Signs, Symptoms, and Distinguishing MDS from Other Conditions
At a Glance
Miller-Dieker syndrome (MDS) is a genetic condition causing a smooth brain (lissencephaly), distinct facial features, and severe seizures like infantile spasms. Unlike isolated lissencephaly sequence (ILS), MDS involves multiple missing genes that affect both brain and physical development.
Miller-Dieker Syndrome (MDS) is more than just a brain malformation; it is a “contiguous gene syndrome” that affects multiple systems of the body [1]. While the smooth brain surface (lissencephaly) is the most prominent feature, the deletion of several neighboring genes creates a recognizable pattern of physical and neurological symptoms.
Physical Characteristics and “MDS Face”
One of the ways doctors first suspect MDS is through a specific group of facial features, often referred to as dysmorphic features. While reading clinical descriptions of your child’s face can feel cold and detached, please remember that your child is beautiful, uniquely yours, and these features are simply medical clues pointing to the genetic deletion on chromosome 17 [2].
Common features include:
- Prominent Forehead: The forehead may appear unusually large or “bossed” [3].
- Bitemporal Hollowing: A sunken or narrowed appearance at the temples (the sides of the forehead) [2].
- Midface Hypoplasia: The middle part of the face, including the cheeks and nose area, may appear flattened or “sunken”.
- Small, Upturned Nose: The nose is often short with nostrils that tilt upward (upturned nares).
- Thick Upper Lip: The upper lip often has a “vermillion” (red) border that is unusually thick.
- Micrognathia: An abnormally small or recessed lower jaw [2].
- Microcephaly: A head circumference that is significantly smaller than average, which occurs because the brain does not grow to its full expected size.
- Omphalocele: A condition where some abdominal organs protrude into the base of the umbilical cord. This is a classic hallmark midline defect strongly associated with MDS [2].
Neurological Symptoms and Seizures
The primary neurological challenge in MDS is classical lissencephaly (Type 1), where the brain lacks the normal folds and grooves [2]. This leads to:
- Severe Developmental Delay: Children typically do not reach milestones like sitting, crawling, or speaking [3].
- Hypotonia: Poor muscle tone, often described as feeling “floppy”.
- Intractable Epilepsy: Most children with MDS develop seizures that are difficult to control with medication (intractable) [2][4].
Early-Onset Seizures
Seizures often begin within the first few months of life. A common and serious type of seizure in MDS is infantile spasms (West Syndrome) [4]. These often look like sudden “jackknife” movements where the body or limbs stiffen in a cluster.
If you witness these movements, try to record a video on your phone if it is safe to do so, and contact your neurologist or go to the emergency room immediately. Prompt, specialized treatment is critical to prevent further impact on brain development [5].
MDS vs. Isolated Lissencephaly Sequence (ILS)
It is common for caregivers to hear the terms MDS and ILS used interchangeably, but they are genetically and clinically different.
| Feature | Miller-Dieker Syndrome (MDS) | Isolated Lissencephaly Sequence (ILS) |
|---|---|---|
| Genetic Cause | A large deletion of multiple genes on chromosome 17 (17p13.3) [1]. | Usually a mutation or a much smaller deletion in only the PAFAH1B1 (LIS1) gene [1]. |
| Brain Findings | Often a more severe grade of lissencephaly (Grade 1 or 2, almost completely smooth) [6]. | Can range from mild to severe lissencephaly [1]. |
| Facial & Systemic Features | Distinct facial features (prominent forehead, small jaw, omphalocele) are present [2]. Often includes growth failure or heart defects due to missing additional genes like CRK [7][8]. | Facial features are usually normal or very subtle [9]. Generally limited to neurological symptoms (brain-only) [1]. |
Why the difference matters: In MDS, the “extra” missing genes (like YWHAE and CRK) act as modifiers. While the PAFAH1B1 gene is responsible for the smooth brain, these other missing genes contribute to the characteristic facial appearance and the physical growth challenges [1][10]. Knowing which condition your child has helps doctors monitor for systemic issues that might not be a concern in ILS.
