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Keratoderma Hereditarium Mutilans

Disease Pathophysiology Research Report

2026-02-04
Falcon MONDO:0007422 Model: Edison Scientific Literature 17 citations

Disease Pathophysiology Research Report

Target Disease - Disease Name: Keratoderma Hereditarium Mutilans (Keratoderma hereditaria mutilans; Vohwinkel syndrome; loricrin keratoderma/Camisa variant) - MONDO ID: Not confidently identified here (leave blank pending authoritative mapping) - Category: Mendelian (autosomal dominant) (maestrini1999amissensemutation pages 1-2, sethuraman2019hereditarypalmoplantarkeratoderma pages 4-5)

Pathophysiology description Vohwinkel syndrome (VS) is a mutilating diffuse transgrediens palmoplantar keratoderma that progresses to constricting bands (pseudo-ainhum) and may culminate in auto-amputation of digits. The classic form is caused by dominant missense mutations in GJB2 encoding connexin 26 (Cx26), which disrupt epidermal gap-junctional communication and can confer aberrant hemichannel properties, leading to impaired intercellular signaling, altered epidermal calcium gradients, disordered keratinocyte differentiation, and barrier dysfunction. Sensorineural deafness commonly co-segregates in the classic GJB2-associated form due to inner-ear gap junction involvement (Human Molecular Genetics, Jul 1999; DOI:10.1093/hmg/8.7.1237) (maestrini1999amissensemutation pages 1-2, garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6, govender2023palmoplantarkeratodermapseudoainhum pages 2-4). The ichthyotic (Camisa) variant is genetically distinct and results from LOR mutations; mutant loricrin mislocalizes to keratinocyte nuclei and fails to incorporate into the cornified envelope, producing defective cornification, parakeratosis, barrier impairment, and ichthyosiform changes in addition to palmoplantar keratoderma (Advances in Dermatology, Jan 2007; DOI:10.1016/j.yadr.2007.07.011) (schmuth2007ichthyosisupdatetowards pages 5-6, schmuth2007ichthyosisupdatetowards pages 14-15).

Key concepts and definitions - Gap junctions and hemichannels: Connexins oligomerize into hexameric connexons (hemichannels) that dock to form gap junction channels permitting passage of ions and small metabolites (<1 kDa) for intercellular coordination in the epidermis and cochlea (Biology, Jan 2021; DOI:10.3390/biology10010059) (garciavega2021connexinsandthe pages 4-6). In VS, Cx26 mutations in extracellular loop 1 (e.g., D66H) impair connexon assembly/docking or gating and can yield abnormal hemichannel activity (maestrini1999amissensemutation pages 1-2, garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6). As one review summarizes, mutant Cx26 can form “nonfunctional gap junctions but hyperactive hemichannels,” perturbing calcium gradients and barrier function (Biology, 2021; https://doi.org/10.3390/biology10010059) (garciavega2021connexinsandthe pages 13-14). - Cornified envelope and loricrin: Loricrin is a major structural protein of the cornified envelope. In the Camisa variant, “mutant loricrin is mislocalized to nuclei of the granular layer, fails to incorporate into the cornified envelope and is retained in parakeratotic stratum corneum,” resulting in hyperkeratosis, parakeratosis, and increased transepidermal water loss (Advances in Dermatology, 2007; https://doi.org/10.1016/j.yadr.2007.07.011) (schmuth2007ichthyosisupdatetowards pages 5-6).

Recent developments and latest research (prioritize 2023–2024) - Case-based mechanistic reinforcement (2023): An African patient with transgrediens PPK, pseudo-ainhum, and knuckle pads illustrated the clinical trajectory toward amputation; the discussion emphasizes connexin biology (connexon hexamers, multi-connexin skin expression) and postulated mechanisms including loss or abnormal gap junction function, trafficking defects, and dominant-negative effects; disruption of the epidermal calcium gradient is highlighted as a mechanism affecting differentiation (SAGE Open Medical Case Reports, Jan 2023; DOI:10.1177/2050313x231204197) (govender2023palmoplantarkeratodermapseudoainhum pages 2-4). - Contemporary connexin 26 mechanism reviews (context to VS, 2021–2022): Reviews detail Cx26 trafficking, oligomerization, and mutation classes, linking VS mutations to extracellular loop 1 and non-inflammatory keratoderma phenotypes; they also discuss hyperactive hemichannel states and potential pharmacologic blockade (Biology, 2021; DOI:10.3390/biology10010059) (garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6). While slightly older, these sources remain mechanistically relevant and are consistent with classic VS data (maestrini1999amissensemutation pages 1-2).

