Neurofibromatosis type 2 in Phelan-McDermid syndrome: Institutional experience and review of the literature

Ziats, Catherine A.; Jain, Lavanya; McLarney, Brittany; Vandenboom, Emily; DuPont, Barbara R.; Rogers, Curtis; Sarasua, Sara M.; Nevado, Julián; Cordisco, Emanuela Lucci; Phelan, Katy; Boccuto, Luigi

doi:10.1016/j.ejmg.2020.104042

Cited by 12 publications

(8 citation statements)

References 18 publications

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“…The three participants with ring chromosome 22 were minimally verbal, however, they did not present with a notably different phenotype compared with the other participants with PMS. Four participants had additional genetic findings including 1q21.1 duplication, neurofibromatosis type 2 (associated with ring chromosome 22 [24]), Ehlers-Danlos syndrome and premutation carrier for fragile X. Ten participants (48%) had existing clinical diagnoses of ASD (typically from a paediatrician and multidisciplinary, skilled team as per health system processes in Australia) and 19 (100%) over the age of four had some degree of ID, ranging from moderate to severe across the group.…”

Section: Participant Characteristicsmentioning

confidence: 99%

Speech and language phenotype in Phelan-McDermid (22q13.3) syndrome

Brignell

Holm

et al. 2020

Eur J Hum Genet

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Communication difficulties are a core feature of Phelan-McDermid syndrome (PMS). However, a specific speech and language phenotype has not been delineated, preventing prognostic counselling and development of targeted therapies. We examined speech, language, social and functional communication abilities in 21 individuals with PMS (with SHANK3 involvement), using standardised assessments. Mean age was 9.7 years (SD 4.1) and 57% were female. Deletion size ranged from 41 kb to 8.3 Mb. Nine participants (45%) were non-verbal. Four (19%) had greater verbal ability, speaking in at least 4-5 word sentences, but with speech sound errors. Standard scores for receptive and expressive language were low (typically >3 SD below the mean). Language age equivalency was 13-16 months on average (range 2-53 months). There was a significant association between deletion size and the ability to use phrases. Participants with smaller deletion sizes were more likely to be able to use phrases (odds ratio: 0.36, 95% CI: 0.14-0.95, p = 0.040). Adaptive behaviour (life skills) was low in all areas (>2 SD below mean). Scores in communication were markedly lower than for daily living (p = 0.008) and socialisation (p < 0.001). A common linguistic profile was characterised by severe impairment across receptive, expressive and social language domains. Yet data indicated greater communicative intent than appeared to be capitalised by current therapies. Early implementation of augmentative (e.g. computer-assisted) modes of communication, alongside promotion of oral language, is essential to harness this intent, accelerate language development and reduce frustration. Future trials should examine the added benefit of targeted speech motor interventions in those with greater verbal capacity.

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Section: Participant Characteristicsmentioning

confidence: 99%

Speech and language phenotype in Phelan-McDermid (22q13.3) syndrome

Brignell

Holm

et al. 2020

Eur J Hum Genet

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“…In PMS individuals with terminal deletions diagnosed with CMA, it is essential to rule out the presence of r(22). Confirmation of r(22) has significant implications for clinical management because individuals with r(22) have an increased risk of tumors in the nervous system due to biallelic loss of the NF2 (neurofibromatosis type 2) gene ( Lyons-Warren et al, 2017 ; Ziats et al, 2020 ). We observed three out of 20 patients with r(22) with neurofibromatosis type 2; these three individuals were included in the series reported by Zyats and others (2020).…”

Section: Discussionmentioning

confidence: 99%

Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals

et al. 2022

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Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed.

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“…For example, recurrent patients showed RC 4 with Wolf-Hirschhorn syndrome, RC 5 with Cri-du-Chat syndrome (OMIM: 123450 ), RC 17 with Miller-Dieker syndrome (OMIM: 247200 ), and RC 22 with Phelan-McDermid syndrome (OMIM: 606232 ). 39 , 79 , 80 , 81 , 82 These syndromic manifestations could be so distinct to conceal the presentation of ring syndrome.…”

Section: Current Understanding Of Constitutional Rcsmentioning

confidence: 99%

The past, present, and future for constitutional ring chromosomes: A report of the international consortium for human ring chromosomes

DuPont

et al. 2022

Human Genetics and Genomics Advances

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Neurofibromatosis type 2 in Phelan-McDermid syndrome: Institutional experience and review of the literature

Cited by 12 publications

References 18 publications

Speech and language phenotype in Phelan-McDermid (22q13.3) syndrome

Speech and language phenotype in Phelan-McDermid (22q13.3) syndrome

Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals

The past, present, and future for constitutional ring chromosomes: A report of the international consortium for human ring chromosomes

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