Two cases of DCDC2‐related neonatal sclerosing cholangitis with developmental delay and literature review

Abstract

Ciliopathies are a group of clinical and molecular heterogeneous conditions with pleiotropic manifestations affecting the central nervous system, renal, liver, skeletal, and ocular systems. Biallelic pathogenic variants in DCDC2 cause a ciliopathy primarily presenting with neonatal sclerosing cholangitis (NSC). Pathogenic variants in DCDC2 have further been reported in the context of nephronophthisis and non‐syndromic recessive deafness. Polymorphisms in DCDC2 have also been associated with dyslexia and DCDC2 has a role in neuronal development. We report on two unrelated patients with DCDC2‐related NSC with additional central nervous system impairment manifesting as microcephaly, global developmental delay, and axial hypotonia. Histological findings of our patients can mimic biliary atresia or congenital hepatic fibrosis. We further show that transmission electron microscopy in patients with NSC does not always show absence of primary cilia. Hence patients with DCDC2 pathogenic variants should also undergo an evaluation of neuromotor development. Review of all reported patients further reveals a risk for supra‐aortic arterial aneurysms.

Neonatal sclerosing cholangitis with novel mutations in DCDC2 (doublecortin domain-containing protein 2) in Chinese children

“…At present, it is not very clear whether nerve, muscle, or immune system involvements are related to mutations in DCDC2. Researchers hypothesized that the involvement of these systems may be related to the inactivation of the cilium function or the disorder of Wnt signaling pathways due to DCDC2 mutations (10). More cases and further studies are needed to confirm this hypothesis.…”

“…It's worth noting that results of the histology on liver biopsies bring to mind the biliary atresia and congenital hepatic fibrosis, which makes it challenging to establish the diagnosis of NSC. DCDC2 immunohistochemical staining was performed in some patients, which revealed DCDC2 staining was heighten in the cytoplasm of cholangiocytes while a lesser extent or absent at the apical margin of cholangiocytes (4,6,10). These findings suggest that mutations in DCDC2 perturbed protein expression and localization.…”

“…The ultrastructural characteristics of hepatocytes were evaluated using a transmission electron microscope (TEM) in individual patient. In liver tissue, lobular cytoplasmic necrosis, dilatation of canalicular lumina with amorphous bile, were seen as well as blunting of microvilli, and cytoplasmic blebbing into the canalicular lumen, while cholangiocellular primary cilia were existent or absent (6,10).…”

“…In 2016, Girard et al (4)and Grammatikopoulos et al (6) verified that doublecortin domain containing 2 (DCDC2) gene mutations can lead to NSC. Apart from that, DCDC2 pathogenic variants were reported to be associated with renal-hepatic ciliopathy with nephronophthisis, nonsyndromic recessive deafness, dyslexia and central nervous system impairment (7)(8)(9)(10). With the development of whole-exome sequencing (WES), more and more DCDC2 mutations have been identified.…”

“…With the development of whole-exome sequencing (WES), more and more DCDC2 mutations have been identified. To our knowledge, seventeen cases of NSC caused by DCDC2 mutation with 12 variants have been reported worldwide (4,6,(10)(11)(12)(13)(14).…”