Miller-Dieker Syndrome

In 1963, Miller reported two siblings with a specific pattern 3. Classification of lissencephaly (Dobyns et al., 1984) of malformations in which lissencephaly was a key feature. a. Type I Later in 1969, Dieker et al. described a similar condition. Jones i. Isolated lissencephaly sequence et al. in 1980 further characterized the phenotype and suggest- ii. Miller-Dieker syndrome ed the designation Miller-Dieker syndrome to distinguish it iii. Nonclassified forms from other lissencephaly syndromes. At present, Miller-Dieker b. Type II syndrome is known to be a contiguous gene disorder caused by i. Walker-Warburg syndrome haplo-insufficiency of a gene or genes having a major role in ii. Fukuyama congenital muscular dystrophy the development of the brain and the face. iii. Nonunclassified forms c. Rare forms GENETICS/BASIC DEFECTS i. Neu-Laxova syndrome 1. Genetics: a contiguous gene deletion syndrome involving ii. Cerebro-cerebellar syndrome chromosome 17p13.3 4. Cytogenetic mechanisms in Miller-Dieker syndrome a. Association of Miller-Dieker syndrome and del(17) (Dobyns et al., 1991) (p13) a. De novo abnormalities (44%) i. First reported by Dobyns et al. in 1983 i. Deletion (terminal or interstitial) (36%) ii. Familial cases reported by Miller (1963) with ii. Dicentric translocation (4%) affected members being carriers of an unbal- iii. Ring chromosome (4%) anced rearrangement from t(15;17)(q26.1;p13.3) b. Familial rearrangement (12%) iii. Family reported by Dieker et al. (1969) with i. Reciprocal translocation (8%) affected members being carriers of an unbal- ii. Pericentric inversions (4%) anced rearrangement from t(12;17) (q24.31; c. Normal karyotype (44%) p13.3) i. Submicroscopic deletion (36%) b. A microdeletion in a critical 350 kb region of chro- ii. No deletion detected (8%) mosome 17p13.3 observed in familial and sporadic 5. Molecular explanation for Miller-Dieker syndrome cases, detected by high resolution banding a. Heterozygous deletions of 17p13.3 result in the c. Southern blot analysis of restriction fragment length human neuronal migration disorders polymorphism with several different DNA markers in i. Isolated lissencephaly sequence 17p13.3, and later FISH analysis using different DNA ii. More severe Miller-Dieker syndrome probes of this segment b. Mutations in PAFAH1B1 (the gene encoding LIS1): i. Observed in >90% of patients with Miller- responsible for isolated lissencephaly sequence and Dieker syndrome contributing to Miller-Dieker syndrome ii. Observed in 38% of patients with isolated c. The gene encoding 14-3-3 Ó (YWHAE), one of a lissencephaly family of ubiquitous phosphoserine/threonine-bind- 2. Mutations and large deletions of the lissencephaly gene ing proteins: always deleted in individuals with (LIS1) Miller-Dieker syndrome, providing a molecular a. Deletions involving LIS1: more common than explanation for the differences in severity of human mutations neuronal migration defects with 17p13.3 deletions b. LIS1 deleted in Miller-Dieker syndrome c. LIS1 mutations observed in patients with isolated CLINICAL FEATURES lissencephaly sequence 1. Prenatal and neonatal history i. Missense mutations a. Polyhydramnios ii. Nonsense mutations b. Prenatal growth deficiency iii. Small deletions or insertions c. Neonatal resuscitation iv. Splice site mutations d. Neonatal jaundice v. Partial deletions e. Postnatal growth deficiency d. Phenotype–genotype correlations 2. CNS anomalies i. Most severe LIS phenotypes observed in patients a. Type I (classical) lissencephaly: can occur either in asso- with large deletions of 17p13.3 ciation with the Miller-Dieker syndrome or as an isolat- ii. Milder phenotypes observed in patients with ed finding, termed “isolated lissencephaly sequence” intragenic mutations i. Agyria (absent gyration of the cerebral cortex) iii. Mildest phenotypes observed in patients with ii. Pachygyria (unusually thick convolutions of the missense mutations cerebral cortex)

