Primary Dwarfism, Microcephaly, and Chorioretinopathy due to a PLK4 Mutation in Two Siblings

Abstract

<b><i>Introduction:</i></b> 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 <i>PLK4</i> gene<i>,</i> 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. <b><i>Case Presentation:</i></b> Here, we describe 2 siblings of different sex from Equatorial Guinea harboring a homozygous frameshift mutation in <i>PLK4</i> (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. <b><i>Discussion/Conclusion:</i></b> Biallelic variants in <i>PLK4</i> 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.

Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size

“…The PLK4 gene (NM_001190799) encodes the Polo-like Kinase 4, the master regulator of centriole duplication, which is activated upon phosphorylation and recruits STIL and SAS6 proteins at the proximal end of the parent centriole, thereby initiating the assembly of the procentriole [ 21 , 177 , 179 , 180 , 181 , 182 ] (see Figure 3 ). Mutations in PLK4 are an exceedingly rare cause of autosomal recessive PMs.…”

“…Mutations in PLK4 are an exceedingly rare cause of autosomal recessive PMs. Since the identification of the first patients [ 46 ], 15 individuals from seven families carrying five different biallelic variants have been reported [ 46 , 48 , 181 , 182 , 183 ]. A recurrent homozygous mutation (c.1299_1303delAAAG; p. Phe433Leufs*6) has been reported in four families from diverse geographical regions (Madagascar, Iran, Pakistan, and Equatorial Guinea).…”

“…Similar to mutations in CEP152 , mutations in the PLK4 gene alter brain growth more than body growth, as the reduction in OFC expression is more pronounced (−11.7 ± 2.3 SD) than in height. The gyral pattern of the brain is extremely simplified [ 182 ] and represents what is called microlissencephaly. Interhemispheric arachnoid cysts have been reported in two cases in unrelated patients.…”

“…Interhemispheric arachnoid cysts have been reported in two cases in unrelated patients. Neuronal heterotopia was observed in three of seven patients who underwent brain imaging [ 46 , 181 , 182 , 183 ]. No cases of epilepsy have been reported to date.…”

Transmission ratio distortion of mutations in the master regulator of centriole biogenesis PLK4

“…The Polo-like kinase 4 (PLK4) is essential for centriole duplication (Sonnen et al 2013 ; Yamamoto and Kitagawa 2021 ), for spindle assembly in the absence of centrioles (Coelho et al 2013 ), and for de novo centriole formation (Eckerdt et al 2011 ). Homozygous mutations in PLK4 lead to primary microcephaly, combined with growth retardation and retinopathy (Martin et al 2014 ; Shaheen et al 2014 ; Tsutsumi et al 2016 ; Dincer et al 2017 ; Martin-Rivada et al 2020 ), while heterozygous mutations might be associated with azoospermia (Miyamoto et al 2016 ). This, however, applies to one case only, has not been validated in an independent study (Cioppi et al 2021 ), and was not observed in the other heterozygote PLK4 probands published so far.…”