650 In 1963, Miller reported two siblings with a specific pattern of malformations in which lissencephaly was a key feature.
Later in 1969, Dieker et al. described a similar condition. Jones et al. in 1980 further characterized the phenotype and suggest- ed the designation Miller-Dieker syndrome to distinguish it from other lissencephaly syndromes. At present, Miller-Dieker syndrome is known to be a contiguous gene disorder caused by haplo-insufficiency of a gene or genes having a major role in the development of the brain and the face.
GENETICS/BASIC DEFECTS
1. Genetics: a contiguous gene deletion syndrome involving chromosome 17p13.3
a. Association of Miller-Dieker syndrome and del(17) (p13)
i. First reported by Dobyns et al. in 1983
ii. Familial cases reported by Miller (1963) with affected members being carriers of an unbal- anced rearrangement from t(15;17)(q26.1;p13.3) iii. Family reported by Dieker et al. (1969) with affected members being carriers of an unbal- anced rearrangement from t(12;17) (q24.31;
p13.3)
b. A microdeletion in a critical 350 kb region of chro- mosome 17p13.3 observed in familial and sporadic cases, detected by high resolution banding
c. Southern blot analysis of restriction fragment length polymorphism with several different DNA markers in 17p13.3, and later FISH analysis using different DNA probes of this segment
i. Observed in >90% of patients with Miller- Dieker syndrome
ii. Observed in 38% of patients with isolated lissencephaly
2. Mutations and large deletions of the lissencephaly gene (LIS1)
a. Deletions involving LIS1: more common than mutations
b. LIS1 deleted in Miller-Dieker syndrome
c. LIS1 mutations observed in patients with isolated lissencephaly sequence
i. Missense mutations ii. Nonsense mutations iii. Small deletions or insertions
iv. Splice site mutations v. Partial deletions
d. Phenotype–genotype correlations
i. Most severe LIS phenotypes observed in patients with large deletions of 17p13.3
ii. Milder phenotypes observed in patients with intragenic mutations
iii. Mildest phenotypes observed in patients with missense mutations
3. Classification of lissencephaly (Dobyns et al., 1984) a. Type I
i. Isolated lissencephaly sequence ii. Miller-Dieker syndrome iii. Nonclassified forms b. Type II
i. Walker-Warburg syndrome
ii. Fukuyama congenital muscular dystrophy iii. Nonunclassified forms
c. Rare forms
i. Neu-Laxova syndrome ii. Cerebro-cerebellar syndrome
4. Cytogenetic mechanisms in Miller-Dieker syndrome (Dobyns et al., 1991)
a. De novo abnormalities (44%)
i. Deletion (terminal or interstitial) (36%) ii. Dicentric translocation (4%)
iii. Ring chromosome (4%) b. Familial rearrangement (12%)
i. Reciprocal translocation (8%) ii. Pericentric inversions (4%) c. Normal karyotype (44%)
i. Submicroscopic deletion (36%) ii. No deletion detected (8%)
5. Molecular explanation for Miller-Dieker syndrome a. Heterozygous deletions of 17p13.3 result in the
human neuronal migration disorders i. Isolated lissencephaly sequence ii. More severe Miller-Dieker syndrome
b. Mutations in PAFAH1B1 (the gene encoding LIS1):
responsible for isolated lissencephaly sequence and contributing to Miller-Dieker syndrome
c. The gene encoding 14-3-3 Ó (YWHAE), one of a family of ubiquitous phosphoserine/threonine-bind- ing proteins: always deleted in individuals with Miller-Dieker syndrome, providing a molecular explanation for the differences in severity of human neuronal migration defects with 17p13.3 deletions
CLINICAL FEATURES
1. Prenatal and neonatal history a. Polyhydramnios
b. Prenatal growth deficiency c. Neonatal resuscitation d. Neonatal jaundice
e. Postnatal growth deficiency 2. CNS anomalies
a. Type I (classical) lissencephaly: can occur either in asso- ciation with the Miller-Dieker syndrome or as an isolat- ed finding, termed “isolated lissencephaly sequence”
i. Agyria (absent gyration of the cerebral cortex) ii. Pachygyria (unusually thick convolutions of the
cerebral cortex)
b. Absent or hypoplastic corpus callosum c. Cavum septi pellucidi
d. Midline calcification e. Ventricular dilatation
f. Abnormal positioning of the olivary nuclei in the midbrain
g. Occasional mild cerebellar vermis hypoplasia h. Microcephaly
i. Seizures usually by age 9 weeks j. Cerebral palsy
k. Profound mental retardation 3. Craniofacial features
a. High, prominent and wrinkled forehead b. Bitemporal narrowing
c. Furrowed brow d. Epicanthal folds e. Broad nasal bridge
f. Short and pointed nose with anteverted nostrils g. Long prominent upper lip with thin upper vermilion
border h. Micrognathia
i. High arched palate
j. Low-set and malformed ears 4. Congenital heart defects 5. Omphalocele
6. Hands and fingers a. Clinodactyly b. Camptodactyly c. Transverse palm crease 7. Sacral dimple
8. Cryptorchidism
9. Prognosis: often die within the first few months of life 10. Differential diagnosis
a. Isolated lissencephaly sequence i. Brain abnormalities
a) Lissencephaly (type I) b) Numerous heterotopias c) Failure of opercularization
d) Enlarged ventricles (usually colpocephaly) e) Probable hypoplasia of the corpus callosum ii. Neurologic abnormalities
a) Profound mental retardation b) Decreased spontaneous activity c) Early hypotonia
d) Subsequent hypertonia e) Poor feeding
f) Seizures iii. Craniofacial features
