Cerebral aneurysms and kidney disease in a child with microcephalic osteodysplastic primordial dwarfism type II: novel homozygous mutation in the PCNT gene

MOPD is known to be caused by homozygous loss-of-function mutations in a specific gene, PCNT. Both intra- and interfamilial clinical variability (even for the same variant) have been frequently observed, which makes it difficult to infer a genotype–phenotype correlation. Pericentrin (PCTN) is a structural protein expressed in the centrosome that plays a fundamental role in anchoring protein complexes, regulating mitotic cycle and thus cell proliferation. High levels of mitotic alterations in the cells of subjects with PCNT mutations suggested that the cells of patients with MOPD II are more susceptible to apoptosis resulting in a decrease in the total cellularity of the embryo with subsequent growth restriction into adulthood. We report the case of a 7 year child that died for cerebral haemorrhage secondary to posterior arterial aneurysm. Genetic analysis evidenced a novel homozygous variant (c.3019_3020del, p.Leu1007Serfs*50), predicted to cause premature truncation of protein synthesis. This child presented with extreme short stature (-9,53 SDS) with no catch-up growth from birth, mental retardation, and distinctive craniofacial features. He had microcephaly, a high forehead with ocular proptosis and prominent beaked nose, micrognathia, a relatively proportionated small mouth with multiple dental caries, brachy-mesophalangy, arthrogryposis of the hands, equinus right foot, micropenis, hypotrophic-like right testis and non-palpable left testis, generalized hypotonus and resistance to dorsiflexion of the right lower limb due to the presence of tendon retraction, brisk and asymmetrical patellar osteotendinous reflexes. Total body skeletal survey showed multiple and distinctive bone anomalies. Abdominal US showed bilateral increased echogenicity of the kidneys with poor corticomedullary differentiation, at variance with the usual findings of kidney cysts in these patients. A first MRI of the brain performed at presentation showed areas of gliosis with encephalomalacia and diffused hypo/delayed myelination, and a thinned appearance of the middle and anterior cerebral arteries. Intracranial hemorrhage due to a cerebral aneurism occurred at age 7 yr, and was associated at that time with the moya-moya malformation, Unlike cases previously published in the literature, intracranial anomalies and kidney findings findings were evidenced very early in the life of this child.