Microdeletion of 16q24.1–q24.2—A unique etiology of Lymphedema–Distichiasis syndrome and neurodevelopmental disorder

Abstract

Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema–Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants in FOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1–q24.2. This report extends the phenotype of both 16q24.1–q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3′‐UTR part of FOXC2.

Haploinsufficiencies of FOXF1, FOXC2 and FOXL1 genes originated from deleted 16q24.1q24.2 fragment related with alveolar capillary dysplasia with misalignment of pulmonary veins and lymphedema-distichiasis syndrome: relationship to phenotype

“…ACDMPV and LDS have been confirmed to be related with the deleted 16q24.1q24.2 fragment until now [ 5 , 14 ]. In this case, CNV-seq detection showed a 2.12-Mb deleted region in 16q24.1q24.2 containing the following definite pathogenetic genes: FOXF1 , FOXC2 and related regulatory genes including forkhead box L1 ( FOXL1 , OMIM 603252) and FOXF1 adjacent non-coding developmental regulatory RNA ( FENDRR ).…”

“…The deleted fragment in our fetus includes the other three genes— FOXC2 , FOXL1 and FENDRR . FOXC2 is the key gene of LDS characterized by lymphedema of the limbs and double rows of eyelashes [ 14 , 24 ], which is essential for lymphatic valve maintenance by regulating lymphatic endothelial cells junctional integrity and cellular quiescence [ 25 ]. FOXC2 pathogenetic variant has been identified in cases with LDS to impair transcriptional activity and cell proliferation [ 26 ] through VEGF-C/VEGFR3 signaling pathway commonly correlated with primary lymphedema, lymphatic valve formation and other lymphatic malformations [ 27 ].…”

Lymphatic System and the Kidney: From Lymphangiogenesis to Renal Inflammation and Fibrosis Development

“…Additional associated signs may include cardiac abnormalities, type II diabetes, and renal disorders like hydronephrosis, ectopic kidney, and renal agenesis. The 16q24.1–q24.2 microdeletion is linked with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities [ 70 , 71 ].…”