# Nonsyndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy

Masashi Akiyama, Keith Choate, Ángela Hernández-Martín, Mandy Aldwin-Easton, Christine Bodemer, Antoni Gostyński, Alain Hovnanian, Akemi Ishida-Yamamoto, Kiril Malovitski, Edel O'Toole, et al.

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## To cite this version:

Masashi Akiyama, Keith Choate, Ángela Hernández-Martín, Mandy Aldwin-Easton, Christine Bodemer, et al. Nonsyndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy. British Journal of Dermatology, 2026, 193 (4), pp.619 - 641. 10.1093/bjd/ljaf154. hal-05509009

HAL Id: hal-05509009

https://hal.science/hal-05509009v1

Submitted on 13 Feb 2026

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# Nonsyndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy

Masashi Akiyama<sup>1</sup>, Keith Choate<sup>2</sup>, Ángela Hernández-Martín<sup>3</sup>, Mandy Aldwin-Easton<sup>4</sup>

Christine Bodemer<sup>5</sup>, Antoni Gostyński<sup>6,7</sup>, Alain Hovnanian<sup>8,9</sup>, Akemi Ishida-Yamamoto<sup>10</sup>

Kiril Malovitski<sup>11,12</sup>, Edel A O'Toole<sup>13</sup>, Amy S Paller<sup>14</sup>, Matthias Schmuth<sup>15</sup>

Janice Schwartz<sup>16</sup>, Eli Sprecher,<sup>11,12</sup> Joyce M C Teng<sup>17</sup>, Céline Granier Tournier<sup>18</sup>

Juliette Mazereeuw-Hautier<sup>19</sup>, Gianluca Tadini<sup>19</sup> and Judith Fischer<sup>20</sup>

## Abstract

Epidermal differentiation disorders (EDDs) encompass inherited conditions characterized by abnormal epidermal differentiation, including nonsyndromic and syndromic subtypes with more extensive cutaneous involvement or palmoplantar keratoderma. Nonsyndromic EDDs (nEDDs) are defined as disorders that primarily affect large areas of skin and adnexal structures without alterations in extracutaneous tissues resulting from the underlying genetic change. To facilitate the development of targeted therapies and to provide clinicians with clearer therapeutic guidance, we have developed a new nomenclature for EDDs that includes the causative altered gene and the nEDD subgroup designation, sometimes with a clinical or histological descriptor or acronym. Historically, many nEDDs have been named on the basis of phenotypic characteristics or associations that are now considered outdated or inappropriate. For example, the term 'harlequin ichthyosis' evokes potentially stigmatizing images. Similarly, the word 'ichthyosis' is derived from the Greek *ichthys*, meaning fish, and the Greek *hystrix*, meaning porcupine, further emphasizing the need to abandon derogatory terminology. As a result, the clinical relevance of the previous classification, which included eponymous and/or descriptive titles, has diminished. In the new, gene-based classification, old terms considered pejorative, such as *ichthyosis, vulgaris, hystrix* and *harlequin* have been eliminated and eponyms have been replaced. Among the 53 genetically distinct nEDDs are conditions formerly known as autosomal recessive congenital ichthyosis, erythrokeratodermia variabilis et progressiva, Hailey-Hailey disease and Darier-White disease. This review outlines the updated nomenclature and classifications of nEDDs, linked to detailed clinical descriptions and representative photographs to guide practitioners.

<footnote n="1"><sup>1</sup>Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan</footnote>

<footnote n="20"><sup>20</sup>Institute of Human Genetics, Medical Center, Faculty of Medicine and Center for Cornification Disorders, Freiburg Center for Rare Diseases, Medical Center, University of Freiburg, Freiburg, Germany</footnote>

<footnote>Correspondence: Judith Fischer. Email: judith.fischer@uniklinik-freiburg.de</footnote>

<footnote>C.B., A.G. and J.M.-H. are members of ERN-Skin.</footnote>

<footnote>See Appendix 1 for the complete list of author affiliations.</footnote>
## Graphical Abstract

<figure><img src="image_3.png" /></figure>

### Lay summary

Epidermal differentiation disorders (or 'EDDs' for short) are a group of inherited skin conditions. They affect the outermost layer of the skin, called the 'epidermis'. The epidermis protects the body from things like germs and harmful substances. When the epidermis does not form properly, it can lead to skin problems like dryness, scaling and thickening.

