Hereditary Hearing Impairment with Cutaneous Abnormalities

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 and researchers build a clear atlas regarding the phenotypic features and pathogenetic mechanisms of syndromic HHI with cutaneous abnormalities, and facilitate clinical and molecular diagnoses of these conditions.


Introduction
Sensorineural hearing impairment (SNHI) is the most common form of inherited sensory defect, which occurs in approximately 1.9/1000 live births [1]. More than 50% of SNHI cases in children can be attributed to genetic causes, and are classified as hereditary 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 associated with syndromic HHI, with symptoms in organ systems outside the auditory pathway. Patients suffering from various forms of syndromic HHI additionally present with skin abnormalities. The goals of this review were to perform a literature survey on comprehensive animal and human studies and to outline the molecular mechanisms underlying HHI with cutaneous abnormalities.
Our search strategy was based on using Online Mendelian Inheritance in Ma (OMIM) and PubMed databases for retrieval of suitable articles relevant to our topic o interest. A collection of these publications was stored and managed on EndNote X (Thomson Reuters, New York City, NY, USA). Publications were eligible only if they wer relevant to HHI associated with cutaneous abnormalities. Affected patients included i case reports or series were considered to be of interest only if relevant phenotypes, includ ing abnormal cutaneous, hair, or nail findings, as well as SNHI were observed. Publica tions focusing on individuals with HHI and developmental disorders (e.g., distinctive fa cial characteristics, congenital heart defect, developmental delay, kyphosis, among oth ers), who did not present with abnormal skin, hair, or nail findings, were not included fo discussion in the present review. Studies in which the subjects discussed presented wit abnormal cutaneous findings due to other proven diseases (e.g., acanthosis nigricans du to diabetes mellitus) were also excluded. A flowchart of the search strategy is shown i Figure 1.

Search Results
Forty-eight entries in the OMIM database with distinct "MIM (Mendelian Inheritanc in Man) numbers" were selected, and a total of 260 publications were retrieved from th PubMed database, including original articles (n = 154), case reports (n = 74), and literatur reviews (n = 32), to perform the analysis. The quality of the articles included was meticu lously evaluated based on the degree of relevance to the topic of this review. A detaile list sorted by phenotypes (Table 1) is included in the following paragraph. The pathogen esis of these syndromes is covered separately by the fourth section of this article.

Search Results
Forty-eight entries in the OMIM database with distinct "MIM (Mendelian Inheritance in Man) numbers" were selected, and a total of 260 publications were retrieved from the PubMed database, including original articles (n = 154), case reports (n = 74), and literature reviews (n = 32), to perform the analysis. The quality of the articles included was meticulously evaluated based on the degree of relevance to the topic of this review. A detailed list sorted by phenotypes (Table 1) is included in the following paragraph. The pathogenesis of these syndromes is covered separately by the fourth section of this article. With an estimated prevalence of 1/42,000, WS is a rare, heterogeneous condition, the features of which include white forelock, depigmented patches of the skin, and SNHI [4,5,97]. These features are characteristic of type 2 WS, while additional clinical symptoms define other types of WS [98]. Patients with type 1 WS present with dystopia canthorum; patients with type 3 WS, a more severe form than type 1 WS, present with dystopia canthorum and musculoskeletal abnormalities of the arms and hands [99,100]. In contrast, patients with type 4 WS present with Hirschsprung disease [101].
WS types 2 and 4 can be further classified into subtypes according to the genetic origins. A summary of the subtypes of WS and the genes affected are shown in Table 2. Among the different subtypes of WS, types 2B and 2C are linked to pathogenic variants in unidentified genes mapping to 1p21-p13.3 and 8p23, respectively [98,[101][102][103][104][105][106]. WS types 2A and 2 with ocular albinism (WS2-OA) both result from pathogenic variants in the microphthalmia-associated transcription factor gene (MITF), and present with SNHI and pigment disorders. WS2-OA also results from pathogenic variants in the TYR gene, the main function of the protein product of which is converting tyrosine into melanin [107,108]. Upstream to MITF, pathogenic variants in KITLG have been found to cause WS type 2 [8,9].
Other pathogenic variants resulting in HHI with pigment disorders include those in PAX3, SOX10, EDNRB, EDN3, and SNAI2 genes. Pathogenic variants in PAX3 lead to WS types 1 and 3, and those in SOX10 to WS types 2E and 4C [109]. Patients with a defective EDNRB signaling pathway develop either WS types 4Aand 4B, or ABCD syndrome (albinism, black lock of hair, cell migration disorder of gut neurocytes, and sensorineural deafness) [110,111]. Manifestations of these syndromes include Hirschsprung disease, depigmented patches of the skin, white eyelashes, pale blue iridis, and white forelock [103,112]. Homozygous deletions of SNAI2 have been detected in patients with WS type 2D [106].

