An unusual presentation of Kabuki syndrome with orbital cysts, microphthalmia, and cholestasis with bile duct paucity

Bögershausen, Nina; Altunoğlu, Umut; Beleggia, Filippo; Yiğit, Gökhan; Kayserili, Hülya; Nürnberg, Peter; Li, Yun; Altmüller, Janine; Wollnik, Bernd

doi:10.1002/ajmg.a.37931

Cited by 19 publications

(8 citation statements)

References 46 publications

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“…In particular, a mutation in KMT2D at 12q13.12 accounts for 55–80% of KS cases, whereas 9–14% of KMT2D -negative patients have a deletion or mutation in KDM6A at Xp11.3 [23]. Bögershausen et al reported on a KS patient with a KMT2D mutation who presented with neonatal cholestasis with bile duct paucity in addition to the typical clinical features of KS, although their case did not show pathogenic variants in either JAG1 or NOTCH2 ; they hypothesized that the KMT2D mutation might have affected several key Notch signaling components [24]. KDM6A encodes lysine-specific demethylase 6A (UTX), a JmjC domain-containing protein that specifically demethylates the H3K27me3/me2 mark [25].…”

Section: Discussionmentioning

confidence: 99%

Cystic biliary atresia with paucity of bile ducts and gene mutation in KDM6A: a case report

et al. 2019

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Background Biliary atresia (BA) cases are generally not associated with congenital abnormalities. However, accurate diagnosis of BA is often challenging because the histopathological features of BA overlap with those of other pediatric liver diseases and rarely overlap with those of other genetic disorders. We experienced a rare case of BA with the histopathological finding of bile duct paucity, a gene mutation in KDM6A , and KS-like phenotypes. Case presentation A male baby was diagnosed with biliary atresia by intraoperative cholangiography at 4 days of age, and histological examination following a liver biopsy revealed a paucity of bile ducts and several typical clinical findings of Alagille syndrome. However, Alagille syndrome was ruled out after neither JAG1 nor NOTCH2 gene mutations were identified. Whole-exome sequencing on DNA from his parents was additionally performed to examine other possible syndromic disorders, and a mutation was identified in KDM6A . However, Kabuki syndrome was not diagnosed as a result. The histological finding of interlobular bile duct paucity and the genetic mutation in KDM6A , as well as several clinical findings consistent with Alagille syndrome or Kabuki syndrome, made it difficult to confirm the diagnosis of BA. Conclusions Based on the interesting findings of the present case, we hypothesized that KDM6A is associated with hepatic malformations via a connection with the Notch signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Cystic biliary atresia with paucity of bile ducts and gene mutation in KDM6A: a case report

et al. 2019

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“…KS1 is characterized by several clinical manifestations including cardinal facial gestalts (long palpebral fissures, eversion of the lower lateral eyelids, arched eyebrows, depressed nasal tip, palate malformations, and large prominent ears), feeding difficulties, digital and hand anomalies, cardiovascular defects, skeletal and growth abnormalities, immune system dysregulation, anxiety and sleep difficulties, neonatal hypotonia, renal anomalies, and endocrine abnormalities (Adam et al, 2019; De Leon & Stanley, 2017; Niikawa et al, 1981; Rapp et al, 2022; Stagi et al, 2016; Yap et al, 2019). Other possible manifestations include orbital vascular malformations and cholestasis, cleft hand, epilepsy, microphthalmia, and pilomatricoma, among many others (Bernier et al, 2017; Bögershausen et al, 2016; Bruni et al, 2021; Huh et al, 2011; Kamada et al, 2019; McVeigh et al, 2015).…”

