Primary Dwarfism, Microcephaly, and Chorioretinopathy due to a PLK4 Mutation in Two Siblings
Álvaro Martín-Rivada1, Jesús Pozo-Román1,2,3, María Güemes1
1Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Research Institute "La Princesa,", Madrid, Spain.
Introduction:
Primary autosomal recessive microcephalies (MCPHs) are characterized by primary dwarfism with MCPH and may present delayed psychomotor development and visual impairment. Biallelic loss of function variants in the PLK4 gene, which encodes the polo-like kinase 4 protein involved in centriole biogenesis, has been recently identified in several patients with MCPH and various ethnic backgrounds.
Case Presentation:
Here, we describe 2 siblings of different sex from Equatorial Guinea harboring a homozygous frameshift mutation in PLK4 (c.1299_1303del, p.Phe433Leufs*6). A Seckel syndrome spectrum phenotype was present in both siblings, with short stature, severe MCPH, reduced brain volume, and distinctive facial features. They also presented severe intellectual disability, lissencephaly/pachygyria, subependymal heterotopia, and ophthalmological impairment. One of them suffered from deafness, and scoliosis was observed in the other.
Discussion/Conclusion:
Biallelic variants in PLK4 lead to a syndrome where severe short stature, MCPH, and cognitive impairment are constant features. However, ocular, skeletal, and other neurological manifestations can vary upon the same genetic basis.
Insights
Genetic variants in the PLK4 gene cause primary autosomal recessive microcephalies (MCPH), a condition characterized by severe dwarfism and intellectual disability. This study details two siblings with a novel PLK4 mutation, highlighting variable associated symptoms.
Area of Science:
- Genetics
- Developmental Biology
- Neurology
Background:
- Primary autosomal recessive microcephalies (MCPH) are a group of genetic disorders characterized by severe head narrowing and dwarfism.
- Loss-of-function variants in the PLK4 gene, crucial for centriole biogenesis, have been linked to MCPH.
- Polo-like kinase 4 (PLK4) plays a vital role in cell division and organelle duplication.
Observation:
- This report describes two siblings from Equatorial Guinea with a homozygous frameshift mutation in the PLK4 gene.
- Both siblings exhibited a Seckel syndrome spectrum phenotype, including severe microcephaly, short stature, reduced brain volume, and distinctive facial features.
- Additional manifestations included severe intellectual disability, lissencephaly/pachygyria, subependymal heterotopia, and ophthalmological impairment, with one sibling also experiencing deafness and the other scoliosis.
Findings:
- Biallelic variants in PLK4 consistently result in severe short stature, microcephaly, and cognitive impairment.
- The identified homozygous frameshift mutation (c.1299_1303del, p.Phe433Leufs*6) in PLK4 leads to a Seckel syndrome spectrum phenotype.
- This mutation underscores the critical role of PLK4 in human development and brain formation.
Implications:
- Biallelic PLK4 variants define a syndrome with core features of severe short stature, microcephaly, and cognitive deficits.
- The study highlights the variable expressivity of PLK4-related disorders, with ocular, skeletal, and neurological symptoms differing among affected individuals.
- Understanding PLK4's function is crucial for diagnosing and potentially managing microcephaly and related developmental disorders.
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