Profound microcephaly, primordial dwarfism with developmental brain malformations: a new syndrome

Area of Science:

• Genetics
• Developmental Biology
• Neurology

Background:

• Congenital microcephaly encompasses a spectrum of disorders characterized by reduced head circumference and brain size.
• Severe forms often involve significant developmental abnormalities and can be lethal.
• Understanding the genetic and phenotypic diversity of microcephaly is crucial for diagnosis and counseling.

Observation:

• Two siblings presented with a lethal form of profound congenital microcephaly, intrauterine and postnatal growth retardation, and severe brain malformations.
• Clinical features included absent cranial vault, distinctive facial dysmorphia (beaked nose, micro-retrognathia), and profound intellectual disability.
• Neuroimaging revealed extremely simplified gyral patterns, agenesis of the corpus callosum, interhemispheric cysts, hippocampal abnormalities, and cerebellar/brainstem hypoplasia.

Findings:

• Funduscopic examination showed foveal hypoplasia and optic nerve atrophy.
• Molecular analysis excluded mutations in known microcephaly-associated genes (RNU4ATAC, SLC25A19, ASPM).
• The unique combination of severe microcephaly, brain malformations, and skeletal anomalies suggests a novel genetic disorder, potentially a new subtype of microcephalic primordial dwarfism.

Implications:

• This case expands the phenotypic spectrum of microcephalic primordial dwarfism.
• The findings highlight the importance of advanced neuroimaging in characterizing complex brain malformations.
• Further research is needed to identify the causative gene(s) and elucidate the underlying pathogenic mechanisms, likely involving autosomal recessive inheritance.