Tietz Albinism-Deafness Syndrome (TADS)
TADS is a rare autosomal-dominant disease featuring SNHI, generalized pigment loss, and lack of retinal pigmentation [113]. Premature graying of hair during adolescence was observed in a patient [10,107]. Pathogenic variants in MITF, including 3-bp del (p.Arg217del), and missense variant c.630C>G (p.Asn210Lys) identified respectively in two families, result in TADS [107,114,115]. Hypopigmentation stems from disrupted transfer of melanosomes from melanocytes to keratinocytes [10]. Although TADS results from alterations in a gene linked to WS type 2, patients do not present with heterochromia or pigmented patches [4,10,114].

COMMAD Syndrome
COMMAD syndrome encompasses coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. Compound heterozygous MITF mutations have been detected in two unrelated families with COMMAD syndrome [11]. In contrast to WS type 2A and TADS, which are associated with autosomal-dominant MITF mutations, COM-MAD syndrome seems to be associated with an autosomal recessive inheritance of MITF, suggesting a crucial role for MITF in ocular morphogenesis and bone homeostasis [11].

Histiocytosis-Lymphadenopathy Plus Syndrome
The "histiocytosis-lymphadenopathy plus syndrome" family is a generic term for the H syndrome, Faisalabad histiocytosis (FHC), sinus histiocytosis with massive lymphadenopathy (SHML), and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID) [12]. In the literature, clinical reports and molecular studies are sparse, since it was only recently discovered. The patients had severe SNHI and extensive hyperpigmentation with dark, long hairs. Histologically, polyclonal perivascular lymphohistiocytic infiltrations of the dermis and subcutis were found in hypertrichotic lesions [12,116]. This group of diseases is caused by pathogenic variants in SLC29A3, which encodes ENT3, equilibrative nucleoside transporter 3 [12, [116][117][118]. This enzyme is in intracellular membranes and mediates cross-membrane nucleoside transportation [119]. Defective ENT3 impairs mitochondrial and lysosomal functions, as well as macrophage homeostasis [12].

Vitiligo-Associated Multiple Autoimmune Disease Susceptibility 1 (VAMAS1)
With an unknown prevalence and unclarified mode of inheritance, VAMAS1 features patchy depigmentation of the hair and skin due to the loss of melanocytes, SNHI in certain cases, and a propensity of developing autoimmune thyroid disease, rheumatoid arthritis, and systemic lupus erythematosus [17,124]. The pathogenic variant p.L155H of NLRP1 has been identified to cause VAMAS1 [125]. NLRP1 encodes the sensor component of the NLRP1 inflammasome. In response to pathogens, drugs, or damage-associated signals, this protein is recruited, possibly along with PYCARD (PYD And CARD Domain Containing) protein, to assemble the NLRP1 inflammasome and facilitates innate immunity and inflammation [17,126]. Autoimmune response has also been identified in Vogt-Koyanagi-Harada disease (VKHD), another rare multisystem inflammatory disease characterized by pan-uveitis, SNHI, vitiligo, and neurological deficits. However, current studies suggest a melanocyte-specific Th1 cytokine response in VKHD [127,128].