We have developed a new naming system for EDDs, based on the specific genes involved. The new system includes many diseases that used to be known by other names. We aim to make it easier for patients and doctors to understand the underlying causes of these conditions. There are 53 types of 'non-syndromic' EDDs (or 'nEDDs' for short). nEDDs affect only the skin and no other parts of the body. Some examples of nEDDs are ichthyosis (pronounced 'ik-thee-oh-sis'), erythrotkeratodermia variabilis et progressiva, Hailey-Hailey disease and Darier-White disease. These conditions were named based on their symptoms or abbreviations. The new classification uses the gene responsible for the disorder in the disease name. It will help patients understand their condition. It will also allow doctors to provide more targeted treatments. In the new classification, names based on individuals, offensive terms and outdated words have been removed.

The new naming system for EDDs is based on the gene that causes the disease. It aims to support more effective treatments.

### Introduction

'Epidermal differentiation disorders' (EDDs) is an umbrella term for the large group of disorders previously known as the ichthyoses, palmoplantar keratodermas (PPKs) and other disorders of differentiation. Nonsyndromic EDDs (nEDDs) typically affect large areas of skin, but some forms are localized, affecting only specific regions such as the trunk or extremities, sometimes with the involvement of adnexal structures but without extracutaneous alterations. The previous classification approach to hereditary EDDs, which includes ichthyoses, was inadequate to guide modern clinical practice. Progress in molecular diagnosis has provided cardinal insights into disease pathophysiology, permitting revision of the prior nomenclature to include therapeutically relevant classification.¹,² As a result, the clinical relevance

of the previous classification, which included eponymous and/or descriptive titles, has diminished. To address this deficit, we have developed a new nomenclature for nEDDs based on the gene defects responsible for these disorders (Table 1).

Our new nomenclature encompasses 53 distinct disorders and expands the traditional classification of these EDDs. Included are conditions previously known as autosomal recessive congenital ichthyosis, erythrotkeratodermia variabilis et progressiva, peeling skin syndrome, Hailey-Hailey disease, Darier-White disease and porokeratosis (Table 1).¹⁻²² The new nomenclature eliminates eponyms and terms that are considered derogatory or outdated, such as 'ichthyosis', 'vulgaris' and 'harlequin'.²³ The new name includes the affected gene, the nEDD designation and sometimes a clinical feature or acronym to help with diagnosis.
<table><caption>**Table 1** New and old nomenclature of functional groups in nonsyndromic epidermal differentiation disorders (nEDDs)</caption><thead><tr><th>Functional group</th><th>Functional subgroup</th><th>Affected protein</th><th>New name</th><th>Previous name(s)</th><th>OMIM#</th><th>Reference(s)</th></tr></thead><tbody><tr><td rowspan="10">Structural proteins</td><td rowspan="2">Filaggrin-associated disorder</td><td>Filaggrin</td><td>FLG-nEDD</td><td>Ichthyosis vulgaris</td><td>146700</td><td>Smith,<sup>47</sup> Palmer<sup>48</sup></td></tr><tr><td>Keratin 1</td><td>KRT1-nEDD-epidermolytic</td><td>Epidermolytic ichthyosis, bullous congenital ichthyosiform erythroderma, epidermolytic hyperkeratosis</td><td>113800</td><td>Rothnagel<sup>51</sup></td></tr><tr><td rowspan="8">Keratin-associated disorders</td><td>Keratin 1</td><td>KRT1-nEDD-nonepidermolytic</td><td>Epidermolytic ichthyosis</td><td>113800</td><td>Eskin-Schwartz<sup>100</sup></td></tr><tr><td>Keratin 1</td><td>KRT1-nEDD-spiny</td><td>Ichthyosis hystrix, Curth-Macklin type</td><td>146590</td><td>Sprecher,<sup>101</sup> Terrinoni<sup>102</sup></td></tr><tr><td>Keratin 1</td><td>KRT1-nEDD-annular</td><td>Annular epidermolytic ichthyosis</td><td>620148</td><td>Zaki<sup>54</sup></td></tr><tr><td>Keratin 10</td><td>KRT10-nEDD-epidermolytic</td><td>Epidermolytic ichthyosis, bullous congenital ichthyosiform erythroderma, epidermolytic hyperkeratosis</td><td>620150</td><td>Rothnagel,<sup>51</sup> Müller<sup>52</sup></td></tr><tr><td>Keratin 10</td><td>KRT10-nEDD-nonepidermolytic</td><td>Epidermolytic ichthyosis</td><td>620150</td><td>Eskin-Schwartz<sup>100</sup></td></tr><tr><td>Keratin 10</td><td>KRT10-nEDD-spiny</td><td>Ichthyosis hystrix, Lambert type</td><td>146600</td><td>Terrinoni<sup>102</sup></td></tr><tr><td>Keratin 10</td><td>KRT10-nEDD-annular</td><td>Annular epidermolytic ichthyosis</td><td>607602, 620150</td><td>Suga<sup>55</sup></td></tr><tr><td>Keratin 2</td><td>KRT2-nEDD</td><td>Superficial epidermolytic ichthyosis</td><td>146800</td><td>Rothnagel<sup>53</sup></td></tr><tr><td>Keratin 1</td><td>KRT1-nEDD-mosaic</td><td rowspan="4">Epidermolytic naevus</td><td>113800</td><td>Tsubota<sup>56</sup></td></tr><tr><td>Keratin 2</td><td>KRT2-nEDD-mosaic</td><td>146800</td><td>Diociaiuti<sup>58</sup></td></tr><tr><td>Keratin 10</td><td>KRT10-nEDD-mosaic</td><td>620150</td><td>Samuelov<sup>59</sup></td></tr><tr><td>Keratin 16</td><td>KRT16-nEDD-mosaic</td><td>148067</td><td>Terrinoni<sup>61</sup></td></tr><tr><td>Keratin 83</td><td>KRT83-nEDD</td><td>Erythrokeratodermia variabilis et progressiva</td><td>617756</td><td>Shah<sup>3</sup></td></tr></tbody></table>

