Characterisation of the clinical phenotype in Phelan-McDermid syndrome

Mónica Burdeus-Olavarrieta,Javier González-Peñas,Alicia García-Alcón,Antonia San José-Cáceres,Patricia Hernández-Jusdado,Mara Parellada-Redondo

doi:10.1186/s11689-021-09370-5

Abstract

BackgroundPhelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability.MethodsWe used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison.ResultsWe found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size.ConclusionsThis study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.

Highlights

Phelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID)
Concerning developmental regression, we identified that half of the 42% of participants that had an apparent loss of abilities regained previous functioning
This study adds to the available information on the clinical manifestation of PMS patients, who typically show impaired adaptive skills, speech acquisition delay or absence of language, and intellectual disability of variable degree, along with a number of medical and behavioural challenges, such as autism spectrum disorder (ASD), developmental regression and hyperactivity, some of which appear to correlate with deletion size

Summary

Introduction

Phelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The exact prevalence of the syndrome remains unknown, and the condition is likely underdiagnosed, due to its unspecific clinical phenotype and the need for molecular genetic testing to establish a diagnosis [8] Recent descriptions of this syndrome reveal several clinical features, such as ASD and ID, attention deficit, hyperactivity and impulsivity, aggressive behaviour, language impairments and medical comorbidities [4, 9]. We aim to conduct a deep phenotypic characterisation of the clinical and neurobehavioural traits of a large national sample of participants with PhelanMcDermid syndrome, using standardised, robust instruments to assess repetitive or otherwise altered behaviours, hyperactivity, attentional problems, sensory processing difficulties, global adaptive functioning and autistic features. Our research questions read: #1 Are the characteristics of our PMS sample like other cohorts described? #2 How is language ability related to other phenotypic characteristics? Do the clinical profiles of verbal and non-verbal individuals differ?

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