Current applications and real-world implementations - Surgical management for pseudo-ainhum: Progressive constriction bands necessitate timely surgical intervention; amputation may be required in advanced cases, as illustrated in the 2023 report (SAGE Open Medical Case Reports, 2023; https://doi.org/10.1177/2050313x231204197) (govender2023palmoplantarkeratodermapseudoainhum pages 2-4). - Medical management: Keratolytics, emollients, and systemic retinoids have been used; isotretinoin has been reported in a Vohwinkel variant (advocated historically), though controlled data are limited (Advances in Dermatology, 2007; DOI:10.1016/j.yadr.2007.07.011) (schmuth2007ichthyosisupdatetowards pages 14-15). Connexin-targeted modulators are discussed in preclinical contexts (hemichannel blockers), but clinical translation specific to VS remains investigational (Biology, 2021; DOI:10.3390/biology10010059) (garciavega2021connexinsandthe pages 13-14).

Expert opinions and analysis from authoritative sources - Landmark genetic causation: The identification of GJB2 D66H as causative in classical VS across three unrelated families provided firm genetic and mechanistic grounding for the gap-junction hypothesis and explained the associated deafness via cochlear gap junction disruption (Human Molecular Genetics, 1999; https://doi.org/10.1093/hmg/8.7.1237) (maestrini1999amissensemutation pages 1-2). The authors infer that VS keratoderma can reflect an abnormal healing/differentiation response arising from defective connexin-mediated growth regulation in keratinocytes (maestrini1999amissensemutation pages 6-6). - Function-driven cornification model: Expert reviews of disorders of cornification position loricrin keratoderma (Camisa variant) as a prototypic cornified envelope substrate defect with downstream barrier failure, parakeratosis, and compensatory responses, mechanistically distinct from connexin channelopathies (Advances in Dermatology, 2007; https://doi.org/10.1016/j.yadr.2007.07.011) (schmuth2007ichthyosisupdatetowards pages 5-6, schmuth2007ichthyosisupdatetowards pages 14-15).

Relevant statistics and data from recent studies - Clinical course markers: The 2023 case report documents prior constriction bands progressing to auto-amputations and current surgical amputation, reflecting the mutilating natural history when constriction bands are untreated or refractory (SAGE Open Medical Case Reports, 2023; https://doi.org/10.1177/2050313x231204197) (govender2023palmoplantarkeratodermapseudoainhum pages 2-4). While formal prevalence statistics are scarce due to extreme rarity, the genetic series demonstrating three unrelated families with GJB2 D66H remains a seminal data point underpinning causality (Human Molecular Genetics, 1999) (maestrini1999amissensemutation pages 1-2).

1) Core Pathophysiology - Primary mechanisms - GJB2/Cx26 (classic VS): Dominant missense variants disrupt gap junction intercellular communication in the epidermis and inner ear and can create hyperactive hemichannel states. Consequences include impaired keratinocyte coordination, altered calcium gradients, dysregulated differentiation, and barrier dysfunction; deafness results from cochlear gap junction defects (maestrini1999amissensemutation pages 1-2, garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6, govender2023palmoplantarkeratodermapseudoainhum pages 2-4). - LOR (Camisa variant): Mutant loricrin shows nuclear mislocalization, deficient incorporation into the cornified envelope, and defective cornification with parakeratosis, driving ichthyosis and palmoplantar hyperkeratosis (schmuth2007ichthyosisupdatetowards pages 5-6, schmuth2007ichthyosisupdatetowards pages 14-15). - Dysregulated molecular pathways - Cell–cell communication via gap junctions/hemichannels; calcium signaling critical for keratinocyte differentiation (garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6, govender2023palmoplantarkeratodermapseudoainhum pages 2-4). - Cornified envelope assembly and keratinocyte terminal differentiation pathways (schmuth2007ichthyosisupdatetowards pages 5-6, schmuth2007ichthyosisupdatetowards pages 14-15). - Affected cellular processes - Connexin biosynthesis/trafficking, connexon assembly/docking, hemichannel gating; keratinocyte differentiation and desquamation; barrier formation and water homeostasis (garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6, schmuth2007ichthyosisupdatetowards pages 5-6).

