Thompson & Thompson Genetics in Medicine, 8th Edition

Case 32. Miller-Dieker Syndrome (17p13.3 Heterozygous Deletion, MIM 247200)

Chromosomal Deletion


• Microdeletion syndrome

• Contiguous gene disorder/genomic disorder

• Haploinsufficiency

Major Phenotypic Features

• Age at onset: Prenatal

• Lissencephaly type 1 or type 2

• Facial dysmorphism

• Severe global intellectual disability

• Seizures

• Early death

History and Physical Findings

B.B., a 5-day-old boy born at 38 weeks of gestation, was admitted to the neonatal intensive care unit because of marked hypotonia and feeding difficulties. He was the product of an uncomplicated pregnancy, with a fetal ultrasound examination at 18 weeks of gestation. B.B. was born by spontaneous vaginal delivery; his Apgar scores were 8 at 1 minute and 9 at 5 minutes. He did not have a family history of genetic, neurological, or congenital disorders. On physical examination, B.B. had hypotonia and mild dysmorphic facial features, including bitemporal narrowing, depressed nasal bridge, small nose with anteverted nares, and micrognathia. The findings from the examination were otherwise normal. His evaluation had included normal serum electrolyte values, normal metabolic screen results, and normal study results for congenital infections. Brain ultrasound scan showed a hypoplastic corpus callosum, mild ventricular dilatation, and a smooth cortex. In addition to those studies, the genetics consultation team recommended magnetic resonance imaging (MRI) of the brain and a chromosomal microarray. MRI showed a thickened cerebral cortex, complete cerebral agyria, multiple cerebral heterotopias, hypoplastic corpus callosum, normal cerebellum, and normal brainstem. A chromosomal microarray revealed a 1.2-Mb deletion on 17p13.3, including the LIS1 gene. On the basis of these results, the geneticist explained to the parents that B.B. had Miller-Dieker syndrome. The parents declined further measures other than those to keep the baby comfortable, and B.B. died at 2 months of age.


Disease Etiology and Incidence

Miller-Dieker syndrome (MDS, MIM 247200) is a contiguous gene deletion syndrome caused by heterozygous deletion of 17p13.3; the mechanism underlying recurrent deletion of 17p13.3 has not yet been elucidated, but it may (like other microdeletion syndromes; see Chapter 6) involve recombination between low-copy repeated DNA sequences. MDS is a rare disorder, occurring in possibly 40 per 1 million births in all populations.


More than 50 genes have been mapped within the MDS deletion region in 17p13.3, but only the LIS1 gene (MIM 601545) has been associated with a specific phenotypic feature of MDS; heterozygosity for a LIS1mutation causes lissencephaly. LIS1 encodes the brain isoform of the noncatalytic β subunit of platelet-activating factor acetylhydrolase (PAFAH). PAFAH hydrolyzes platelet-activating factor, an inhibitor of neuronal migration. PAFAH also binds to and stabilizes microtubules; preliminary observations suggest that PAFAH may play a role in the microtubule reorganization required for neuronal migration.

Haploinsufficiency of LIS1 alone, however, does not cause the other dysmorphic features associated with MDS. Mutations within LIS1 cause isolated lissencephaly sequence (ILS) (MIM 607432), that is, lissencephaly without other dysmorphism. Because all patients with MDS have dysmorphic facial features, this dysmorphism must be caused by haploinsufficiency of one or more different genes in the common MDS deletion interval.

Phenotype and Natural History

The features of MDS include brain dysgenesis, hypotonia, failure to thrive, and facial dysmorphism. The brain dysgenesis is characterized by lissencephaly type 1 (complete agyria) or type 2 (widespread agyria with a few sulci at the frontal or occipital poles), a cerebral cortex with four instead of six layers, gray matter heterotopias, and attenuated white matter (see Chapter 14). Some patients also have heart malformation and omphalocele.

A patient's facial features and an MRI finding of lissencephaly often suggest a diagnosis of MDS (Fig. C-32). Confirmation of the diagnosis, however, requires detection of a 17p13.3 deletion by chromosome analysis, FISH with a LIS1-specific probe, or chromosomal microarray. Approximately 60% of patients have a cytogenetically visible deletion of the MDS critical region. Normal FISH or microarray study results do not exclude the diagnosis of MDS; some patients have a partial gene deletion. Patients with ILS may have a mutation in LIS1, and males may have a mutation in DCX (an X-linked gene also associated with ILS).


FIGURE C-32 Brain magnetic resonance images of infants without lissencephaly (A) and with Miller-Dieker syndrome (B). Note the smooth cerebral surface, the thickened cerebral cortex, and the classic “figure-8” appearance of the brain of the patient with Miller-Dieker syndrome. See Sources & Acknowledgments.

Patients with MDS feed and grow poorly. Smiling, brief visual fixation, and nonspecific motor responses are the only developmental skills most patients acquire. In addition to intellectual disability, patients usually suffer from opisthotonos, spasticity, and seizures. Nearly all patients die by 2 years of age.


MDS is incurable; therefore treatment focuses on the management of symptoms and palliative care. Nearly all patients require pharmacological management of their seizures. Also, many patients receive nasogastric or gastrostomy tube feedings because of poor feeding and repeated aspiration.

Inheritance Risk

Eighty percent of patients have a de novo microdeletion of 17p13.3, and 20% inherit the deletion from a parent who carries a balanced chromosomal rearrangement. Because of the frequency with which the deletion is inherited from a parent with a balanced translocation, karyotype analysis and FISH for LIS1 should be performed in both parents. A parent with a balanced translocation involving 17p13.3 has approximately a 25% risk for having an abnormal liveborn child (MDS or dup17p) and approximately a 20% risk for pregnancy loss. In contrast, if a patient has MDS as a result of a de novo deletion, the parents have a low risk for recurrence of MDS in future children (but not zero, due to the possibility of gonadal mosaicism).

Although the brain malformations of MDS result from incomplete migration of neurons to the cerebral cortex during the third and fourth months of gestation, lissencephaly is not detected by fetal MRI or ultrasonography until late in gestation. Prenatal diagnosis of MDS requires detection of a 17p13.3 deletion in fetal chorionic villi or amniocytes.

Questions for Small Group Discussion

1. Rubenstein-Taybi syndrome is caused either by deletion of 16p13.3 or by mutation of the CREBBP transcription factor. Compare and contrast the relationship of CREBBP and Rubenstein-Taybi syndrome with the relationship of LIS1 and MDS. Why is MDS a contiguous gene deletion syndrome, whereas Rubenstein-Taybi syndrome is not?

2. Mutations of either LIS1 on chromosome 17 or DCX on the X chromosome account for approximately 75% of ILS cases. What features of the family history and brain MRI scan can be used to focus testing on DCX as opposed to LIS1?

3. At 30 weeks of gestation, a woman has a fetal ultrasound examination showing fetal lissencephaly. The pregnancy was otherwise uncomplicated, and fetal ultrasound findings earlier in gestation had been normal. What counseling and evaluation are indicated? Discuss your counseling approach if she and her spouse wish to terminate the pregnancy at 32 weeks of gestation.


Dobyns WB, Das S. LIS1-Associated lissencephaly/subcortical band heterotopia. [Available from]

Hsieh DT, Jennesson MM, Thiele EA, et al. Brain and spinal manifestations of Miller-Dieker syndrome. Neurol Clin Pract. 2013;3:82–83.

Wynshaw-Boris A. Lissencephaly and LIS1: insights into molecular mechanisms of neuronal migration and development. Clin Genet. 2007;72:296–304.