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b. Absent or hypoplastic corpus callosum b) Submicroscopic deletions by FISH observed c. Cavum septi pellucidi in increasing numbers d. Midline calcification b. Norman-Roberts syndrome e. Ventricular dilatation i. Probably an autosomal recessive disorder f. Abnormal positioning of the olivary nuclei in the ii. Brain abnormalities midbrain a) Lissencephaly (type I) g. Occasional mild cerebellar vermis hypoplasia b) Numerous heterotopias h. Microcephaly c) Failure of opercularization i. Seizures usually by age 9 weeks d) Slightly enlarged ventricles (probable j. Cerebral palsy colpocephaly) k. Profound mental retardation e) Probable hypoplasia of the corpus callosum 3. Craniofacial features iii. Neurologic abnormalities a. High, prominent and wrinkled forehead a) Profound mental retardation b. Bitemporal narrowing b) Decreased spontaneous activity c. Furrowed brow c) Poor feeding d. Epicanthal folds d) Seizures e. Broad nasal bridge iv. Cranial abnormalities f. Short and pointed nose with anteverted nostrils a) Microcephaly g. Long prominent upper lip with thin upper vermilion b) Bitemporal hollowing border c) Slightly prominent occiput h. Micrognathia d) Low, sloping forehead i. High arched palate v. Facial features j. Low-set and malformed ears a) Widely set eyes 4. Congenital heart defects b) Broad, prominent nasal bridge 5. Omphalocele c) Micrognathia 6. Hands and fingers d) Absence of upturned nares a. Clinodactyly e) Normal eyes b. Camptodactyly vi. Other features c. Transverse palm crease a) Clinodactyly 7. Sacral dimple b) Chordee 8. Cryptorchidism c) Low birth weight 9. Prognosis: often die within the first few months of life vii. Normal chromosomes 10. Differential diagnosis c. Walker-Warburg syndrome a. Isolated lissencephaly sequence i. Most commonly seen in the United Kingdom i. Brain abnormalities ii. An autosomal recessive disorder a) Lissencephaly (type I) iii. Type II lissencephaly b) Numerous heterotopias iv. Hydrocephalus c) Failure of opercularization v. Cerebellar malformation (vermian hypoplasia) d) Enlarged ventricles (usually colpocephaly) vi. Eye abnormalities e) Probable hypoplasia of the corpus callosum a) Retinal dysplasia ii. Neurologic abnormalities b) Microphthalmia a) Profound mental retardation c) Colobomata b) Decreased spontaneous activity d) Cataracts c) Early hypotonia e) Glaucoma d) Subsequent hypertonia f) Corneal clouding commonly due to a Peter e) Poor feeding anomaly f) Seizures g) Congenital muscular dystrophy in all patients iii. Craniofacial features h) Elevated CK a) Microcephaly i) Abnormal EMG b) Bitemporal hollowing j) Pathological changes on muscular histology c) Prominent occiput vii. Other abnormalities d) Micrognathia a) Cleft lip/palate iv. Occasional abnormalities b) Genital anomalies in males: cryptorchidism, a) Prenatal: polyhydramnios, decreased fetal small penis movement c) Occasional contractures b) Postnatal: may require resuscitation at birth d. Muscle-eye-brain disease c) Neurological: infantile spasms i. Mainly reported in Finnish population v. Chromosome studies ii. An autosomal recessive disorder a) Normal chromosomes by conventional studies iii. Type II lissencephaly 652 MILLER-DIEKER SYNDROME