Genophotodermatoses
Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are autosomal recessive genophotodermatoses resulting from variants in genes involved in DNA repair [22,129,130]. The prevalence of XP is 1/1,000,000 in Europe and the United States (US), and higher in Japan, the Middle East, and North Africa, whereas CS holds a prevalence of 2-3/1,000,000 in the US and Europe [131,132].
Photosensitivity, SNHI, and neurologic dysfunction are shared cardinal features of XP and CS [21,22,129,133,134]. Lentiginous macules and poikiloderma are more severe in XP, while loss of subcutaneous orbital fat is distinctive of CS [24,135]. Manifestations of these genophotodermatoses can be attributed to accumulated unrepaired DNA damage following defects in key components of the DNA nucleotide excision repair (NER) pathway. Pathogenic variants in ERCC6 and ERCC8 lead to CS types B and A, respectively. Pathogenic variants in XPA, XPC, RAD2, DDB1, ERCC2, ERCC3, ERCC4, ERCC5, and ERCC6 lead to XP groups A-G. Pathogenic variants in POLH result in a variant type of XP, which is called XPV [19,20,130,131,134,136].
SNHI is a shared manifestation among PPK with deafness, Bart-Pumphrey syndrome, HID, KID, and the classic form of Vohwinkel syndrome. By contrast, patients with the variant form of Vohwinkel syndrome do not suffer from SNHI. As for cutaneous manifestation, generalized spiky hyperkeratotic skin is characteristic of HID and KID, while hyperkeratosis is mostly limited to the fingers, palms, and soles in PPK with deafness, Vohwinkel syndrome, and Bart-Pumphrey syndrome [139]. Leukonychia and thickening of the nails have also been reported in cases with Bart-Pumphrey syndrome [31,32, [140][141][142].
GJB2 and GJB6 variants cause both syndromic and non-syndromic HHI. The causal relationship of non-syndromic HHI and pathogenic variants in GJB2 and GJB6 have been well-established. Pathogenic variants in GJB2 serve as the most common cause of autosomal recessive HHI and 20% of non-syndromic hearing loss overall [150,151]. GJB6 variants are less prevalent than GJB2 variants but have been identified in 8% of patients with known GJB2 variants [152]. Whether variants in specific domains of GJB2 or GJB6 genes cause syndromic or non-syndromic HHI remains to be elucidated.

Heimler Syndrome and Other Peroxisomal Biogenesis Disorders (PBDs)
PBDs are a spectrum of autosomal recessive disorders of different severity, of which Zellweger syndrome (ZS) is the most severe form; neonatal adrenoleukodystrophy (NALD) presents with milder symptoms, and infantile Refsum disease (IRD) and Heimler syndrome constitute the mildest forms. The prevalence of PBDs is 1/50,000 and 1/500,000 in North America and Japan, respectively, while epidemiological figures on Heimler syndrome are to be determined [51, 160,161]. PBDs result from pathogenic variants in peroxin-encoding genes, i.e., PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX11β, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26 [50]. Heimler syndromes 1 and 2 are at the mildest end of the PBD spectrum, and are caused by pathogenic variants in PEX1 and PEX6, respectively [47,51,54]. Errors in the production of peroxins result in impaired myelin sheath formation and neurological deficits, including neonatal seizures, hypotonia, and developmental delays. Decreased peroxisome functionality in the liver and kidneys gives rise to the associated symptoms, including hepatomegaly, intrahepatic biliary dysgenesis, and hydronephrosis. SNHI and distinctive craniofacial features are also cardinal features of PBDs. Nail abnormalities, including Beau lines and leukonychia, have been reported in patients with Heimler syndrome [46,51,53-55].

Nail-Patella Syndrome (NPS)
NPS is an autosomal dominantly inherited syndrome with a prevalence of 1/50,000 live births. Nail dysplasia is the cardinal dermatologic manifestation of NPS. Nail changes include partially exposed and/or narrow nail beds, median or partial median clefts, dystrophic nail surfaces, and absence of nails. Fifth finger clinodactyly, hyperextensibility of the proximal interphalangeal joint, loss of creases over the distal interphalangeal joint and triangular lunulae have been reported in NPS patients. Other key features include malformation of dorsal mesenchyme-derivatives, including muscles, tendons, and the patella, along with ocular or renal involvement [162][163][164][165]. Hearing loss has also been reported in patients with NPS [59]. Genetically, pathogenic variants in LMX1B are considered to be causative of NPS [57,59,166,167].

