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Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.

ABSTRACT: Au-Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fissures, ptosis, deeply grooved tongue, broad nose, and down-turned mouth. Patients frequently also have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies. In this report, we describe six new patients and review the clinical information on all reported AKS patients, further delineating the phenotype of AKS. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK. While there is considerable overlap between AKS and Kabuki syndrome (KS), these additional patients demonstrate that AKS does have a distinct facial gestalt and phenotype that can be differentiated from KS. This growing AKS patient cohort also informs an emerging approach to management and health surveillance for these patients.

SUBMITTER: Au PYB

PROVIDER: S-EPMC6117294 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.

Au P Y Billie PYB Goedhart Caitlin C Ferguson Marcia M Breckpot Jeroen J Devriendt Koenraad K Wierenga Klaas K Fanning Elizabeth E Grange Dorothy K DK Graham Gail E GE Galarreta Carolina C Jones Marilyn C MC Kini Usha U Stewart Helen H Parboosingh Jillian S JS Kline Antonie D AD Innes A Micheil AM

European journal of human genetics : EJHG 20180614 9

Au-Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fiss ...[more]

PMID: 29904177

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Project description:ImportancePatients with germline mutations in BAP1 may develop several flesh-colored melanocytic BAP1-mutated atypical intradermal tumors (MBAITs). These tumors generally develop earlier than other BAP1-associated tumors, highlighting an important role for dermatologists in identifying and screening patients with a history suggestive of a germline mutation.ObjectiveTo describe 8 new families with germline mutations in BAP1 and provide a comprehensive review of reported cases.Design, settings and participantsPatients were identified in an outpatient dermatology clinical setting over a 6-month period (10 mutation carriers from 8 families) and through a literature review using PubMed (205 patients).ExposuresMutations were identified through next-generation sequencing of saliva or blood samples, and RNA was extracted from fibroblasts cultured from a patient with an intronic variant to determine the impact of the mutation on the coding sequence.Main outcomes and measuresAll 215 patients were assessed for personal and/or family history and genotype. These findings were compiled and assessed for any association between genotype and phenotype.ResultsOverall, this study included 215 patients (108 women, 91 men, and 16 gender unspecified; median [range] age, 46.5 [10.0-79.0] years). Nine of the 10 patients who were identified in the outpatient dermatology setting were found to have MBAITs on clinical examination. Forty of 53 patients (75%) identified in the literature review who underwent total-body skin examinations (TBSE) were found to have MBAITs, suggesting a high penetrance in patients who have undergone TBSE. The most prevalent malignancies among BAP1 mutation carriers were uveal melanoma (n?=? 60 [28%]), mesothelioma (n?=?48 [22%]), cutaneous melanoma (n?=?38 [18%]), and renal cell carcinoma (n?=?20 [9%]). A total of 71 unique mutations in BAP1 have been reported.Conclusions and relevanceOur results indicate that germline mutations in both coding and noncoding regions throughout the BAP1 gene can impair protein function, leading to an increased risk for several associated malignancies. Four of the 8 probands we present had no history of BAP1-associated malignancies and were assessed for germline mutations when found to have MBAITs on dermatologic examination. Dermatologists can identify patients with a high likelihood of the BAP1 cancer syndrome through personal and family history and TBSE for the presence of possible MBAITs.

Dataset Information

Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.

Publications

Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.

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