorly rotated ears
POR** deficiency (201750) Conductive hearing loss, simple ears
Progeroid facial appearance with hand anomalies (602249) Prominent ears, conductive hearing loss; one case report
Renpenning’s syndrome 1 (309500) Cupped ears
Rubinstein–Taybi syndrome (180849) Low-set ears, hearing loss
Shprinzten–Goldberg craniosynostosis (182212) Low-set ears, posteriorly rotated ears, conductive hearing loss (rare)
Townes–Brocks syndrome (107480) Multiple external ear abnormalities; sensorineural hearing loss
Trichorhinophalangeal syndrome type II (15030) Hearing loss, large protruding ears
Velocardiofacial syndrome (192430) Occasional microcephaly and minor auricular abnormalities seen
Waardenburg’s syndrome (148820) Hearing loss
Williams–Beuren syndrome (194050) Early-onset progressive sensorineural hearing loss
Wolf–Hirschhorn syndrome (194190) (602952) Preauricular tags, preauricular pits, hearing loss, narrow external auditory canals

* Adapted from Ashwal S, et al. Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 73:887–897, 2009. From OMIM (www.ncbi.nlm.nih.gov/sites/entrez). Gene map loci are listed in each OMIM entry. Disorders are listed alphabetically; prevalence data are not known.

** POR – cytochrome P450 oxido reductase deficiency.

*** GOMBO – Growth retardation, ocular abnormalities, Microcephaly, Brachydactyly and Oligophrenia.

Etiology

Mild MIC, which we define as −2 to −3 SD, has been associated with a variety of maternal and other prenatal disorders, prenatal and postnatal brain injuries, familial forms, chromosome disorders, and numerous syndromes with either prenatal- or postnatal-onset MIC. Here we can review only a small selection of the more common causes.

Extrinsic Causes

Extrinsic injuries before birth or early in life can certainly lead to MIC. The developing nervous system is highly vulnerable to infections, including cytomegalovirus, toxoplasmosis, rubella, herpes simplex, and group B coxsackievirus. Intrauterine infections with these can result in MIC [Evrard, 1992; Norman et al., 1995; Volpe, 2000]. MIC also has been reported in infants of women exposed to ionizing radiation, as shown in studies following exposure to atomic bomb radiation or to radium implantation in the cervix during the first trimester [Dekaban, 1968; Wood et al., 1967]. Maternal metabolic disorders during pregnancy, such as diabetes mellitus, uremia, and undiagnosed or inadequately treated phenylketonuria, may result in neonatal MIC [Levy et al., 1996; Rouse et al., 1997]. Malnutrition, hypertension, and placental insufficiency may all result in intrauterine growth retardation and MIC.

Maternal alcoholism during pregnancy has also been linked with MIC as part of the fetal alcohol syndrome [Clarren et al., 1978; Loebstein and Koren, 1997; Ouellette et al., 1977; Spohr et al., 1993]. The clinical features include growth and mental retardation, midfacial hypoplasia, short palpebral fissures, epicanthal folds, and behavioral disturbances. Neuropathologic findings include MIC, heterotopia, widespread cortical and white-matter dysplasias, and defects of neuronal and glial migration [Wisniewski et al., 1983]. MIC has also been reported with maternal exposure to cocaine [Loebstein and Koren, 1997]. Some other reports are largely anecdotal, so the associations are often not proven.

Familial Mild Microcephaly

Mild MIC may have either complex (polygenic) or autosomal-dominant inheritance. The autosomal-recessive forms typically present with severe primary MIC and many reviews have not clearly separated patients with mild and severe MIC, often making clinical data difficult to interpret. The polygenic or autosomal-dominant forms are generally associated with mild to moderate cognitive problems, with epilepsy being uncommon. The risk of recurrence in siblings may be as high as 50 percent with the assumption of autosomal-dominant inheritance, but is probably lower, considering that polygenic inheritance may be involved. The genetic basis for familial mild MIC is not known, but several genes have been identified that cause mild MIC, as indicated in Table 25-6.

Severe MIC, which we define as birth OFC at or below −3 SD or later OFC at or below −4 SD, is more likely to be associated with a wide variety of genetic disorders, although exceptions are likely (but not well documented).

