Extending the phenotype of DeSanto‐Shinawi syndrome: A case report and literature review

Abstract

DeSanto-Shinawi syndrome (DESSH, OMIM #616708) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in the WAC gene. Affected individuals are characterized by neonatal hypotonia, developmental delay, intellectual disability, behavioral problems, and dysmorphism. Epilepsy is present in some of the patients with DESSH. By far, less than 30 affected individuals have been reported worldwide. Herein, we report a 9-year-old Chinese girl with molecularly substantiated DESSH with a de novo nonsense c. 1648C>T p.(Arg550*) variant identified in the WAC gene. Aside from developmental delay and the characteristic facial gestalt, our proband also exhibited tethered cord syndrome due to filar lipoma and left duplex kidney complicated with hydronephrosis, features not observed in any of the previously reported individuals with DESSH.

Novel LSS variants in alopecia and intellectual disability syndrome: New case report and clinical spectrum of LSS‐related rare disease traits

“…Future studies should evaluate the functional impact of the variants as it is still unclear whether the different phenotypes represent different diseases or a continuum of one disorder due to allelic combinations and allelic severity at the locus. 13 Our report provides novel LSS variants to be added to the list of APMR4 and highlights the clinical heterogeneity of LSS-related disorders. Moreover, we suggest that some neuroimaging clues can be relevant for an early diagnosis.…”

“…13,15,16 The p.(Ile342Ser) variant was found to significantly reduce LSS protein expression and completely abolish its enzymatic activity resulting in no lanosterol production. 13,15 The p. phenotype-genotype correlation, we found that the map positions of the individual pathogenic variant alleles were not related to the observed clinical disease. However, cases with a more severe phenotype were more likely to have a biallelic combination of a LoF allele plus a missense.…”

“…5 This assumption was later questioned after a family from China with both cataract and hypotrichosis and had biallelic LSS variants localized toward the N-terminus. 13 Several families with the HS phenotype have been described with the variants spread across both domains. [8][9][10][11]14,18 Then the phenotypic spectrum of LSS was expanded to include a third and more severe neuro-ectodermal phenotype, APMR4, with a report of 11 patients from seven unrelated families having alopecia and intellectual disability secondary to LSS biallelic variants.…”

“…6 A total of 29 families with all three LSS-related disorders have been reported worldwide amongst which are 10 families with 15 affected individuals with the APMR4 phenotype. 2,5,[7][8][9][10][11][12][13][14][15][16][17][18] We describe an Egyptian patient with biallelic novel variants in LSS and APMR4 to potentially expand the mutational and phenotypic spectrum of the syndrome.…”

“…A total of 29 families with all three LSS ‐related disorders have been reported worldwide amongst which are 10 families with 15 affected individuals with the APMR4 phenotype 2,5,7–18 …”