Objective: We report a case of Trisomy 8 Mosaicism (T8M, Warkany Syndrome) with craniocervical and hand dystonia, an hitherto unreported disease association.

Background: T8M is a rare genetic condition (1/25000 to 1/50000 live births) with a protean clinical phenotype including facial dysmorphism, deep palmar and plantar creases, camptodactyly, agenesis of the corpus callosum and a variable degree of intellectual disability. An expressive speech disorder has been described in this condition but not extensively characterised.(1) Movement disorders are not a reported feature.

Methods: Case: A 17-year-old male student was referred to adult neurology services with dysarthria. He was the product of a normal pregnancy with normal early motor milestones but delayed speech until age 3, at which time poor tongue control was noted on speech therapy. Since age 5 he had a stable speech impediment with impaired volitional tongue movements, smiling, and whistling, but normal comprehension, lip function, and swallowing. Handwriting was impaired with both hands when he first started to learn at age 8 and dystonic posturing of his hands was observed on writing. His gait was remarkable for involuntary neck flexion and Fogs’ test revealed mild symmetrical posturing of the upper limbs.  Deep plantar creases and camptodactyly were also noted. There was a family history of late-onset cervical dystonia in his paternal grandmother. Skin biopsy confirmed T8M. Genetic testing for hereditary dystonias revealed no mutation of TOR1A (DYT1) and a mutation of THAP1 (DYT6) of uncertain pathogenicity (c.530T>C, p.Leu177Pro) not listed in the ExAC or ClinVar databases. His father, who had no dystonia, had the same THAP1 mutation. Our patient subsequently developed a severe cervical dystonia at age 19 which progressed rapidly to peak severity over one month and responded well to botulinum toxin therapy.

Results: In our case T8M presented with a young-onset, predominantly craniocervical dystonia with prominent speech involvement, reminiscent of the clinical phenotype of DYT6. We hypothesise that overexpression of THAP1, which may be due to an extra copy of chromosome 8 on which it is located or due to failure of autoregulation from a DYT6-causative THAP1 mutation(2), may represent a common mechanistic pathway to explain the presence of a DYT6-like dystonia in T8M.

Conclusions: Dystonia can occur in T8M and may be a mechanism for the well‑reported phenomenon of impaired speech in this condition.

References: 1.            Gagliardi AR, Tajara EH, Varella-Garcia M, Moreira LM. Trisomy 8 syndrome. Journal of medical genetics. 1978;15(1):70-3.

2.            Erogullari A, Hollstein R, Seibler P, Braunholz D, Koschmidder E, Depping R, et al. THAP1, the gene mutated in DYT6 dystonia, autoregulates its own expression. Biochimica et biophysica acta. 2014;1839(11):1196-204.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/trisomy-8-mosaicism-and-dystonia-a-thap1-overdose/