Patients with primary MIC tend to fall into two further, albeit somewhat heterogeneous, subgroups [Dobyns, 2002]. The first subgroup includes children with severe MIC but only moderate neurologic problems, usually with moderate mental retardation and with no spasticity or epilepsy. The second subgroup consists of severe MIC with a much more severe neurologic phenotype that consists of abnormal neonatal reflexes, generalized spasticity, and epilepsy [Barkovich et al., 1998; Dobyns, 2002; Sztriha et al., 1999; ten Donkelaar et al., 1999]. These children have poor feeding and recurrent vomiting, leading to poor weight gain, profound mental retardation, and severe spastic quadriparesis. Most of these children also have early-onset intractable epilepsy. The wide clinical spectrum suggests pathogenetically heterogeneous conditions, and several syndromes and genes have been identified (see Table 25-6).

Primary Microcephaly

When congenital MIC is the only abnormality on evaluation, the disorder has been designated primary MIC. As discussed previously, this designation becomes much more useful when restricted to children with birth occipitofrontal circumference below −3 SD. Most patients with primary MIC also have mild growth deficiency, with stature typically −2 to −3 SD, which may be part of the syndrome or partly nutritional. This deficiency is much less striking than their head size, which is typically −4 to −8 SD after early childhood. Most affected persons fall into one of two groups described below [Dobyns, 2002].

The first group is composed of children with extreme MIC but only moderate neurologic problems, usually with only moderate mental retardation without spasticity or epilepsy [Barkovich et al., 1998; Peiffer et al., 1999; Tolmie et al., 1987]. Their neonatal examinations are usually normal, except for MIC, but many children initially have poor feeding and weight gain. They may have normal tone or mild distal spasticity, but do not have moderate or severe spasticity. Seizures are uncommon and are easily controlled. Febrile seizures occur and should be managed as in any other child. Early development is only mildly delayed and many infants progress to walking between 1 and 2 years of age and develop limited language skills. Several genes have been identified from studies of patients with this disorder (see Table 25-6).

The second group consists of primary MIC with a severe neurologic phenotype that includes severe spasticity and epilepsy [Barkovich et al., 1998; Dobyns, 2002; Sztriha et al., 1999; ten Donkelaar et al., 1999; Tolmie et al., 1987]. Neonatal examination demonstrates abnormal neonatal reflexes and generalized spasticity, and these children subsequently develop impaired feeding and recurrent vomiting, leading to poor weight gain, severe developmental delay, profound mental retardation, and severe spastic quadriparesis. Most of these infants have early-onset intractable epilepsy. In addition to a simplified gyral pattern, brain magnetic resonance imaging (MRI) may demonstrate other abnormalities, as summarized above (see Figure 25-1). Children with Amish lethal microcephaly have this phenotype, except that hypotonia predominates rather than spasticity, and seizures are not prominent [Kelley et al., 2002; Rosenberg et al., 2002].

The term radial microbrain was introduced by Evrard to describe the brain in some patients with severe mental retardation, profound MIC, and early death, describing an abnormally small brain that has a normal gyral pattern, normal cortical thickness, and normal cortical lamination, although the number of cortical neurons was only 30 percent of normal [Evrard et al., 1989; Evrard, 1992]. He hypothesized that a decreased number of radial neuronal-glial units was responsible for this form of MIC. This subgroup fits into the lower-functioning group of patients with primary MIC, rather than comprising an independent syndrome. However, multiple causes with different pathologic changes and clinical courses are likely to emerge from this group.

Severe Microcephaly with Cortical Malformation

Although still incompletely delineated, several syndromes with severe congenital microcephaly and additional severe brain malformations are known. The combination of severe microcephaly and true lissencephaly (with an abnormally thick cortex) has been reported, with at least three different patterns [Barth et al., 1982; Dobyns and Barkovich, 1999; Sztriha et al., 1998]. The most common of these very rare syndromes is probably the Barth microlissencephaly syndrome, which consists of severe microcephaly, diffuse complete agyria, and severe brainstem and cerebellar hypoplasia [Barth et al., 1982; Kroon et al., 1996]. Severe microcephaly with diffuse periventricular nodular heterotopia has been described, and clearly differs from other forms of heterotopia [Robain and Lyon, 1972; Sheen et al., 2004]. Some patients with severe microcephaly also have had diffuse polymicrogyria [Dobyns and Barkovich, 1999].