(Continued)

Each disorder is subgrouped based on the function of the product of the defective gene. By classifying nEDDs based on associated genetic variants and functions of the encoded proteins, this system facilitates a deeper understanding of disease pathophysiology and highlights potential targets for therapeutic intervention, ranging from gene therapy to repurposing therapies in current use for other indications (Tables 1 2).²⁴

## From old to new nomenclature

The updated nomenclature classifies disorders based on functional group, such as structural proteins (filaggrin, keratins, and adhesion proteins), channels (gap junction or ion channels), enzymes (particularly those involved in ceramide and cholesterol metabolism) and other molecules (Table 1). Many nEDDs are associated with abnormal epidermal
<table><caption>**Table 1 (Continued)**</caption><tbody><tr><td></td><td></td><td>Keratin 1</td><td>KRT1-nEDD-revertant mosaic</td><td>Ichthyosis with confetti</td><td>113800</td><td>Choate<sup>63</sup></td></tr><tr><td></td><td></td><td>Keratin 10</td><td>KRT10-nEDD-revertant mosaic</td><td></td><td>609165</td><td>Choate<sup>65</sup></td></tr><tr><td rowspan="3">Adhesion protein-associated disorders</td><td rowspan="3"></td><td>Desmosomal component, p53/p63 tetraspan plasma membrane protein (PERP)</td><td>PERP-nEDD-AR</td><td>Erythrukeratodermia variabilis et progressiva</td><td>619209</td><td>Duchatelet<sup>11</sup></td></tr><tr><td>Corneodesmosome component, corneodesmosin</td><td>CDSN-nEDD</td><td>Peeling skin syndrome</td><td>270300</td><td>Oji<sup>14</sup></td></tr><tr><td>Filaggrin 2</td><td>FLG2-nEDD</td><td>Peeling skin syndrome</td><td>618084</td><td>Mohamad<sup>15</sup></td></tr><tr><td>Cell envelope precursor protein-associated disorder</td><td></td><td>Cornified cell envelope component, cystatin A</td><td>CSTA-nEDD</td><td>Peeling skin syndrome</td><td>607936</td><td>Blaydon<sup>16</sup></td></tr><tr><td rowspan="7">Lipid synthesis and transport</td><td rowspan="7">Cholesterol metabolism enzyme-associated disorders</td><td>Sulfotransferase family 2B member 1 (SULT2B1)</td><td>SULT2B1-nEDD</td><td>Lamellar ichthyosis, CIE, ARCI</td><td>617571</td><td>Heinz<sup>36</sup></td></tr><tr><td>Mevalonate pyrophosphate decarboxylase (MVD)</td><td>MVD-nEDD</td><td rowspan="5">Porokeratosis, disseminated (superficial) actinic porokeratosis, linear porokeratosis, porokeratosis of Mibelli</td><td>614714</td><td>Zhang<sup>20</sup></td></tr><tr><td>Mevalonate kinase (MVK)</td><td>MVK-nEDD</td><td>175900</td><td>Zhang<sup>20</sup></td></tr><tr><td>Phosphomevalonate kinase (PMVK)</td><td>PMVK-nEDD</td><td>175800</td><td>Zhang<sup>20</sup></td></tr><tr><td>Farnesyl diphosphate synthase (FDPS)</td><td>FDPS-nEDD</td><td>134629</td><td>Zhang<sup>20</sup></td></tr><tr><td>Solute carrier family 17 member 9 (SLC17A9)</td><td>SLC17A9-nEDD</td><td>616063</td><td>Cui<sup>21</sup></td></tr></tbody></table>