a) Microcephaly b) Bitemporal hollowing c) Prominent occiput d) Micrognathia iv. Occasional abnormalities
a) Prenatal: polyhydramnios, decreased fetal movement
b) Postnatal: may require resuscitation at birth c) Neurological: infantile spasms
v. Chromosome studies
a) Normal chromosomes by conventional studies
b) Submicroscopic deletions by FISH observed in increasing numbers
b. Norman-Roberts syndrome
i. Probably an autosomal recessive disorder ii. Brain abnormalities
a) Lissencephaly (type I) b) Numerous heterotopias c) Failure of opercularization
d) Slightly enlarged ventricles (probable colpocephaly)
e) Probable hypoplasia of the corpus callosum iii. Neurologic abnormalities
a) Profound mental retardation b) Decreased spontaneous activity c) Poor feeding
d) Seizures
iv. Cranial abnormalities a) Microcephaly b) Bitemporal hollowing c) Slightly prominent occiput d) Low, sloping forehead v. Facial features
a) Widely set eyes
b) Broad, prominent nasal bridge c) Micrognathia
d) Absence of upturned nares e) Normal eyes
vi. Other features a) Clinodactyly b) Chordee
c) Low birth weight vii. Normal chromosomes c. Walker-Warburg syndrome
i. Most commonly seen in the United Kingdom ii. An autosomal recessive disorder
iii. Type II lissencephaly iv. Hydrocephalus
v. Cerebellar malformation (vermian hypoplasia) vi. Eye abnormalities
a) Retinal dysplasia b) Microphthalmia c) Colobomata d) Cataracts e) Glaucoma
f) Corneal clouding commonly due to a Peter anomaly
g) Congenital muscular dystrophy in all patients h) Elevated CK
i) Abnormal EMG
j) Pathological changes on muscular histology vii. Other abnormalities
a) Cleft lip/palate
b) Genital anomalies in males: cryptorchidism, small penis
c) Occasional contractures d. Muscle-eye-brain disease
i. Mainly reported in Finnish population
ii. An autosomal recessive disorder
iii. Type II lissencephaly
iv. Hydrocephalus v. Eye abnormalities
a) Primarily myopia
b) Occasional glaucoma, retinal dystrophy, and cataracts
vi. Congenital muscular dystrophy: a constant feature vii. Elevated CK levels
viii. Hypotonia
ix. Feeding difficulties x. Severe mental retardation xi. Seizures common
e. Fukuyama congenital muscular dystrophy i. Mainly reported in the Japanese population ii. An autosomal recessive disorder
iii. Cobblestone lissencephaly (type II) iv. Eye abnormalities
a) Myopia
b) Optic atrophy in some patients v. Muscular dystrophy in all patients
vi. CK levels ranging from 10–50 times of normal vii. Hypotonia
viii. Marked mental retardation
DIAGNOSTIC INVESTIGATIONS
1. Chromosome analysis to detect microdeletion at 17p13.3 a. High resolution analysis indicated for all patients
with type I or atypical lissencephaly
b. Molecular cytogenetic technology using FISH to detect a submicroscopic deletion when chromosome analysis is normal and Miller-Dieker syndrome is sus- pected based on clinical evaluation
c. Parental studies in case of positive findings 2. MRI of the newborn brain
a. Smooth brain
b. Bilateral primitive Sylvian fissure giving rise to a
“figure 8” appearance of the brain
c. Persistent fetal configuration of the posterior horns of the ventricular system (colpocephaly)
3. DNA mutation analysis a. Direct sequencing b. Southern blot analyses
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: based on the specific cytogenetic mech- anism involved
i. Very low recurrence risk in most patients whose abnormalities occur de novo
ii. Very high recurrence risk in families where one parent is the carrier of a balanced chromosome rearrangement involving 17p13
b. Patient’s offspring: patients not surviving to repro- ductive age
c. A high risk for abnormal phenotypes for an individu- als carrying a balanced translocation with a break- point in 17p13 ascertained because of a relative with Miller-Dieker syndrome or dup(17p)
i. Approximately 26% risk in all recognized preg- nancies
ii. 33% risk in pregnancies which remain viable in the second trimester or after
iii. Frequency of spontaneous miscarriages and still- births not appear to be unduly elevated in these families
2. Prenatal diagnosis
a. Ultrasonography for pregnancy at risk i. Polyhydramnios
ii. IUGR iii. Lissencephaly
iv. Microcephaly
v. Mild ventriculomegaly vi. Absence of corpus callosum vii. Cardiac and other malformations b. Prenatal diagnosis by amniocentesis or CVS
i. Indications
a) Carrier parents with balanced chromosome rearrangements involving 17p13
b) Probably parents of all Miller-Dieker syn- drome patients because of the small possi- bility of gonadal mosaicism in apparently de novo cases
c) Normal relatives of unknown karyotype ii. Cytogenetic analysis
a) High resolution analysis of chromosome 17 b) Molecular cytogenetic studies (FISH) 3. Management
a. Supportive care
b. Early infant intervention c. Anticonvulsants for seizures
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Fig. 1. A child with Miller-Dieker syndrome showing high forehead, frontal bossing, bilateral temporal narrowing, small nose with antev- erted nares, prominent upper lip, micrognathia, and a surgically repaired omphalocele.
Fig. 2. A child with Miller-Dieker syndrome showing characteristic facial traits like the previous child. The MRI of the brain showed dif- fuse and complete type I lissencephaly. FISH revealed one chromo- some 17 lacked a signal at 17p13 indicating the presence of a deletion.