Severe Microcephaly with Proportionate Growth Deficiency

Several syndromes with severe intrauterine and postnatal growth deficiency and proportionate MIC have been described, although the head size does not keep up with even slow body growth, leading to disproportionate MIC in childhood and later. The best known of these are Seckel syndrome, Majewski syndrome, microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), also known as Taybi–Linder syndrome and microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2). Several other syndromes with severe growth deficiency and microcephaly have been described in a few patients, however, so it is likely that this group will become a large and complex group of syndromes. In some children, the skeletal changes may be absent or less prominent than in Seckel’s syndrome or the MOPD syndromes.

Seckel’s syndrome consists of severe intrauterine and postnatal growth deficiency and microcephaly, and abnormal facial features. including large eyes, beaklike protrusion of the nose, narrow face, and receding lower jaw [Majewski and Goecke, 1982; Seckel, 1960]. All affected individuals have severe mental retardation, although the severity varies considerably and some patients live to adulthood. Abnormalities of the brain seen on postmortem examination or brain imaging demonstrate pure microcephaly with deficient production of neurons and other cell types in some patients [Hori et al., 1987], whereas other patients have severe brain malformations, including lissencephaly [Capovilla et al., 2001; Shanske et al., 1997; Sugio et al., 1993]. Some patients have had various hematological disorders, such as pancytopenia or acute myeloid leukemia [Butler et al., 1987; Hayani et al., 1994].

MOPD1, or Taybi–Linder syndrome, consists of similar severe intrauterine and postnatal growth deficiency and microcephaly, combined with abnormal body proportions and short limbs. Typical skeletal changes consist of a low and broad pelvis with poor formation of the acetabulum, short and bowed humerus and femur, dislocated hips and elbows, retarded epiphyseal maturation, cleft vertebral arches, platyspondyly, horizontal acetabular roofs, and short long bones with enlarged metaphyses. Patients with MOPD1 also may have skin abnormalities, including hyperkeratosis and sparseness of hair and eyebrows [Meinecke et al., 1991; Sigaudy et al., 1998; Taybi, 1992]. Brain malformations, in addition to the severe microcephaly, are common and include lissencephaly, heterotopia, callosal agenesis, and cerebellar vermis hypoplasia [Klinge et al., 2002; Sigaudy et al., 1998].

MOPD2 consists of similar severe intrauterine and postnatal growth deficiency, proportionate microcephaly at birth that progresses to disproportionate microcephaly, shortening of the middle and distal segments of the limbs, a progressive bony dysplasia, abnormal facial appearance, including prominent nose and malformed ears, and a high squeaky voice [Hall et al., 2004; Majewski and Goecke, 1998; Majewski et al., 1982]. These patients may have dilated arteries in the brain that resemble aneurysms or moyamoya disease [Kannu et al., 2004; Young et al., 2004]. Although all affected individuals have severe microcephaly, no other brain malformations have been described [Fukuzawa et al., 2002].

Although these syndromes dominate the literature concerning intrauterine and postnatal growth deficiency and microcephaly, review of many reports suggests an overall substantial causal heterogeneity, with probable confusion among these and other syndromes in this group. In support of this likelihood, several novel syndromes have been reported [Kantaputra, 2002; Okajima et al., 2002].

MLIS MOPD1-type

MLIS occurs in some patients with microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), a syndrome that is difficult to distinguish from severe forms of Seckel’s syndrome [Juric-Sekhar et al., 2010; Klinge et al., 2002; Meinecke et al., 1991; Ozawa et al., 2005]. The phenotype consists of severe prenatal growth deficiency and microcephaly, sparse hair and dry scaling skin, skeletal anomalies such as platyspondyly, slender ribs, short and bowed proximal humeri and femurs, small iliac wings, dysplastic acetabulum and small hands and feet, and profound developmental handicaps. A few have developed aplastic anemia, another overlap with Seckel’s syndrome. The neuropathology consists of a variant form of LIS-3L with frontal predominance.