ESPE Abstracts (2015) 84 P-1-91

Mutation in RTTN, a Regulator of Ciliary Function, Causes a Complex Syndrome Characterized by Severe Congenital Microcephaly, Lissencephaly and Profound Growth Failure in Two Siblings

Anna Grandone, Vincenzo Nigro, Annalaura Torella, Adalgisa Festa, Caterina Luongo, Pierluigi Marzuillo, Ruggero Coppola, Emanuele Miraglia del Giudice & Laura Perrone

Second University of Naples, Naples, Italy

Background: Primordial dwarfism (PD) is a phenotype characterized by profound growth retardation and microcephaly that is prenatal in onset. Recently mutations in genes involved in ciliogenesis have been described in patients with primordial dwarfism phenotype. In 2012 mutations in rotatin (RTTN), a protein involved in cilia structure and function, have been described in in individuals with bilateral diffuse polymicrogyria, but not growth failure.

Case presentation: We report on a consanguineous Moroccan family with two siblings with a severe congenital microcephaly syndrome with growth failure resembling PD. The affected individuals in this family were born to consanguineous parents. The two affected children, a 21 months old boy and 11 months old girl, presented with severe microcephaly, failure to thrive and are also very short and microcephalic (the boy, at 21 months was 6.5 kg (<2th) and 68.7 cm (<4 SDS), W/L<2th; head circumference 34 cm; the girl months was 4.559 kg (<2th) and 57 cm (<4 SDS), W/L<2th; head circumference 31 cm); they had both dermatitis from newborn period and have very high level of IgE. Brain MRI showed lissencephaly of frontal lobe. They both had severe development delay. We identified by next generation sequencing a new homozygous mutation in exon 23 of RTTN gene (Arg985Gly). We analysed cDNA from leukocytes of the patients and found an abnormal splicing with two different transcripts: one lacking the entire exon 23 and one lacking exons 22 and 23.

Conclusion: For the first time we describe a new phenotype characterized by primordial microcephaly, severe growth failure, cortical malformation and severe dermatitis caused by a mutation in RTTN, a gene involved in ciliary function. We suggest that our mutation, more severe than the ones described till now affecting splicing, causes a more extreme phenotype disrupting cortical differentiation, growth and skin formation. Thus, our study adds PD to a growing list of ciliopathy phenotypes in humans.