Imaging Case Book

Miller–Dieker syndrome, type 1 lissencephaly

Case presentation

A 1910 g infant was born at 41-weeks gestation to a 19-year-old gravida 1 mother after a pregnancy complicated by hydramnios and poor fetal movement. The child was delivered by a cesarean section because of fetal decelerations with labor. Severe intrauterine growth retardation was present with the infant's weight, length and head circumference all less than the tenth percentile for gestational age. The patient's head demonstrated a wasted appearance with bitemporal shallowness. The ears were low set. Retromicrognathia, and microphthalmia, more marked on the left, were also present. The child had a cranial sonogram (Figure 1) and cranial magnetic resonance imaging (Figure 2).

Figure 1

(a) Coronal cranial sonogram at the level of the third ventricle demonstrating a figure-of-8 appearance of the brain with wide sylvian fissure and with no sulci or gyri. (b) Sagittal right lateral cranial sonogram demonstrating absence of gyri over the ipsilateral hemisphere. (c) Right sagittal sonogram demonstrating echogenic linear thalamostriate vessels (arrow). The left hemisphere had a similar appearance. (d) Sagittal left lateral sonogram demonstrating absent sulci, gyri.

Figure 2

(a) T2-weighted coronal MRI and (b). T2-weighed axial MRI views of the brain. There is a thickened cortex without gyri or sulci and a figure-of-8 appearance of the brain with a wide, shallow sylvian fissure (arrows). (c) Posterior coronal T2-weighed images demonstrating a left parafalcine arachnoid cyst (AC). (d) T1-weighted image through the orbits demonstrating left microphthalmia (arrow). MRI, magnetic resonance imaging.

Denouement and discussion

The cranial sonogram demonstrated an abnormally smooth brain with no gyration or sulcation with a wide, shallow sylvian fissure creating a figure-of-8 appearance. The absence of all gyri is referred to as lissencephaly (smooth brain).1 The corpus callosum was incompletely formed. In addition, at cranial sonography there were echogenic thalamostriate vessels, or so-called thalamostriate vasculopathy. The magnetic resonance imaging demonstrated the partial agenesis of the corpus callosum, lissencephaly, left microphthalmia and a small arachnoid cyst along the parafalcine left parietooccipital cortex. The cerebral cortex, usually measuring less than 3 mm, measured over 5 mm. The colprocephaly and incomplete opercularization with wide shallow sylvian fissures were noted to produce a figure-of-8 appearance to the brain. This appearance is typical of classical or type 1 lissencephaly.1, 2 Chromosomal analysis of the infant demonstrated a deletion of 17p3, confirming a diagnosis of Miller–Dieker syndrome with type 1 lissencephaly.

Lissencephaly is a rare condition. Three types have been described.1 Type l or classical lissencephaly is a neuronal migrational abnormality with a thickened, smooth cerebral cortex, failure of opercularization (closure of the sylvian fissure to cover the insula), colprocephaly and occasional calcifications of the septum pellucidum.2 At birth, there is usually a normal head circumference or a head circumference within 2 s.d. of normal.1 Four genes are known to be associated with classical lissencephaly: LIS1, DCX, ARX and TUBA3. LIS1 gene, located at 17p3, is known to be necessary for the neuronal precursors to undergo normal neuronogenesis and migration. Miller–Dieker syndrome is associated with 17p3 deletions, usually with complete absence of the LIS1 gene, and it is the most common cause of classical lissencephaly. Norman–Roberts syndrome is an autosomal recessive condition associated with type 1 lissencephaly, but with severe microcephaly (less than 3 s.d. below normal). Type 2 lissencephaly, so-called cobblestone lissencephaly, has a granular surface with effacement of gyri. It is found in the autosomal recessive conditions: Walker–Warbury syndrome and Fukuyama syndrome. Type 2 lissencephaly is associated with O-glycosylation enzyme defects resulting in abnormal laminin. Type 3 lissencephaly is associated with severe microcephaly and is a neurodegenerative process with abnormal apoptosis. It occurs in the Neu–Laxova and Encha Razavi Larroche syndromes.

The clinical appearance of children with Miller–Dieker syndrome is characteristic. There is a high forehead, often with vertical furrows, due to an unusual ability to wrinkle the skin of the forehead.1, 3 The ears are low set and the eyes widely separated. The upper lip is thickened, but with a thin vermillion border. There is an elongated philtrum with rounded pillars. There is bitemporal narrowing and the nose is short and anteverted.4 The degree of agyria in lissencephaly may vary and has been stratified by Dobyns into six different grades of severity.1, 5 Grade 1, as occurred in this patient, is complete agyria. Grade 2 has some minimal gyration in the frontal region. The remaining grades have decreasing extent agyria and increased pachygyria or abnormally broad gyri.

The magnetic resonance imaging and sonographic appearance of the brain in this patient are characteristic of Miller–Dieker syndrome. However, several additional imaging features were present in this patient not described, to our knowledge, in other patients with Miller–Dieker syndrome. These include the presence of thalamostriate vasculopathy, arachnoid cyst and microophthalmia. Thalamostriate vasculopathy on transcranial sonography has been reported in TORCH infections, particularly cytomegalovirus infection, trisomy 13, translocation chromosome 11 and various other metabolic and dysmorphic syndromes.6 Intracranial subarachnoid cysts are usually supratentorial, but primarily in the temporal fossa and not parafalcine as in this patient.7 Although microphthalmia is common in type 2 lissencephaly syndromes, it is not a frequent finding in Miller–Dieker syndrome.

The clinical presentation of children with grade 1 type 1 lissencephaly is also usually typical. They are hypotonic at birth, but quickly develop spasticity. They have difficulties in swallowing, seizures (90% by 1 year of age) and profound neurodevelopmental retardation.

The differential diagnosis of Miller–Dieker syndrome includes other syndromes, with facial dysmorphism, microcephaly, seizures and hypotonia, such as Cornelia de Lange syndrome, Wolf–Hirschorn syndrome, Smith–Lemli–Opitz syndrome and Zellweger syndrome.8 However, none of these have lissencephaly. Chromosomal analysis to show a 17p3 deletion reliably excludes other causes of type 1 lissencephaly. The syndromes with types 2 and 3 lissencephaly have associated typical manifestations and can be usually easily excluded. Type 2 lissencephaly is a specific component of Walker–Warbur syndrome, Fukuyama congenital muscular dystrophy and some other familial syndromes. Type 3 lissencephaly occurs in association with stippled epiphyses and metacarpal-phalangeal bone dysplasia.

Treatment of Miller–Dieker syndrome is usually antiepileptic medications and support. Death usually occurs within the first year of life.6


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Correspondence to T E Herman.

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Herman, T., Siegel, M. Miller–Dieker syndrome, type 1 lissencephaly. J Perinatol 28, 313–315 (2008).

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