Nephropathy with Pretibial Epidermolysis Bullosa and Deafness (NPEBD)
The only three cases with NPEBD feature nail dystrophy, blisters in the lower extremities, SNHI, and proteinuria in the nephrotic range [65]. Single-nucleotide insertion (383_384insG) in CD151, a gene encoding a component of hemidesmosomes, has been found in all cases. This result implies a role for CD151 in the maintenance of the normal structure and function of the skin, inner ear, and the glomeruli and tubules in the kidney [62][63][64].
3.5. HHI with Connective Tissue Disorders 3.5.1. Hyperelasticity of the Skin, Excess Skin, or Hypermobility of the Joints Brittle cornea syndrome (BCS), Ehlers-Danlos syndrome musculocontractural type 1 (EDSMC1), congenital symmetric circumferential skin creases (CSCSC) types 1 and 2, and microphthalmia with linear skin defects syndrome (MLS) are connective tissue disorders that present with distinct cutaneous findings and hearing impairment. Epidemiological data are scant due to the rarity of these conditions. BCS1 and BCS2 are characterized by hyperelasticity of the skin, hypermobility of the joints, blue sclerae, keratoconus, and keratoglobus. Mixed conductive and sensorineural hearing impairments have been reported in cases of BCS, with frequent manifestations that are milder and of later onset than the ophthalmic symptoms. BCS1 and BCS2 result from pathogenic variants in ZNF469 and PRDM5, respectively [66,69,[168][169][170][171].
EDSMC1 is characterized by dysmorphisms throughout the musculoskeletal system, easy bruisability, joint hypermobility, and hearing impairment, in certain cases. EDSMC1 can be attributed to pathogenic variants in CHST14 [67,72,74,172,173].
Patients with CSCSC1 and CSCSC2 feature excess skin and ringed creases, as well as hearing impairment [77,174]. CSCSC is considered a tubulinopathy. Accordingly, pathogenic variants in TUBB and MAPRE2 are the causative genetic alterations associated with CSCSC1 and CSCSC2, respectively [77,79,174].

Frequency of SNHI in HHI with Cutaneous Abnormalities
The frequency of SNHI differs among various syndromic HHI with cutaneous abnormalities. For instance, SNHI has been found in over 70% of cases with WS, TADS, COMMAD, or NSML syndromes [11,15,97,114]; and in approximately half of patients with other syndromes such as histiocytosis-lymphadenopathy plus syndrome [196]. On the contrary, the frequency of SNHI is difficult to estimate in rarer conditions such as NPS, DOORS, or DDOD.

Molecular Mechanisms Underlying Various Types of HHI with Cutaneous Abnormalities
The pathogenesis behind some of the syndromes discussed in the present study has been documented in the literature. Generally, cutaneous manifestations associated with HHI can be classified into three categories: pigment, hyperkeratosis/nail, and connective tissue disorders (Table 3). We herein summarize the molecular mechanisms underlying syndromic HHI with different cutaneous involvements.

HHI with Pigment Disorders
Syndromic HHI with pigmentary disorders was found associated with diverse molecular mechanisms, including differentiation and migration of melanocytes, RAS-MAPK signaling, and DNA repair.

Differentiation and Migration of Melanocytes
As mentioned above, certain subtypes of WS type 2, TADS, and COMMAD syndrome can be attributed to pathogenic variants in MITF, while other types of WS are linked to pathogenic variants in PAX3, SNAI2, SOX10, EDNRB, EDN3, and KITLG. These genes are crucial for the differentiation and migration of melanocytes.
The MITF gene on chromosome 3p14.1-p12.3 encodes the protein MITF, which is a basic helix-loop-helix (hHLH)-leucine zipper and plays a role in the development of various cell types, including neural crest-derived melanocytes, optic cup-derived retinal pigment epithelial cells, and melanocytes [199]. In melanocyte differentiation, MITF transactivates the promoter activity of the tyrosinase gene TYR [200][201][202][203]. Thus, pathogenic variants in the MITF gene might lead to absence of melanocytes in the skin, hair, eyes, and stria vascularis of the cochlea. PAX3 and SOX10 encode transcription factors that synergistically regulate the expression of MITF, and pathogenic variants in these two genes also result in pigmentary abnormalities of the hair, skin, and eyes, as well as in SNHI. Specifically, SOX10 activates the MITF pathway by binding onto the MITF promoter. Loss-of-function variants including a 1076delGA in exon 5, a 6-bp insertion in exon 4, along with a tyr83-to-ter variant and a glu189-to-ter variant were found to cause WS type 4C [101]. On the other hand, a ser135-to-thr variant was identified in a patient with WS type 2E [109]. The activation of KITLG-KIT signaling pathway leads to the activation of downstream MITF, and defective KITLG has been linked to WS type 2 [8,9].
Pathogenic variants in EDNRB, the gene encoding the endothelin-B receptor, and those in the gene for its ligand endothelin-3 (EDN3) also result in a lack of melanocytes. EDNRB and EDN3 take part in the migration and proliferation of neural crest-derived cells including melanocytes [204]. SNAI2 encodes a zinc finger protein essential to the development of neural crest-derived cells [205]. A pathogenic variant in Slugh, the murine homolog of the human SNAI2 gene, causes pigmentary disorders in mice including white forelock and patchy depigmentation over the ventral body, tail, and feet. Hyperactivity and circling behavior observed in Slugh-deficient mice implied the presence of auditory and vestibular dysfunctions. These findings implicate a role for SNAI2 in the development and/or migration of neural crest-derived cells [98,106].

