Primary Microcephaly in a Child with a Novel Deletion in ASPM Gene

An 18-month-old boy, firstborn to second-degree consanguineously married parents, presented with delayed speech and hyperactivity. His motor milestones were normal for his age. There was no history of seizures, encephalopathy, tone changes, or movement disorder. He was born at term with a birth weight of 2.5 kg and cried immediately after birth. He had a history of poor feeding at birth and neonatal jaundice. Family history was unremarkable. On examination, his weight was 11.5 kg (0.4 Z-score), length was 41 cm (−1.2 Z-score), and head circumference was 41 cm (−4.8 Z-score). There were no dysmorphism or neurocutaneous markers. He had normal tone, good muscle power in all limbs, and normal deep tendon reflexes. A clinical diagnosis of microcephaly with language delay due to neonatal sepsis, hypoxic-ischemic insult, or intrauterine infections was considered. The possibility of primary microcephaly was also considered in view of the normal motor examination and severe microcephaly. Magnetic resonance imaging (MRI) brain showed a simplified gyral pattern [Figure 1a-c]. Cytomegalovirus IgG titres were elevated, but polymerase chain reaction (PCR) was negative. Fundus examination was not suggestive of old/active chorioretinitis. Ultrasound examination of the liver and spleen was normal. Mass spectroscopic analysis of the blood and urine showed normal amino acid, organic acid, and acylcarnitine profiles. Next-generation sequencing revealed an autosomal recessive, pathogenic, homozygous frameshift variant c. 8508_8509delG in exon 18 of the ASPM gene, resulting in the amino acid substitution p. Lys2837fs*34, suggestive of microcephaly primary hereditary-5 (MCPH 5).Figure 1: Neuroimaging in Primary Microcephaly - MCPH 5. (a-d) MRI brain Axial T1W (a) and Axial T2W (b) showing the presence of a mild simplified gyral pattern (white and black arrows). Axial T2W (c) showing the prominence of posterior aspects of bilateral lateral ventricles. Coronal T2W (d) showing the presence of mild supratentorial brain volume loss with a normal cerebellumMCPH 5 (MIM#608716) is non-syndromic primary microcephaly, characterized by microcephaly, speech delay, and intellectual disability due to biallelic pathogenic variations in ASPM (abnormal spindle-like microcephaly-associated) gene (MIM*605481) on chromosome 1q31.[1] It is the most common cause of primary microcephaly.[2]ASPM protein is a significant determinant of cerebral cortical size by maintaining cleavage plane orientation for symmetric proliferative division of neuroepithelial cells.[2] The severity of cellular defect is proportional to the microcephaly severity.[3] The predominant genetic causes involve several genes encoding centrosomal proteins of centriole biogenesis that influence brain size.[3] In MCPH 5, the development is usually normal in young children, but in older children, variable levels of intellectual disability occur.[1] Epilepsy and autistic features are not common, as opposed to secondary microcephaly.[1] The common neuroimaging features include reduced brain volume, especially gray matter volume loss, and simplified gyral pattern.[4] Primary microcephaly is a distinct entity that needs differentiation from secondary causes such as hypoxia, sepsis, and intrauterine infections. Presence of intrauterine microcephaly and postnatal reduced growth are important clinical clues. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.