PMC10206130_01
Features of the child with microcephalic osteodysplastic primordial dwarfism type II (MOPDII) at age 7 years. (A) Extreme short stature, arthrogryposis of the hands, and the forced posture can be observed; (B) equinus right foot; (C) high forehead with ocular proptosis, prominent beaked nose, and micrognathia.
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Brisk and asymmetrical patellar osteotendinous reflexes were observed ( Figure 2 ).
PMC10206130_02
Bone Rx -ray anomalies at 3 years of age: (A) pelvis and lower limbs: bilateral subluxation of the femoral heads, more pronounced on the left with wide acetabular angles; flared appearance of the distal metaphysis of both femurs; (B, C) shoulders and upper limbs: dislocation of the humeral ossification center, convex shape of the radius bilaterally. The red arrows point at the anomalies described.
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A total-body skeletal survey showed multiple and distinctive bone anomalies, including bone age delay (according to the Greulich and Pyle standards, this was 1 year and 3 months at a chronological age of 3 years and 10 months); dislocation of the humeral ossification center; convex shape of the radius bilaterally; and bilateral subluxation of the femoral heads, more pronounced on the left (which evolved to luxation within three years), with wide acetabular angles and flared appearance of the distal metaphysis of both femurs as a consequence of severe skeletal dysplasia ( Figure 3 ).
NGS and Sanger sequencing showed a novel homozygous c.3019_3020del deletion in the PCNT gene on genomic DNA. The forward DNA sequencing electropherogram of exon 15 and of the PCNT gene is reported in panel (A), the reverse in (B). Ref Seq (reference sequencing) was used for variant annotations: NM_006031.6 and NP_006022.3. The identified pathogenic variant in the PCNT gene, visualized using the Integrative Genome Viewer (IGV) software, is presented in (C). In panels (D, E), the identified mutation and the predicted consequence for the pericentrin protein are detailed. The pericentrin structure was derived from https://www.uniprot.org/uniprotkb/O95613/entry.
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The molecular analysis identified the c.3019_3020del in exon 15 predicted to lead to a premature codon termination fifty bases after codon 1007, p.(Leu1007Serfs*50) and production of truncated protein ( Figures 4D, E ). This could not be verified experimentally due to the small amount of peripheral blood available from the proband. The pathogenic variant identified by NGS technology was validated by Sanger sequencing ( Figures 4A-C ) and reported using the Human Genome Variation Society nomenclature guidelines (https://varnomen.hgvs.org/).
MRI performed at diagnosis. (A) Axial T2-weighted image (WI) showing a diffuse attenuation of the flow void of the middle cerebral arteries; (B) coronal T2WI shows multiple areas of prior infarction, seen as areas of high signal intensity. MRI performed at age 8 yr. (C) axial T2-WI shows a decrease in flow void of the anterior cerebral arteries; (D) an acute hemorrhagic infarction is also visible in the left cerebellar hemisphere on T2-WI coronal image. (E, F) MIP/3D TOF MRA: the coronal projection shows diffuse stenosis/dilatations of the vessels of the circle of Willis, with Moyamoya appearance, consisting in sub/occlusion of the middle cerebral arteries, stenosis of the anterior cerebral arteries (with a mouse-tail appearance), bilateral carotid siphons, basilar apex and tonsillar branch of the posterior-inferior cerebellar artery aneurysmal dilatation. The myriad of small collateral blood vessels including the rete mirabilis in the region of the perforating arteries is also visible. The red arrows point at the anomalies described.
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The MRI also highlighted an occlusion of the M1 segment of both middle cerebral arteries and an irregular and stenotic appearance of the A3-A4 segments of the anterior cerebral arteries associated with the development of a collateral vessel network (Moyamoya disease) ( Figures 5C-F ).
PMC10206130_03
MRI performed at diagnosis. (A) Axial T2-weighted image (WI) showing a diffuse attenuation of the flow void of the middle cerebral arteries; (B) coronal T2WI shows multiple areas of prior infarction, seen as areas of high signal intensity. MRI performed at age 8 yr. (C) axial T2-WI shows a decrease in flow void of the anterior cerebral arteries; (D) an acute hemorrhagic infarction is also visible in the left cerebellar hemisphere on T2-WI coronal image. (E, F) MIP/3D TOF MRA: the coronal projection shows diffuse stenosis/dilatations of the vessels of the circle of Willis, with Moyamoya appearance, consisting in sub/occlusion of the middle cerebral arteries, stenosis of the anterior cerebral arteries (with a mouse-tail appearance), bilateral carotid siphons, basilar apex and tonsillar branch of the posterior-inferior cerebellar artery aneurysmal dilatation. The myriad of small collateral blood vessels including the rete mirabilis in the region of the perforating arteries is also visible. The red arrows point at the anomalies described.
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The MRI also highlighted an occlusion of the M1 segment of both middle cerebral arteries and an irregular and stenotic appearance of the A3-A4 segments of the anterior cerebral arteries associated with the development of a collateral vessel network (Moyamoya disease) ( Figures 5C-F ).