2) Key Molecular Players - Genes/Proteins (HGNC): - GJB2 (Connexin 26/Cx26) — causal in classical VS (maestrini1999amissensemutation pages 1-2). - LOR (Loricrin) — causal in ichthyotic/Camisa variant (schmuth2007ichthyosisupdatetowards pages 14-15, schmuth2007ichthyosisupdatetowards pages 5-6). - Chemical Entities (CHEBI; examples contextual): Calcium ions (Ca2+) as a key differentiation cue; ATP/IP3 as hemichannel-permeant signaling molecules implicated in connexin gain-of-function states (mechanistic reviews) (garciavega2021connexinsandthe pages 13-14). - Cell Types (CL): Keratinocytes (CL:0000312) as primary cells; epidermal resident immune cells may respond secondarily to barrier failure (garciavega2021connexinsandthe pages 13-14, schmuth2007ichthyosisupdatetowards pages 5-6). - Anatomical Locations (UBERON): Palmoplantar skin — skin of palm (UBERON:0002427), skin of sole (UBERON:0002428), epidermis (UBERON:0001003) (sethuraman2019hereditarypalmoplantarkeratoderma pages 4-5, maestrini1999amissensemutation pages 1-2).

3) Biological Processes (for GO annotation) - Gap junction-mediated intercellular communication (GO:0007154), cell–cell signaling (GO:0007267), ion transport including calcium handling (GO:0006816) — disrupted in GJB2-associated VS (garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6). - Keratinocyte differentiation (GO:0030216) and cornified envelope formation/cornification (e.g., GO:0070268) — disrupted in LOR-associated Camisa variant (schmuth2007ichthyosisupdatetowards pages 5-6, schmuth2007ichthyosisupdatetowards pages 14-15). - Barrier function and desquamation processes inferred from parakeratosis and TEWL increases in LOR disease (schmuth2007ichthyosisupdatetowards pages 5-6).

4) Cellular Components - Gap junction plaques at the plasma membrane; connexin hemichannels at the plasma membrane/extracellular interface (garciavega2021connexinsandthe pages 4-6). - Cornified envelope at the corneocyte periphery; nuclear mislocalization of mutant loricrin within granular layer keratinocytes (schmuth2007ichthyosisupdatetowards pages 5-6).

5) Disease Progression - Sequence of events - Classic VS (GJB2): Early-life diffuse/transgrediens palmoplantar hyperkeratosis and acral keratoses/knuckle pads, progressing to circumferential constriction bands (pseudo-ainhum) that can cause auto-amputation if untreated; many patients have concomitant sensorineural deafness (maestrini1999amissensemutation pages 1-2, govender2023palmoplantarkeratodermapseudoainhum pages 2-4). - Camisa variant (LOR): Similar palmoplantar keratoderma with prominent ichthyosis and parakeratosis due to defective cornified envelope, with risk of constricting bands and mutilation (schmuth2007ichthyosisupdatetowards pages 14-15, schmuth2007ichthyosisupdatetowards pages 5-6).

6) Phenotypic Manifestations - Key clinical phenotypes and mechanistic links - Diffuse/transgrediens palmoplantar keratoderma (HP:0000982) — hyperproliferation/hyperkeratosis from disturbed differentiation (GJB2/LOR) (maestrini1999amissensemutation pages 1-2, schmuth2007ichthyosisupdatetowards pages 14-15). - Pseudo-ainhum/constriction bands (HP:0001052) with progression to auto-amputation — chronic mechanical/keratinization dysregulation driving fibrous bands around digits (govender2023palmoplantarkeratodermapseudoainhum pages 2-4, maestrini1999amissensemutation pages 1-2). - Knuckle pads and starfish-like keratoses — focal acral hyperkeratoses related to altered keratinocyte homeostasis (maestrini1999amissensemutation pages 1-2, govender2023palmoplantarkeratodermapseudoainhum pages 2-4). - Sensorineural deafness (HP:0000407) in classic GJB2 VS — cochlear gap junction dysfunction (maestrini1999amissensemutation pages 1-2). - Ichthyosis/parakeratosis in Camisa variant — defective cornified envelope assembly due to mutant loricrin (schmuth2007ichthyosisupdatetowards pages 5-6, schmuth2007ichthyosisupdatetowards pages 14-15).

