PTPRD copy number variants and Ewing's sarcoma: Strengthening the association and therapeutic implications.

Ewing sarcoma (ES), a common pediatric primary bone neoplasm, has a well-defined genomic landscape with various predisposing genomic elements including TP53, PMS2 and RET. Additionally, germline and somatic variants in protein tyrosine phosphatase delta (PTPRD), a tumor suppressor gene, have been identified in a limited number of ES patients. Here we present an ES patient, remarkable in terms of his young age and extent at presentation, found to have a PTPRD CNV. We explore the pathogenicity of this CNV, describe the patient's clinical course and touch upon the potential therapeutic implications in this subset of patients.

Pachyonychia Congenita Associated with a Novel Variant of KRT17 Presenting Unusual Oral Manifestations.

Pachyonychia congenita (PC) is a rare autosomal dominant condition caused by heterozygous mutation in one of five keratin genes. The purpose of this paper is to report a five-day-old infant with PC whose initial presentation revealed multiple malformed natal teeth and gingival lesions on the alveolar crest. Further investiga- tions led to genetic molecular testing of the child and his parents, which revealed a de novo and novel missense variant of KRT17 (c. 307C>T, p. Arg103Cys), resulting in a non-conservative amino-acid substitution and a diagnosis of PC. This case high- lights the need for multidisciplinary care and the relevance of molecular investigations for patients with multiple natal teeth. (J Dent Child 2019;86(1):61-3)
Received September 26, 2018; Last Revision November 19, 2018; Accepted November 19, 2018.

Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.

Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4(-/-) mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome.