G C A T T A C G G C A T genes Review Hereditary Hearing Impairment with Cutaneous Abnormalities Tung-Lin Lee 1 , Pei-Hsuan Lin 2,3, Pei-Lung Chen 3,4,5,6 , Jin-Bon Hong 4,7,* and Chen-Chi Wu 2,3,5,8,* 1 Department of Medical Education, National Taiwan University Hospital, Taipei City 100, Taiwan; [email protected] 2 Department of Otolaryngology, National Taiwan University Hospital, Taipei 11556, Taiwan; [email protected] 3 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei City 100, Taiwan; [email protected] 4 Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei City 100, Taiwan 5 Department of Medical Genetics, National Taiwan University Hospital, Taipei 10041, Taiwan 6 Department of Internal Medicine, National Taiwan University Hospital, Taipei 10041, Taiwan 7 Department of Dermatology, National Taiwan University Hospital, Taipei City 100, Taiwan 8 Department of Medical Research, National Taiwan University Biomedical Park Hospital, Hsinchu City 300, Taiwan * Correspondence: [email protected] (J.-B.H.); [email protected] (C.-C.W.) Abstract: Syndromic hereditary hearing impairment (HHI) is a clinically and etiologically diverse condition that has a profound influence on affected individuals and their families. As cutaneous findings are more apparent than hearing-related symptoms to clinicians and, more importantly, to caregivers of affected infants and young individuals, establishing a correlation map of skin manifestations and their underlying genetic causes is key to early identification and diagnosis of syndromic HHI. In this article, we performed a comprehensive PubMed database search on syndromic HHI with cutaneous abnormalities, and reviewed a total of 260 relevant publications. Our in-depth analyses revealed that the cutaneous manifestations associated with HHI could be classified into three categories: pigment, hyperkeratosis/nail, and connective tissue disorders, with each category involving distinct molecular pathogenesis mechanisms. This outline could help clinicians Citation: Lee, T.-L.; Lin, P.-H.; and researchers build a clear atlas regarding the phenotypic features and pathogenetic mechanisms Chen, P.-L.; Hong, J.-B.; Wu, C.-C. of syndromic HHI with cutaneous abnormalities, and facilitate clinical and molecular diagnoses of Hereditary Hearing Impairment with Cutaneous Abnormalities. Genes 2021, these conditions. 12, 43. https://doi.org/10.3390/ genes12010043 Keywords: syndromic hereditary hearing impairment; cutaneous abnormalities; genetic diagnosis; precision medicine Received: 21 November 2020 Accepted: 26 December 2020 Published: 30 December 2020 1. Introduction Publisher’s Note: MDPI stays neu- Sensorineural hearing impairment (SNHI) is the most common form of inherited tral with regard to jurisdictional clai- sensory defect, which occurs in approximately 1.9/1000 live births [1]. More than 50% of ms in published maps and institutio- SNHI cases in children can be attributed to genetic causes, and are classified as hereditary nal affiliations. hearing impairment (HHI) [2]. Over the past two decades, the genetic causes of HHI have been decoded rapidly, especially with the advent of next-generation sequencing (http://hereditaryhearingloss.org)[3]. Among the deafness genes known, some are associ- Copyright: © 2020 by the authors. Li- ated with syndromic HHI, with symptoms in organ systems outside the auditory pathway. censee MDPI, Basel, Switzerland. Patients suffering from various forms of syndromic HHI additionally present with skin ab- This article is an open access article normalities. The goals of this review were to perform a literature survey on comprehensive distributed under the terms and con- animal and human studies and to outline the molecular mechanisms underlying HHI with ditions of the Creative Commons At- cutaneous abnormalities. tribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Genes 2021, 12, 43. https://doi.org/10.3390/genes12010043 https://www.mdpi.com/journal/genes GenesGenes 20202021, 11, 12, ,x 43 FOR PEER REVIEW 2 of 30 2 of 27 Our search strategy was based on using Online Mendelian Inheritance in Man 2.(OMIM) Materials and and PubMed Methods databases for retrieval of suitable articles relevant to our topic of interest.Oursearch A collection strategy wasof these based onpublications using Online was Mendelian stored Inheritance and managed in Man on (OMIM) EndNote X9 and(Thomson PubMed Reuters, databases New for York retrieval City, of NY, suitable USA). articles Publications relevant were to our eligible topic of only interest. if they were Arelevant collection to ofHHI these associated publications with was cutaneous stored and abnormalities. managed on EndNoteAffected X9 patients (Thomson included in Reuters,case reports New Yorkor series City, were NY, USA). considered Publications to be wereof interest eligible only only if if relevant they were phenotypes, relevant to includ- HHIing abnormal associated withcutaneous, cutaneous hair, abnormalities. or nail findings, Affected as patients well as included SNHI were in case observed. reports or Publica- series were considered to be of interest only if relevant phenotypes, including abnormal tions focusing on individuals with HHI and developmental disorders (e.g., distinctive fa- cutaneous, hair, or nail findings, as well as SNHI were observed. Publications focusing on individualscial characteristics, with HHI andcongenital developmental heart defect, disorders developmental (e.g., distinctive delay, facial kyphosis, characteristics, among oth- congenitalers), who did heart not defect, present developmental with abnormal delay, skin, kyphosis, hair, or amongnail findings, others), were who not did included not for presentdiscussion with in abnormal the present skin, hair,review. or nail Studies findings, in which were not the included subjects for discussed discussion presented in the with presentabnormal review. cutaneous Studies infindings which the due subjects to other discussed proven presented diseases with (e.g., abnormal acanthosis cutaneous nigricans due findingsto diabetes due tomellitus) other proven were diseasesalso excluded. (e.g., acanthosis A flowchart nigricans of the due search to diabetes strategy mellitus) is shown in wereFigure also 1. excluded. A flowchart of the search strategy is shown in Figure1. FigureFigure 1. 1.Article Article selection. selection. 3.3. VariousVarious Types Types of HHIof HHI Present Presen witht with Cutaneous Cutaneous Abnormalities Abnormalities 3.1. Search Results 3.1. Search Results Forty-eight entries in the OMIM database with distinct “MIM (Mendelian Inheritance in Man)Forty-eight numbers” entries were selected,in the OMIM and a database total of 260 with publications distinct “MIM were (Mendelian retrieved from Inheritance thein Man) PubMed numbers” database, were including selected, original and a articles total of (n 260= 154), publications case reports were (n =retrieved 74), and from the literaturePubMed reviewsdatabase,(n =including 32), to perform original the articles analysis. (n The= 154), quality case ofreports the articles (n = 74), included and literature wasreviews meticulously (n = 32), evaluated to perform based the on analysis. the degree The of qual relevanceity of to the the articles topic of included this review. was A meticu- detailedlously evaluated list sorted bybased phenotypes on the degree (Table1 )of is releva includednce in to the the following topic of paragraph.this review. The A detailed pathogenesislist sorted by of phenotypes these syndromes (Table is covered 1) is included separately in the bythe following fourth section paragraph. of this article.The pathogen- esis of these syndromes is covered separately by the fourth section of this article. Table 1. Summary of syndromic hereditary hearing impairment (HHI) with cutaneous abnormali- ties. Clinical Find- OMIM Num- Mode of Inher- Syndrome Genes Involved ings Other Ref. ber itance Than SNHI Pigment disor- ders Pigmentary ab- Waardenburg normalities of syndrome type PAX3 193500 AD the hair, skin, [4–6] 1 and eyes, dysto- pia canthorum Waardenburg 184745, 193510, MITF, SNAI2, Pigmentary ab- syndrome type 600193, 606662, AD, AR [4,5,7–9] SOX10, KITLG normalities of 2 608890, 611584 Genes 2021, 12, 43 3 of 27 Table 1. Summary of syndromic hereditary hearing impairment (HHI) with cutaneous abnormalities. OMIM Mode of Clinical Findings Other Than Syndrome Genes Involved Ref. Number Inheritance SNHI Pigment disorders Pigmentary abnormalities of the Waardenburg PAX3 193500 AD hair, skin, and eyes, dystopia [4–6] syndrome type 1 canthorum 184745, 193510, Waardenburg MITF, SNAI2, Pigmentary abnormalities of the 600193, 606662, AD, AR [4,5,7–9] syndrome type 2 SOX10, KITLG hair, skin, and eyes 608890, 611584 Pigmentary abnormalities of the Waardenburg hair, skin, and eyes, dystopia PAX3 148820 AD, AR [4,5] syndrome type 3 canthorum, upper limb abnormalities Pigmentary abnormalities of the Waardenburg EDNRB, EDN3, 277580, 613265, AD, AR hair, skin, and eyes, Hirschsprung [4,5] syndrome type 4 SOX10 613266 disease Tietz Albinism, lack of retinal albinism-deafness MITF 103500 AD [10] pigmentation, absent eyebrows syndrome Microphthalmia, coloboma, cranial dysmorphism, cataract, COMMAD MITF 617306 AR osteopetrosis, pigmentary [11] syndrome abnormalities of the hair, skin, and eyes Hyperpigmentation, Histiocytosis- hypertrichosis, lymphadenopathy, lymphadenopathy SLC29A3 602782