(Continued)

ceramide synthesis or transport.<sup>12,25-40</sup> Historically, many nEDDs have been named on the basis of phenotypic characteristics or associations that are now considered outdated or inappropriate. For example, the term 'harlequin ichthyosis' evokes potentially stigmatizing images.<sup>41,42</sup> Similarly, the word 'ichthyosis' is derived from the Greek *ichthys*, meaning fish, and the Greek *hystrix*, meaning porcupine, further emphasizing the need to abandon derogatory terminology.

Recent research has shown that pathogenic variants in ceramide synthesis, transport or formation of the lipid barrier result in a similar phenotype at birth (previously

called 'collodion baby') and a range of phenotypic features with extensive erythroderma and fine scaling (previously grouped as congenital ichthyosiform erythroderma) to lamellated scaling skin with variable underlying cutaneous erythema (formerly called lamellar ichthyosis).<sup>25,43</sup> These disorders are now linked functionally and named based on their affected gene. Similarly, what was formerly called 'porokeratosis' was initially thought to be linked to abnormal keratinization of sweat 'pores' but these disorders are now recognized as nEDDs caused by deficiencies in enzymes involved in the mevalonate/cholesterol biosynthesis pathway, leading us to abandon the inaccurate term
<table><caption>**Table 1** (Continued)</caption><tr><td></td><td>Farnesyldiphosphate farnesyltransferase 1 (FDFT1)</td><td>FDFT1-nEDD</td><td>184420</td><td>Saito<sup>22</sup></td></tr><tr><td rowspan="10">Ceramide synthesis and transport disorders</td><td>12R-lipoxygenase (12R-LOX)</td><td>ALOX12B-nEDD</td><td>Lamellar ichthyosis/CIE, ARCI</td><td>242100</td><td>Jobard,<sup>26</sup> Harting<sup>27</sup></td></tr><tr><td>Epidermal type lipoxygenase 3 (eLOX3)</td><td>ALOXE3-nEDD</td><td>Lamellar ichthyosis, CIE, ARCI</td><td>606545</td><td>Jobard,<sup>26</sup></td></tr><tr><td>Cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22)</td><td>CYP4F22-nEDD</td><td>Lamellar ichthyosis, CIE, ARCI</td><td>604777</td><td>Lefèvre,<sup>29</sup> Noguera-Morel<sup>30</sup></td></tr><tr><td>Lipase family member N (LIPN)</td><td>LIPN-nEDD</td><td>Lamellar ichthyosis, CIE, ARCI</td><td>613943</td><td>Israeli<sup>31</sup></td></tr><tr><td>Ceramide synthase 3</td><td>CERS3-nEDD</td><td>Lamellar ichthyosis, CIE, ARCI</td><td>615023</td><td>Radner<sup>32</sup></td></tr><tr><td>Patatin-like phospholipase domain-containing 1 (PNPLA1)</td><td>PNPLA1-nEDD</td><td>Lamellar ichthyosis, CIE, ARCI</td><td>615024</td><td>Grall<sup>33</sup></td></tr><tr><td>Short chain dehydrogenase/reductase family 9C member 7 (SDR9C7)</td><td>SDR9C7-nEDD</td><td>Lamellar ichthyosis, ARCI</td><td>617574</td><td>Shigehara<sup>34</sup></td></tr><tr><td>NTPase KAP family P-loop domain-containing protein 1 (NKPD1)</td><td>NKPDI-nEDD</td><td>Autosomal dominant lamellar ichthyosis</td><td>—</td><td>Komlosi<sup>40</sup></td></tr><tr><td>3-Ketodihydro-sphingosine reductase (KDSR)</td><td>KDSR-nEDD<sup>a</sup></td><td>Erythrotjeratodermia variabilis et progressiva, PERIOPTER syndrome</td><td>617526</td><td>Boyden,<sup>12</sup> Takeichi,<sup>39</sup> Wijsmans<sup>73</sup></td></tr><tr><td>ATP-binding cassette transporter family A member 12 (ABCA12)</td><td>ABCA12-nEDD</td><td>Harlequin ichthyosis, ARCI, CIE, erythrotjeratodermia variabilis et progressiva</td><td>607800</td><td>Kelsell,<sup>41</sup> Akiyama,<sup>42</sup> Lefèvre<sup>83</sup> Hotz,<sup>92</sup> Noda<sup>93</sup></td></tr><tr><td>Magnesium transporter NIPA4 isoform 1 (NIPAL4)</td><td>NIPAL4-nEDD</td><td>Lamellar ichthyosis, CIE, ARCI</td><td>612281</td><td>Lefèvre,<sup>85</sup> Rossel<sup>86</sup></td></tr><tr><td>Solute carrier family 27 member 4 (fatty acid transporter protein)</td><td>SLC27A4-nEDD</td><td>Ichthyosis prematurity syndrome</td><td>608649</td><td>Klar,<sup>77</sup> Esperón-Moldes,<sup>78</sup> Sobol<sup>79</sup></td></tr></table>