Section: Ks1 In the Clinicmentioning

confidence: 99%

Molecular insights of KMT2D and clinical aspects of Kabuki syndrome type 1

Golden

Williams

Serrano

2023

Birth Defects Research

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BackgroundKabuki syndrome type 1 (KS1), a rare multisystem congenital disorder, presents with characteristic facial features, intellectual disability, persistent fetal fingertip pads, skeletal abnormalities, and postnatal growth delays. KS1 results from pathogenic variants in the KMT2D gene, which encodes a histone methyltransferase protein involved in chromatin remodeling, promoter and enhancer regulation, and scaffold formation during early development. KMT2D also mediates cell signaling pathways, responding to external stimuli and organizing effector protein assembly. Research on KMT2D's molecular mechanisms in KS1 has primarily focused on its histone methyltransferase activity, leaving a gap in understanding the methyltransferase‐independent roles in KS1 clinical manifestations.MethodsThis scoping review examines KMT2D's role in gene expression regulation across various species, cell types, and contexts. We analyzed human pathogenic KMT2D variants using publicly available databases and compared them to research organism models of KS1. We also conducted a systematic search of healthcare and governmental databases for clinical trials, studies, and therapeutic approaches.ResultsOur review highlights KMT2D's critical roles beyond methyltransferase activity in diverse cellular contexts and conditions. We identified six distinct groups of KMT2D as a cell signaling mediator, including evidence of methyltransferase‐dependent and ‐independent activity. A comprehensive search of the literature, clinical databases, and public registries emphasizes the need for basic research on KMT2D's functional complexity and longitudinal studies of KS1 patients to establish objective outcome measurements for therapeutic development.ConclusionWe discuss how KMT2D's role in translating external cellular communication can partly explain the clinical heterogeneity observed in KS1 patients. Additionally, we summarize the current molecular diagnostic approaches and clinical trials targeting KS1. This review is a resource for patient advocacy groups, researchers, and physicians to support KS1 diagnosis and therapeutic development.

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“…All monogenic causes were previously associated with MAC except EPHA2, for which association with microphthalmia was validated and published, 19 3, figure 2B). [19][20][21][22][23][24][25][26][27] According to Association for Clinical Genomic Science classification guidelines, ALDH1A3 variant c.104T>C;p.(Phe35Ser) in patient 22-1 is a variant of 'uncertain significance'. However, the multidisciplinary team considered this patient's phenotype to be compatible with reported ALDH1A3 cases and there were no other relevant mutations found in MAC panels applied to this patient's genome data.…”

Section: Molecular Diagnosismentioning

confidence: 99%

Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma

et al. 2022

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Background/aimsMicrophthalmia, anophthalmia and coloboma (MAC) are clinically and genetically heterogenous rare developmental eye conditions, which contribute to a significant proportion of childhood blindness worldwide. Clear understanding of MAC aetiology and comorbidities is essential to providing patients with appropriate care. However, current management is unstandardised and molecular diagnostic rates remain low, particularly in those with unilateral presentation. To further understanding of clinical and genetic management of patients with MAC, we charted their real-world experience to ascertain optimal management pathways and yield from molecular analysis.MethodsA prospective cohort study of consecutive patients with MAC referred to the ocular genetics service at Moorfields Eye Hospital between 2017–2020.ResultsClinical analysis of 50 MAC patients (15 microphthalmia; 2 anophthalmia; 11 coloboma; and 22 mixed) from 44 unrelated families found 44% had additional ocular features (complex) and 34% had systemic involvement, most frequently intellectual/developmental delay (8/17). Molecular analysis of 39 families using targeted gene panels, whole genome sequencing and microarray comparative genomic hybridisation identified genetic causes in, 28% including novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3), and a molecular diagnostic rate of 33% for both bilateral and unilateral cohorts. New phenotypic associations were found for FOXE3 (bilateral sensorineural hearing loss) and MAB21L2 (unilateral microphthalmia).ConclusionThis study highlights the importance of thorough clinical and molecular phenotyping of MAC patients to provide appropriate multidisciplinary care. Routine genetic testing for both unilateral and bilateral cases in the clinic may increase diagnostic rates in the future, helping elucidate genotype–phenotype correlations and informing genetic counselling.

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An unusual presentation of Kabuki syndrome with orbital cysts, microphthalmia, and cholestasis with bile duct paucity

Cited by 19 publications

References 46 publications

Cystic biliary atresia with paucity of bile ducts and gene mutation in KDM6A: a case report

Cystic biliary atresia with paucity of bile ducts and gene mutation in KDM6A: a case report

Molecular insights of KMT2D and clinical aspects of Kabuki syndrome type 1

Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma

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