RAS-MAPK Signaling
NSML types 1, 2, and 3 result from pathogenic variants in PTPN11, RAF1, and BRAF genes, respectively, products of which all participate in the RAS-MAPK signaling cascade. The tyrosine phosphatase encoded by PTPN11 relays signals from cell membrane receptors to cytoplasmic tyrosine kinases and up-regulates the MAPK signaling pathway [206]. The serine/threonine-protein kinase encoded by RAF1 links Ras GTPases to the MAPK/ERK (extracellular signal-regulated kinases) cascade and serves as a decision point leading cells to proliferate, differentiate, or undergo apoptosis. The serine/threonine-protein kinase Braf, encoded by BRAF, facilitates cell membrane-nucleus signaling through phosphorylation of MAP2K1 [207,208]. It may further contribute to postsynaptic responses of hippocampal neurons [209].
Histological specimens of lentiginous lesions of NSML cases with pathogenic PTPN11 variants revealed increased numbers of melanocytes and pigments throughout the epidermis, while immunohistochemical studies revealed increased expression levels of endothelin-1 (ET-1), phosphorylated Akt, mTOR, and STAT3 in lentiginous epidermis compared with non-lentiginous skin areas. Higher melanin synthesis rates of human melanoma cells expressing tyrosine-protein phosphatase non-receptor type 11 have been observed in vitro, supporting the link between PTPN11 and hyperpigmentation in NSML patients [210]. Vestibulocochlear anomalies and atrophic cochlear neurons have been observed in patients with pathogenic PTPN11 variants [211].

DNA Repair
XP and CS are caused by defective DNA repair pathways. Defects in XPC and XPE, factors in charge of global genome nucleotide excision repair (GG-NER), in XPA, XPG, XPB, and XPD, which oversee DNA unwinding, as well as in XPF and XPG, mediating excision of the damaged nucleotides, lead to hyper-and hypopigmented macules in sun-exposed areas and an increased risk of skin malignancies [212]. Defects in POLH lead to XPV, a rare subtype of XP.
Increased numbers of melanocytes and elevated melanin levels have been found in skin specimens of freckles from XPC patients. Hyperpigmentation in XP results from increased proliferation and early differentiation of melanocytes due to the mutagenic tendency of cells with impaired GG-NER [21]. UV(ultraviolet)-induced oxidative stress could also induce hyperpigmentation. Melanogenesis is regulated through the ERK signaling pathway activated by mitochondrial reactive oxidative species [213]. The production of UV-induced protective pigments is up-regulated by the mitochondrial protein prohibitin [214,215]. Defective repair mechanisms and UV-induced changes in microenvironment spark apoptotic pathways in XP melanocytes, resulting in hypopigmented areas. Apoptosis of cells in XP patients is triggered by lower doses of UV than needed to induce apoptosis in normal cells [216][217][218][219]. Compared to XP, the phenotype of CS includes progeroid appearance, generally without pigmentary changes [220]. XP and CS are associated with SNHI of cochlear origin on audiological assessments. Temporal bone histology at autopsy revealed atrophy of the sensory epithelium and neurons in the cochlea. Atrophies of the stria vascularis, hair cells, or Scarpa's ganglion have been observed in different cases of XP [133,221].