Gene/protein annotations with ontology terms - GJB2 (HGNC:4286) — Connexin 26; Processes: GO:0007154, GO:0007267, GO:0006816; Components: plasma membrane, gap junction; Phenotypes: HP:0000982, HP:0001052, HP:0200041, HP:0000407; Cells: CL:0000312; Anatomy: UBERON:0002427/0002428/0001003 (maestrini1999amissensemutation pages 1-2, garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6, govender2023palmoplantarkeratodermapseudoainhum pages 2-4). - LOR (HGNC:6667) — Loricrin; Processes: GO:0030216, GO:0070268; Components: cornified envelope; Phenotypes: HP:0000982, HP:0001052; Cells: CL:0000312; Anatomy: UBERON:0002427/0002428/0001003 (schmuth2007ichthyosisupdatetowards pages 5-6, schmuth2007ichthyosisupdatetowards pages 14-15).

Cell type involvement (CL terms) - Keratinocyte (CL:0000312) — site of connexin expression/communication and loricrin cornified envelope assembly; aberrant signaling/cornification underlies VS phenotypes (garciavega2021connexinsandthe pages 13-14, schmuth2007ichthyosisupdatetowards pages 5-6).

Anatomical locations (UBERON terms) - Skin of palm (UBERON:0002427); skin of sole (UBERON:0002428); epidermis (UBERON:0001003) as the primary anatomical sites, consistent with palmoplantar specificity (sethuraman2019hereditarypalmoplantarkeratoderma pages 4-5, maestrini1999amissensemutation pages 1-2).

Chemical entities (CHEBI; examples) - Calcium ion (CHEBI:29108) — epidermal calcium gradient essential for differentiation; perturbed by connexin dysfunction (review context) (govender2023palmoplantarkeratodermapseudoainhum pages 2-4, garciavega2021connexinsandthe pages 13-14). - ATP (CHEBI:15422) and IP3 (CHEBI:16595) — candidate hemichannel-permeant signals in connexin gain-of-function states discussed in reviews (garciavega2021connexinsandthe pages 13-14).

Evidence items with PMIDs/URLs/dates (representative) - Maestrini et al., Human Molecular Genetics, 1999-07; “A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel’s syndrome) …” DOI:10.1093/hmg/8.7.1237; URL: https://doi.org/10.1093/hmg/8.7.1237 (maestrini1999amissensemutation pages 1-2). - Schmuth et al., Advances in Dermatology, 2007-01; “Mutant loricrin is mislocalized to nuclei … fails to incorporate into the cornified envelope …” DOI:10.1016/j.yadr.2007.07.011; URL: https://doi.org/10.1016/j.yadr.2007.07.011 (schmuth2007ichthyosisupdatetowards pages 5-6, schmuth2007ichthyosisupdatetowards pages 14-15). - Garcia-Vega et al., Biology, 2021-01; connexin 26 in epithelial barrier, gap junction vs hemichannel dysfunction, potential pharmacology. DOI:10.3390/biology10010059; URL: https://doi.org/10.3390/biology10010059 (garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6). - Govender & Pillay, SAGE Open Medical Case Reports, 2023-01; palmoplantar keratoderma with pseudo-ainhum/knuckle pads, surgical amputation; connexin mechanisms overview. DOI:10.1177/2050313x231204197; URL: https://doi.org/10.1177/2050313x231204197 (govender2023palmoplantarkeratodermapseudoainhum pages 2-4).

