Neuro / Head & Neck for Wednesday, April 9th, 2025

History

1 day old male, prenatally diagnosed with cortical malformation and occipital cephalocele. Normal fetal imaging of chest and abdomen.

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Question

What is the most common genetic mutation associated with this syndrome?

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Correct answer

POMT1

Discussion

The case shows characteristic imaging findings of Walker Warburg Syndrome:

• Cobblestone lissencephaly
• Z-shaped/kinked brainstem
• Cerebellar and vermian hypoplasia
• Occipital cephalocele
• Ocular abnormalities, including PHPV, retinal detachment, coloboma, microphthalmos, optic nerve hypoplasia
• Corpus callosum dysgenesis
• Cochlear hypoplasia

Identified genetic mutations include POMT1, POMT2, FKRP, FKTN, LARGE and POMGNT1.

POMT1 mutations are the most common and reported in up to 20% cases.

Differential diagnosis

Classical imaging findings of Meckel Gruber Syndrome include -

1. Renal cystic dysplasia in 98-100%

2. Encephalocele or other CNS abnormalities, however 'cobblestone lissencephaly' and 'z-shaped brainstem' is more characteristic of Walker Warburg syndrome

3. postaxial polydactyly

MKS1 gene is associated with Meckel Gruber Syndrome.

SOX2 gene mutations have been associated with anophthalmia, hearing loss and brain abnormalities. 

LIS1 gene mutations are known to cause lissencephaly.

Additional images

References

• de Bernabé, Daniel Beltrán-Valero, et al. "Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome." The American Journal of Human Genetics 71.5 (2002): 1033-1043.
• Suthar, Renu, et al. "Walker–Warburg syndrome." Neurology India 66.6 (2018): 1849-1850.
• Talenti, G., et al. "Characteristic Cochlear Hypoplasia in Patients with Walker-Warburg Syndrome: A Radiologic Study of the Inner Ear in α-Dystroglycan–Related Muscular Disorders." American Journal of Neuroradiology 42.1 (2021): 167-172.
• Aref, Fawzya, et al. "Walker-Warburg syndrome: A case report of congenital muscular dystrophy with hydrocephalus." Radiology Case Reports 19.11 (2024): 5063-5065.
• Currier, Sophie C., et al. "Mutations in POMT1 are found in a minority of patients with Walker–Warburg syndrome." American Journal of Medical Genetics Part A 133.1 (2005): 53-57.
• Barisic, Ingeborg, et al. "Meckel–Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe." European Journal of Human Genetics 23.6 (2015): 746-752.
• Hagstrom, Stephanie A., et al. "SOX2 mutation causes anophthalmia, hearing loss, and brain anomalies." American journal of medical genetics Part A 138.2 (2005): 95-98.
• Saillour, Yoann, et al. "LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity." Archives of neurology 66.8 (2009): 1007-1015.