HHI with Hyperkeratosis
Syndromic HHI with hyperkeratosis are caused by pathogenic variants in two gap junction genes, GJB2 and GJB6, which encode connexins that are key to intercellular signaling [222]. The ectoderm-derived epithelia of the inner ear and the epidermis share the expression of Cx26 and Cx30 [223,224]. In the skin, Cx26 is mainly expressed in the palmoplantar epidermis and the inner and outer root sheaths of the human hair follicle, while Cx30 is predominantly expressed in the differentiated layers of the interfollicular epidermis [225][226][227]. Defective connexins result in leaky hemichannels and impaired intercellular communication [139,228]. Cx26 plays a role in wound healing and is also involved in the normal differentiation and proliferation of keratinocytes, which may explain the hyperkeratosis observed in individuals with defective Cx26 [228,229].
In the inner ear, connexins are abundantly expressed in the cochlear sensory epithelium, and are key factors in maintaining the potassium levels of the endolymph [20]. Immunochemical stainings have revealed that Cx26 and Cx30 are expressed in the spiral limbus, spiral ligament, stria vascularis, and supporting cells of the organ of Corti. Cx26 contributes to normal development of the cochlear sensory epithelium, and compromised inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) permeability of Cx26 has been implicated as a cause of SNHI [230,231]. Additionally, the endocochlear potential generated by the stria vascularis is remarkably disturbed in Cx30-deficient mice [232].
GJB4 encodes Cx30.3, pathogenic variants in which have been linked to erythrokeratodermia variabilis et progressiva, or EKVP [233]. EKVP is a rare, mostly autosomaldominant genodermatosis featuring erythema gyratum repens and stable hyperkeratotic plaques [234]. How GJB4 variants induce EKVP remains hypothetical. The link between GJB4 and SNHI has not yet been well-established either; however, GJB4 variants have been identified in 11 patients with non-syndromic hearing loss in Taiwan. These patients suffered from congenital bilateral SNHI but no skin lesion was found [235,236]. GJB4 variants have also been identified in Iranian patients with autosomal recessive non-syndromic hearing loss [237,238]. These pilot genotype-phenotype correlation studies serve as the steppingstone to clarify the link between GJB4 and SNHI.

HHI with Nail Disorders
The molecular underpinnings of syndromic HHI with nail disorders involve a plethora of genes related to proton transportation, vesicle transportation, peroxisome function, and hemidesmosomes.
The DDOD-linked ATP6V1B2 gene encodes a component of the vacuolar ATPase for proton transportation. Impaired lysosomal acidification due to V-ATPase deficiency undermines the Wnt signaling pathway, which is important for normal limb organogenesis. This may explain the dystrophic or atrophic nails present in DDOD patients [239][240][241]. Immunostaining of mouse cochlea showed predominant expression of Atp6v1b2 in the organ of Corti and spiral ganglion neurons. Consistent with histological findings, auditory brainstem response tests showed elevated hearing thresholds in cochlea-specific Atp6v1b2knockdown mice, supporting the link between ATP6V1B2 and SNHI [39].
The DOORS-linked TBC1D24 encodes a GTPase-activating protein crucial to vesicle transportation [242,243]. TBC1D24 regulates migration of neural crest cells in coordination with ephrinB2 and the scaffold protein Dishevelled (Dsh) [244]. Immunostaining of mouse cochlea showed predominant expression of Tbc1d24 in inner and outer hair cells, and weaker expression in spiral ganglion neurons [245]. Nails and membranous labyrinth are both ectoderm-derived, which underlies the coexistence of nail dystrophy and SNHI [155].
Heimler syndromes 1 and 2 arise from pathogenic variants in PEX1 and PEX6, respectively, which lead to impaired peroxisome biogenesis [49,52]. Decreased metabolism of very long chain fatty acids underpins the cutaneous findings in the PBD spectrum [45,48]. Reduced or defective peroxisomes in Heimler syndrome patients have been found through immunofluorescence microscopy [51,246]. As oxidative stress is linked to hearing loss, this finding consolidates the relationship between peroxisomal dysfunction and SNHI in Heimler syndrome [49,247,248].
The NPS-related gene LMX1B encodes the LIM homeobox transcription factor, defects in which hinder limb and skin development; the dystrophic nails and orthopedic abnormalities may result from altered embryonic dorsoventral patterning [58,60,61]. Strong expression of the mouse homolog Lmx1b in the hindbrain implies that LMX1B variants disturb inner ear development [249].
The NPEBD-linked CD151 encodes a tetraspan protein crucial to hemidesmosome integrity [63]. CD151 facilitates basement membrane formation, migration of keratinocytes, and adhesion and migration of epithelial cells, highlighting its role in skin integrity and wound healing [250]. Hearing loss has been observed in laminin-deficient mice. As CD151 is key to laminin-binding among other tetraspanin-integrin interactions, defective CD151 may impair normal hearing [251,252].