(Continued)

'porokeratosis'.<sup>20</sup> These disorders are now named according to the specific gene involved: MVD-nEDD, MVK-nEDD, PMVK-nEDD, FDPS-nEDD, SLC17A9-nEDD and FDFT1-nEDD (see Table 1).<sup>20-22</sup>

Pathogenesis typically depends not only on the genes responsible for critical components of epidermal differentiation (e.g. corneocytes and extracellular lipids – 'bricks

and mortar'), but also those for epidermal cell–cell contacts, channel proteins and others (Table 1). The gene alterations result in disturbance of epidermal homeostasis and an impaired epidermal barrier with increased transepidermal water loss. The response is scaling, characterized histologically by hyperkeratosis and acanthosis. Cutaneous inflammation is another feature of EDDs and the increased
<table><caption>**Table 1** (Continued)</caption><tbody><tr><td rowspan="3">Enzymes: proteases and others</td><td>Serine protease inhibitor-associated disorder</td><td>Serpin family B member 8 (SERPINB8)</td><td>SERPINB8-nEDD</td><td>Peeling skin syndrome</td><td>617115</td><td>Pigors<sup>68</sup></td></tr><tr><td>Cell envelope forming enzyme-associated disorders</td><td>Transglutaminase 1</td><td>TGM1-nEDD</td><td>Lamellar ichthyosis, CIE, ARCI, self-healing collodion baby, bathing suit ichthyosis</td><td>242300</td><td>Huber,<sup>80</sup> Russell,<sup>81</sup> Raghunath,<sup>87</sup> Oji,<sup>88</sup> Mazereew-Hautier<sup>89</sup></td></tr><tr><td>Other enzyme-associated disorders</td><td>Caspase-14</td><td>CASP14-nEDD</td><td>Lamellar ichthyosis, ARCI</td><td>617320</td><td>Kirchmeier<sup>49</sup></td></tr><tr><td rowspan="5">Channels</td><td rowspan="3">Connexin-associated disorders</td><td>Retroviral-like aspartic protease 1 (ASPRV1)</td><td>ASPRV1-nEDD</td><td>Autosomal dominant lamellar ichthyosis</td><td>146750</td><td>Boyden<sup>50</sup></td></tr><tr><td>Kallikrein-11</td><td>KLK11-nEDD</td><td>Autosomal dominant cornification disorder</td><td>620507</td><td>Gong,<sup>94</sup> Takeichi<sup>95</sup></td></tr><tr><td>Gap junction protein, connexin 31</td><td>GJB3-nEDD</td><td>Erythrotjeratodermia variabilis et progressiva</td><td>133200</td><td>Richard,<sup>4</sup> Gottfried<sup>5</sup></td></tr><tr><td rowspan="3">Other channel protein-associated disorders</td><td>Gap junction protein, connexin 30.3</td><td>GJB4-nEDD</td><td>Erythrotjeratodermia variabilis et progressiva</td><td>617524</td><td>van Steensel,<sup>6</sup> Macari<sup>7</sup></td></tr><tr><td>Gap junction protein, connexin 43</td><td>GJA1-nEDD</td><td>Erythrotjeratodermia variabilis et progressiva</td><td>617525</td><td>Boyden<sup>9</sup></td></tr><tr><td>Secretary pathway Ca<sup>2+</sup> ATPase 1 (SPCA1)</td><td>ATP2C1-nEDD</td><td>Hailey-Hailey disease, chronic benign familial pemphigus</td><td>169600</td><td>Hu,<sup>17</sup> Sudbrak<sup>18</sup></td></tr><tr><td rowspan="3">Miscellaneous</td><td rowspan="2">Sarcoplasmic reticulum Ca<sup>2+</sup> ATPase 2 (SERCA2)</td><td>Sarcoplasmic reticulum Ca<sup>2+</sup> ATPase 2 (SERCA2)</td><td>ATP2A2-nEDD</td><td>Darier-White disease, keratosis follicularis</td><td>124200</td><td>Sakuntabhai<sup>19</sup></td></tr><tr><td>Transient receptor potential cation channel subfamily M member 4 (TRPM4)</td><td>TRPM4-nEDD</td><td>Erythrotjeratodermia variabilis et progressiva</td><td>618531</td><td>Wang<sup>10</sup></td></tr><tr><td>Caspase recruitment domain-containing protein 14 (CARD14)</td><td>CARD14-nEDD</td><td>CARD14-associated papulosquamous eruption, pityriasis rubra pilaris type V</td><td>173200</td><td>Takeichi,<sup>96</sup> Craiglow<sup>97</sup></td></tr><tr><td></td><td>Protease maturation protein (POMP)</td><td>POMP-nEDD</td><td>KLICK syndrome</td><td>601952</td><td>Dahlqvist<sup>99</sup></td></tr></tbody></table>