iv. Hydrocephalus i. Approximately 26% risk in all recognized preg- v. Eye abnormalities nancies a) Primarily myopia ii. 33% risk in pregnancies which remain viable in b) Occasional glaucoma, retinal dystrophy, and the second trimester or after cataracts iii. Frequency of spontaneous miscarriages and still- vi. Congenital muscular dystrophy: a constant feature births not appear to be unduly elevated in these vii. Elevated CK levels families viii. Hypotonia 2. Prenatal diagnosis ix. Feeding difficulties a. Ultrasonography for pregnancy at risk x. Severe mental retardation i. Polyhydramnios xi. Seizures common ii. IUGR e. Fukuyama congenital muscular dystrophy iii. Lissencephaly i. Mainly reported in the Japanese population iv. Microcephaly ii. An autosomal recessive disorder v. Mild ventriculomegaly iii. Cobblestone lissencephaly (type II) vi. Absence of corpus callosum iv. Eye abnormalities vii. Cardiac and other malformations a) Myopia b. Prenatal diagnosis by amniocentesis or CVS b) Optic atrophy in some patients i. Indications v. Muscular dystrophy in all patients a) Carrier parents with balanced chromosome vi. CK levels ranging from 10–50 times of normal rearrangements involving 17p13 vii. Hypotonia b) Probably parents of all Miller-Dieker syn- viii. Marked mental retardation drome patients because of the small possi- bility of gonadal mosaicism in apparently de novo cases DIAGNOSTIC INVESTIGATIONS c) Normal relatives of unknown karyotype 1. Chromosome analysis to detect microdeletion at 17p13.3 ii. Cytogenetic analysis a. High resolution analysis indicated for all patients a) High resolution analysis of chromosome 17 with type I or atypical lissencephaly b) Molecular cytogenetic studies (FISH) b. Molecular cytogenetic technology using FISH to 3. Management detect a submicroscopic deletion when chromosome a. Supportive care analysis is normal and Miller-Dieker syndrome is sus- b. Early infant intervention pected based on clinical evaluation c. Anticonvulsants for seizures c. Parental studies in case of positive findings 2. MRI of the newborn brain REFERENCES a. Smooth brain Alvarado M, Bass HN, Caldwell S, et al.: Miller-Dieker syndrome: Detection of b. Bilateral primitive Sylvian fissure giving rise to a a cryptic chromosome translocation using in situ hybridization in a family “figure 8” appearance of the brain with multiple affected offspring. Am J Dis Child 147:1291–1294, 1993. c. Persistent fetal configuration of the posterior horns of Cardoso C, Leventer RJ, Dowling JJ, et al.: Clinical and molecular basis of classical lissencephaly: mutations in the LIS1 gene (PAFAH1B1). Hum the ventricular system (colpocephaly) Mutat 19:4–15, 2002. 3. DNA mutation analysis Chitayat D, Toi A, Babul R, et al.: Omphalocele in Miller-Dieker syndrome: a. Direct sequencing Expanding the phenotype. Am J Med Genet 69:293–298, 1997. b. Southern blot analyses De Rijk-van Andel JF, Arts WF, Barth PG, et al.: Diagnostic features and clin- ical signs of 21 patients with Lissencephaly type I. Dev Med Child Neurol 32:707–717, 1990. Dieker H, Edwards RH, ZuRhein G, et al.: The lisssencephaly syndrome. Birth GENETIC COUNSELING Defects Original Article Series V(2):53–64, 1969. 1. Recurrence risk Dobyns WB, Stratton RF, Parke JT, et al.: Miller-Dieker syndrome: a. Patient’s sib: based on the specific cytogenetic mech- Lissencephaly and monosomy 17p. J Pediatr102:552–558, 1983. Dobyns WB, Stratton RF, Greenberg F: Syndromes with lissencephaly I: anism involved Miller-Dieker and Norman-Robert syndromes and isolated lissencephaly. i. Very low recurrence risk in most patients whose Am J Med Genet 18:509–526, 1984. abnormalities occur de novo Dobyns WB, Pagon RA, Armstrong D, et al.: Diagnostic criteria for Walker- ii. Very high recurrence risk in families where one Warburg syndrome. Am J Med Genet 32:195–210, 1989. parent is the carrier of a balanced chromosome Dobyns WB, Curry CJR, Hoyme HE, et al.: Clinical and molecular diagnosis of Miller-Dieker syndrome. Am J Hum Genet 48:584–594, 1991. rearrangement involving 17p13 Dobyns WB, Elias ER, Newlin AC, et al.: Causal heterogeneity in isolated b. Patient’s offspring: patients not surviving to repro- lissencephaly. Neurology 42:1375–1388, 1992. ductive age Dobyns WB, Reiner O, Carrozzo R, et al.: Lissencephaly. A human brain mal- c. A high risk for abnormal phenotypes for an individu- formation associated with deletion of the LIS1 gene located at chromo- als carrying a balanced translocation with a break- some 17p13. J Am Med Assoc 270:2838–2842, 1993. Fukuyama Y, Osawa M, Suzuki H: Congenital progressive muscular dystrophy point in 17p13 ascertained because of a relative with of the Fukuyama type-clinical, genetic and pathological considerations. Miller-Dieker syndrome or dup(17p) Brain Dev 3:1–29, 1981. MILLER-DIEKER SYNDROME 653

Jones KL, Gilbert EF, Kaveggia EG, et al.: The Miller-Dieker syndrome. Pollin TI, Dobyns WB, Crowe CA, et al.: Risk of abnormal pregnancy outcome Pediatrics 66:277–281, 1980. in carriers of balanced reciprocal translocations involving the Miller- Ledbetter SA, Kuwano A, Dobyns WB, et al.: Microdeletions of chromosome Dieker syndrome (MDS) critical region in chromosome 17p13.3. Am J 17p13 as a cause of isolated lissencephaly. Am J Hum Genet 50:182–189, Med Genet 85:369–375, 1999. 1992. Santavuori P, Somer H, Sainio K, et al.: Muscle-eye-brain disease (MEB). Miller JQ: Lissencephaly in 2 siblings. Neurology 13:841–850, 1963. Brain Dev 11:147–153, 1989. Miny P, Holzgreve W, Horst J: Genetic factors in lissencephaly syndromes: a Stratton RF, Dobyns WB, Airhart SD, et al.: New chromosomal syndrome: Miller- review. Child’s Nerv Syst 9:413–417, 1993. Dieker syndrome and monosomy 17p13. Hum Genet 67:193–200, 1984. Norman MG, Roberts M, Sirois J, et al.: Lissencephaly. Can J Neurol Sci Toyo-oka K, Shionoya A, Gambello MJ, et al.: 14-3-3Ó is important for neu- 3:39–46, 1976. ronal migration by binding to NUDEL: a molecular explanation for Pilz DT, Quarrell OWJ: Syndromes with lissencephaly. J Med Genet Miller-Dieker syndrome. Nat Genet 34:274–285, 2003. 33:319–323, 1996. Van Zelderen-Bhola SL, Breslau-Siderius EJ, Beverstock GC, et al.: Prenatal Pilz DT, Macha ME, Precht KS, et al.: Fluorescence in situ hybridization analy- and postnatal investigation of a case with Miller-Dieker syndrome due to sis with LIS1 specific probes reveals a high deletion mutation rate in iso- a familial cryptic translocation t(17;20)(p13.3;q13.3) detected by fluores- lated lissencephaly sequence. Genet Med 1:29–33, 1998. cence in situ hybridization. Prenat Diagn 17:173–179, 1997 654 MILLER-DIEKER SYNDROME

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.