Characterisation of the clinical phenotype in Phelan-McDermid syndrome

Abstract

Background: 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 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.

Methods: We 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.

Results: We 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.

Conclusions: This 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.

Keywords: 22q13 deletion syndrome; Autism; Intellectual disability; Phelan-McDermid syndrome; SHANK3.

Fig. 1

VABS-3 standard scores by language level and receptive and expressive scores for every participant. A Differences based on language (only participants over age 3 considered): communication (U=84.500, Z= −3.146, p=.002), daily living (t(40)= −1.561, 95% CI [−18.84, 2.42], p=.126), socialization (t(40)=-2.432, 95% CI [−26.49, −2.44], p=.020), total adaptive (t(40)= −2.510, 95% CI [−22.85, −2.47], p=.016). “Verbal” n=15; “Minimally verbal” n=27. Error bars represent confidence interval of the mean. B Scores in receptive and expressive subdomains for each participant. Solid and dashed lines represent population mean and SD, respectively

Fig. 2

Behavioural alterations reported in ABC, SDQ and CBCL. A ABC (Aberrant Behavior Checklist), “Verbal” n=16, “Minimally verbal” n=28. Error bars represent confidence interval of the mean. B SDQ (Strengths and difficulties Questionnaire), “Verbal” n=10, “Minimally verbal” n=23. Percentage of participants over the borderline cutoff for each subscale. C CBCL for ages 6–18 years, “Verbal” n=12, “Minimally verbal” n=17. Percentage of participants over the borderline cutoff for each subscale. D CBCL (Child Behavior Checklist) for ages 1.5 to 5 years, n=10, all minimally verbal. Percentage of participants over the borderline cutoff for each subscale

Fig. 3

Differences in sample characteristics and 22q13 deletion sizes. A Deletion size and language level. “No language” n=34; “Single words” n=5, outlier experienced a regression during puberty; “Simple sentences” n=8; “Fluid speech” n=6, outlier is a mosaic. B Deletion size and motor milestones. “No delayed walking” n=23; “Delayed walking” n=28. C Deletion size and regression status. “No regression” n=31; “Regression” n=21. D Deletion size and ADOS-2 Total CSS scores