3 generation pedigree with paternal transmission of the 22q11.2 deletion syndrome: Intrafamilial phenotypic variability

Abstract

In this case report, we present a paternal transmission of a classic 3 Mb 22q11.2 deletion syndrome (22q11.2 DS) in a 3 generation family. In this family a young girl, her father, her uncle and her grandfather were diagnosed with this disorder. All carriers showed phenotypic expression, there were no unaffected siblings in the second or third generation. Presenting symptoms in the patient in first generation (grandfather) were psoriatic arthritis, thrombocytopenia and a right aortic arch. There was no intellectual disability. The second generation uncle was known with a severe intellectual disability, mild facial characteristics, a septal defect and a clubfoot, whereas the second generation father had a tetralogy of Fallot, no intellectual disability and minimal facial characteristics. The third generation daughter had a moderate intellectual disability, hypernasal speech, triphalangeal thumb, severe speech and language development delay, pronounced facial characteristics and a diagnosis of ADHD. It was notable that the expression in the two brothers of the second generation gives two very different clinical phenotypes with a severe intellectual disability in the oldest brother. This report describes a pronounced clinical variability in a 3 generation familial 22q11.2 deletion with paternal transmission. We can assume that several mechanisms play an important role in the heterogeneity and part of the answer should be found in the genetic background underlying the 22q11.2 deletion. In addition in this family the neuropsychiatric phenotype and intellectual disability seem to be associated with a lower level of social and occupational functioning while a congenital heart disease does not. This clinical report illustrates that a detailed description of these patients can be very informative and still increase the knowledge on this heterogeneous syndrome. For the clinicians working with these patients it emphasizes the need for a multidisciplinary approach that takes into account the individual needs.

Keywords: 22q11 deletion syndrome; Adaptive functioning; Intellectual disability; Paternal transmission; Phenotypic variability.