Direct quotes (supporting key statements) - “A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel’s syndrome)” (Human Molecular Genetics, 1999) (maestrini1999amissensemutation pages 1-2). - “Mutant loricrin is mislocalized to nuclei of the granular layer, fails to incorporate into the cornified envelope and is retained in parakeratotic stratum corneum” (Advances in Dermatology, 2007) (schmuth2007ichthyosisupdatetowards pages 5-6). - “Gap junctions are intercellular channels… each connexon is composed of six connexin sub-units” and mutant connexins may “disrupt the epidermal calcium gradient affecting keratinocyte differentiation” (SAGE Open Medical Case Reports, 2023) (govender2023palmoplantarkeratodermapseudoainhum pages 2-4).

Embedded summary artifact | Gene (HGNC) | Protein | Variant examples | Primary mechanism | Dysregulated pathways/processes (GO IDs/names) | Principal cell types (CL IDs) | Anatomical sites (UBERON IDs) | Key phenotypes (HPO IDs) | Representative sources | |---|---|---|---|---|---|---|---|---| | GJB2 | Connexin 26 (Cx26) | D66H (classic VS), other missense (e.g., p.Tyr65His) | Dominant missense → impaired gap‑junction assembly/function ± gain‑of‑function hemichannels → disrupted intercellular communication, altered Ca2+ gradient and keratinocyte differentiation | GO:0007154 (cell communication); GO:0007267 (cell–cell signaling); GO:0006816 (ion transport/calcium handling) | Keratinocyte (CL:0000312) | Skin of palm (UBERON:0002427), skin of sole (UBERON:0002428), epidermis (UBERON:0001003) | Palmoplantar keratoderma; pseudo‑ainhum/ constriction bands; knuckle pads; sensorineural hearing impairment (HP:0000982; HP:0001052; HP:0200041; HP:0000407) | (maestrini1999amissensemutation pages 6-6, maestrini1999amissensemutation pages 1-2, garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6, govender2023palmoplantarkeratodermapseudoainhum pages 2-4) | | LOR | Loricrin | Recurrent insertion/frameshift mutations observed in Camisa (ichthyotic) variant (reported recurrent LOR mutations) | Mutant loricrin mislocalized (nuclear accumulation), fails to incorporate into cornified envelope → defective cornified envelope assembly, abnormal cornification/desquamation, barrier dysfunction and hyperkeratosis/ichthyosis | GO:0030216 (keratinocyte differentiation); GO:0070268 (cornified envelope formation / cornification) | Keratinocyte (CL:0000312) | Skin of palm (UBERON:0002427), skin of sole (UBERON:0002428), epidermis (UBERON:0001003) | Diffuse/transgrediens palmoplantar hyperkeratosis; ichthyosis variant; pseudo‑ainhum; risk of mutilation (HP:0000982; HP:0001052) | (schmuth2007ichthyosisupdatetowards pages 5-6, schmuth2007ichthyosisupdatetowards pages 14-15, sethuraman2019hereditarypalmoplantarkeratoderma pages 4-5) | | Connexin/hemichannel (general) | Connexin hemichannels / gap junctions (GJB family) | Disease‑associated alleles across GJB family (e.g., S17F, F142L among others) | Gain‑of‑function hemichannels → leaky ATP/Ca2+/IP3 release, inflammation; loss or dominant‑negative loss of gap‑junctional coupling → impaired tissue coordination, altered proliferation/differentiation | GO:0007154 (cell communication); GO:0006816 (ion transport); GO:0006954 (inflammatory response) | Keratinocyte (CL:0000312); epidermal resident immune cells (various CL IDs) | Epidermis and epidermal appendages; palmoplantar skin (UBERON:0001003, UBERON:0002427, UBERON:0002428) | Palmoplantar hyperkeratosis, inflammation, susceptibility to secondary infection/complications; hearing loss in syndromic forms (HP:0000982; HP:0000407) | (garciavega2021connexinsandthe pages 13-14, garciavega2021connexinsandthe pages 4-6, govender2023palmoplantarkeratodermapseudoainhum pages 2-4, sethuraman2019hereditarypalmoplantarkeratoderma pages 4-5) |

Table: Compact summary of key genes/proteins, variant examples, primary mechanisms, relevant GO/CL/UBERON/HPO ontology mappings, and representative evidence IDs for Keratoderma Hereditarium Mutilans (Vohwinkel syndrome). This table supports rapid integration into a disease knowledge base and links claims to source context IDs.