HHI with Connective Tissue Disorders
Syndromic HHI with connective tissue disorders result from the deregulation of the extracellular matrix (ECM), dermatan-sulfate (DS) biosynthesis, microtubule assembly, mitochondria-mediated cell death, and inflammatory cascades.
The products of BCS1 and BCS2-associated genes, i.e., zinc finger protein 469 encoded by ZNF469, and PR domain-containing protein 5 encoded by PRDM5, regulate and maintain the ECM [169,253]. Pathogenic variants in PRDM5 lead to decreased or disorganized vital ECM components, including collagen I fibers and decorin, which has been shown in patient-derived fibroblast models [253,254]. Disorganized ECM leads to skin fragility and hyperelasticity in BCS patients [171]. SNHI has been documented in both PRDM5and ZNF469-associated types of BCS [169,253].
The enzyme products of EDSMC1 and EDSMC2-causing genes CHST14 and dermatansulfate epimerase (DSE) are dermatan-4-sulfotransferase-1 (D4ST1) and dermatan-sulfate epimerase, respectively. These enzymes facilitate DS biosynthesis [173,255]. D4ST1 dysfunction hinders normal production and assembly of the ECM. Additionally, disrupted ECM components, including fibronectin and fibrillar collagen types I, III, and V, have been found in D4ST1-deficient patients [74,173]. These ECM defects lead to skin hyperextensibility, easy bruising, increased palmar wrinkling, and propensity to subcutaneous hematoma formation in EDSMC patients [71,173]. EDSMC1 patients with high-tone SNHI have been reported in the literature [72,173]. EDSMC2-causing variants in DSE also result in dysfunctional DS and ECM disarray; however, SNHI has not been reported in EDSMC2 patients [256].
Products of CSCSC1 and CSCSC2-associated genes, i.e., tubulin β chain encoded by TUBB and end-binding protein 2 encoded by MAPRE2, are crucial to microtubule assembly and polymerization [77,78]. Altered MAPRE2 expression perturbs branchial arch pattering, explaining the skin and craniofacial anomalies in CSCSC1 patients [77]. In cochlear sensory cells, microtubules form both dynamic and supporting structures of the organ of Corti [257]. Immunohistochemical staining of the inner ear revealed diffuse expression of β-tubulin, an autoantigen targeted in autoimmune inner ear disease [258][259][260][261][262][263][264]. Antibodies recognizing β-tubulin were isolated in the serum of 59% of patients with Meniere's disease [265]. Taken together, microtubule assembly and dynamics are crucial for maintaining normal hearing.
The product of the MLS gene HCCS is crucial to mitochondrial-mediated apoptosis [175][176][177]. Defects in this synthase results in a shift from apoptosis to necrosis and induces inflammation and damage to neighboring cells, inducing the cutaneous manifestation of MLS [266].
The CAPS-linked NLRP3 and NLPR12 are mainly expressed in neutrophils and chondrocytes, and gain-of-function variants lead to over-activation of the inflammasome, overstimulation of interleukin (IL)-1β receptors, and overproduction and secretion of IL-1β [185,267,268]. Following the constitutive activation of the NLRP3 inflammasome, mast cells in CAPS patients produce IL-1β, induce neutrophil migration, and promote vascular leakage independent of stimuli [269]. Tissue-resident macrophage/monocyte-like cells reside perivascularly throughout the cochlea [185,270]. NLRP3 inflammasome-induced secretion of IL-1β induces cochlear inflammation, and thus SNHI [271,272]. The recombinant IL-1 receptor antagonist (IL-1Ra) Anakinra ameliorates SNHI, consolidating the role of IL-1β in hearing loss [185,268]. IL-1β also causes higher permeability of cytokines between the perilymph and CSF (cerebrospinal fluid) space via the modiolus, prompting spiral ligament fibrocytes to produce inflammatory mediators [182].

Conclusions
Listed in this review is a comprehensive array of syndromic HHI with abnormal cutaneous findings. This provides an outline for clinicians and researchers encountering patients with abnormal manifestations, which are evident in the setting of an outpatient clinic appointment (e.g., in a well-baby clinic). The pathogenesis of the skin manifestations and syndromic HHI of certain syndromes has not yet been fully elucidated. Further molecular and functional studies are necessary to unveil the underlying mechanisms.