Common questions in this guide
What are the common facial features of Miller-Dieker syndrome?
What is the difference between MDS and Isolated Lissencephaly Sequence (ILS)?
What do seizures look like in a child with MDS?
What should I do if I think my child is having infantile spasms?
Questions to Ask Your Doctor
Curated prompts to bring to your next appointment.
- 1.Based on my child's genetic report, which specific genes are included in the deletion?
- 2.What specific type of seizures are you seeing on the EEG, and do they include infantile spasms?
- 3.How does the severity of my child's lissencephaly (grade) compare to what is typically seen in MDS?
- 4.Does my child have any systemic signs, like heart or kidney issues, that are more common in MDS than in ILS?
- 5.Are there specific growth charts we should be using if the CRK gene is missing?
Questions For You
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References
References (10)
- 1
Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome.
Baker EK, Brewer CJ, Ferreira L, et al.
American journal of medical genetics. Part A 2023; (191(2)):526-539 doi:10.1002/ajmg.a.63057.
PMID: 36433683 - 2
Rare Concurrence of Two Congenital Disorders: Miller-Dieker Syndrome and T-Cell Lymphopenia.
Chee SY, Guo JW, Huang CJ, et al.
Cytogenetic and genome research 2019; (157(4)):227-230 doi:10.1159/000499956.
PMID: 31030199 - 3
Diagnosis of Lissencephaly in a Neonate After Antenatal Polyhydramnios and Suspicion of Fetal Esophageal Atresia: A Case Report.
Watanabe H, Ibi K, Yoneda K, Kakiuchi S
Cureus 2025; (17(9)):e92565 doi:10.7759/cureus.92565.
PMID: 41111707 - 4
Management of general anesthesia in a child with Miller-Dieker syndrome: a case report.
Wakiguchi C, Godai K, Mukaihara K, et al.
JA clinical reports 2015; (1(1)):14 doi:10.1186/s40981-015-0017-2.
PMID: 29497646 - 5
Spectrum and time course of epilepsy and the associated cognitive decline in MECP2 duplication syndrome.
Marafi D, Suter B, Schultz R, et al.
Neurology 2019; (92(2)):e108-e114 doi:10.1212/WNL.0000000000006742.
PMID: 30552298 - 6
17p13.3 Microdeletion: Insights on Genotype-Phenotype Correlation.
Barros Fontes MI, Dos Santos AP, Rossi Torres F, et al.
Molecular syndromology 2017; (8(1)):36-41 doi:10.1159/000452753.
PMID: 28232781 - 7
Crk Haploinsufficiency Is Associated with Intrauterine Growth Retardation and Severe Postnatal Growth Failure.
Deodati A, Inzaghi E, Germani D, et al.
Hormone research in paediatrics 2021; (94(11-12)):456-466 doi:10.1159/000521629.
PMID: 35086092 - 8
Disruption of YWHAE gene at 17p13.3 causes learning disabilities and brain abnormalities.
Noor A, Bogatan S, Watkins N, et al.
Clinical genetics 2018; (93(2)):365-367 doi:10.1111/cge.13056.
PMID: 28542865 - 9
Ring Chromosome 17 Syndrome-A Case Report and Discussion of Diagnostic Methods.
Kim SY, Wohler E, Gutierrez MJ, et al.
American journal of medical genetics. Part A 2025; (197(3)):e63925 doi:10.1002/ajmg.a.63925.
PMID: 39513527 - 10
Responsible Genes for Neuronal Migration in the Chromosome 17p13.3: Beyond Pafah1b1(Lis1), Crk and Ywhae(14-3-3ε).
Liu X, Bennison SA, Robinson L, Toyo-Oka K
Brain sciences 2021; (12(1)) doi:10.3390/brainsci12010056.
PMID: 35053800
This page provides educational information about the signs and symptoms of Miller-Dieker syndrome. Always consult your child's neurologist or medical geneticist for professional medical advice, diagnosis, and treatment planning.
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