Notes and gaps - MONDO ID should be confirmed in a dedicated ontology resource before entry finalization. Emerging therapeutic concepts targeting connexin hemichannels are promising but remain preclinical or exploratory in VS.

References

  1. (maestrini1999amissensemutation pages 1-2): E. Maestrini, B. Korge, Juan Ocaña-Sierra, E. Calzolari, S. Cambiaghi, Pat Scudder, A. Hovnanian, A. Monaco, and C. Munro. A missense mutation in connexin26, d66h, causes mutilating keratoderma with sensorineural deafness (vohwinkel's syndrome) in three unrelated families. Human molecular genetics, 8 7:1237-43, Jul 1999. URL: https://doi.org/10.1093/hmg/8.7.1237, doi:10.1093/hmg/8.7.1237. This article has 401 citations and is from a domain leading peer-reviewed journal.

  2. (sethuraman2019hereditarypalmoplantarkeratoderma pages 4-5): Gomathy Sethuraman, Tanvi Dev, and VikramK Mahajan. Hereditary palmoplantar keratoderma: a practical approach to the diagnosis. Indian Dermatology Online Journal, 10:365-379, Jul 2019. URL: https://doi.org/10.4103/idoj.idoj_367_18, doi:10.4103/idoj.idoj_367_18. This article has 45 citations.

  3. (garciavega2021connexinsandthe pages 13-14): Laura Garcia-Vega, Erin M. O’Shaughnessy, Ahmad Albuloushi, and Patricia E. Martin. Connexins and the epithelial tissue barrier: a focus on connexin 26. Biology, 10:59, Jan 2021. URL: https://doi.org/10.3390/biology10010059, doi:10.3390/biology10010059. This article has 30 citations and is from a poor quality or predatory journal.

  4. (garciavega2021connexinsandthe pages 4-6): Laura Garcia-Vega, Erin M. O’Shaughnessy, Ahmad Albuloushi, and Patricia E. Martin. Connexins and the epithelial tissue barrier: a focus on connexin 26. Biology, 10:59, Jan 2021. URL: https://doi.org/10.3390/biology10010059, doi:10.3390/biology10010059. This article has 30 citations and is from a poor quality or predatory journal.

  5. (govender2023palmoplantarkeratodermapseudoainhum pages 2-4): Kellicia Courtney Govender and Somasundram Pillay. Palmoplantar keratoderma, pseudo-ainhum and knuckle pads in an african patient: a case report. SAGE Open Medical Case Reports, Jan 2023. URL: https://doi.org/10.1177/2050313x231204197, doi:10.1177/2050313x231204197. This article has 3 citations and is from a peer-reviewed journal.

  6. (schmuth2007ichthyosisupdatetowards pages 5-6): Matthias Schmuth, Robert Gruber, Peter M. Elias, and Mary L. Williams. Ichthyosis update: towards a function-driven model of pathogenesis of the disorders of cornification and the role of corneocyte proteins in these disorders. Advances in dermatology, 23:231-56, Jan 2007. URL: https://doi.org/10.1016/j.yadr.2007.07.011, doi:10.1016/j.yadr.2007.07.011. This article has 136 citations.

  7. (schmuth2007ichthyosisupdatetowards pages 14-15): Matthias Schmuth, Robert Gruber, Peter M. Elias, and Mary L. Williams. Ichthyosis update: towards a function-driven model of pathogenesis of the disorders of cornification and the role of corneocyte proteins in these disorders. Advances in dermatology, 23:231-56, Jan 2007. URL: https://doi.org/10.1016/j.yadr.2007.07.011, doi:10.1016/j.yadr.2007.07.011. This article has 136 citations.

  8. (maestrini1999amissensemutation pages 6-6): E. Maestrini, B. Korge, Juan Ocaña-Sierra, E. Calzolari, S. Cambiaghi, Pat Scudder, A. Hovnanian, A. Monaco, and C. Munro. A missense mutation in connexin26, d66h, causes mutilating keratoderma with sensorineural deafness (vohwinkel's syndrome) in three unrelated families. Human molecular genetics, 8 7:1237-43, Jul 1999. URL: https://doi.org/10.1093/hmg/8.7.1237, doi:10.1093/hmg/8.7.1237. This article has 401 citations and is from a domain leading peer-reviewed journal.