The rarest nEDDs are in bold. ARCI, autosomal recessive congenital ichthyosis; CIE, congenital ichthyosiform erythroderma; KLICK, keratosis linearis with ichthyosis congenita and sclerosing keratoderma; PERIOPTER, periorificial and ptychotropic erythroderatoderma. <sup>a</sup>About half of patients have haematological symptoms, including thrombocytopenia.

metabolic rate sometimes leads to short stature. The underlying pathogenic variant and a variety of other factors (e.g. gene modifiers and environmental factors) dictate the quality and severity of these morphological consequences, distribution of skin lesions, disease onset and disease course. Despite homeostatic repair efforts, a residual defect in the barrier and thus increased water evaporation often remains.

## From new nomenclature to clinical manifestations

The clinical phenotypes associated with each nEDD are listed in Table 2; Figures 1–4 provide visual representations of the clinical manifestations of the major nEDDs. Figure 1 depicts the representative neonatal appearance of various
nEDDs. Figures 2–4 show the clinical features of major forms of nEDDs.

Among these clinical features is often prominent PPK, but the generalized nature of scaling placed the disorder into nEDD rather than the palmoplantar EDDs (pEDDs) subgroup. That said, disorders typically considered nEDDs can actually be pEDDs (e.g. *FLG*-pEDD)44,45 and vice versa (*LOR*-pEDD is commonly associated with generalized fine scaling, resembling a mild nEDD).46

nEDDs caused by variants in genes related to filaggrin (FLG), a protein essential to epidermal barrier function, include the following. *FLG*-nEDD (formerly known as ichthyosis vulgaris) is characterized by generalized fine scaling and palmoplantar hyperlinearity (Figure 2),47 with a predisposition to atopic dermatitis.48 Patients with *CASP14*-nEDD show generalized fine, whitish scaling similar to that seen in patients with *FLG*-nEDD.49 Only three patients from two families with identical homozygous *CASP14* variants (a two-base pair deletion) have been reported, so clinical experience is limited. Caspase 14 (*CASP14*) is a major interacting partner with FLG, suggesting a similar function and phenotype. Patients with *ASPRV1*-nEDD have severe hyperlinearity of the palms and soles that resembles biallelic *FLG*-nEDD;50 the similarity is pathogenesis-based as the gene product of *ASPRV1* cleaves pro-FLG to FLG monomers.

nEDDs caused by abnormalities in keratin proteins primarily expressed in epidermal keratinocytes include the following. Patients with the epidermolytic types of *KRT1*-nEDD and *KRT10*-nEDD present with blistering, erosions and erythema at birth, with skin thickening and scaling developing over time (Figure 2).51,52 PPK is severe in *KRT1*-nEDD-epidermolytic, whereas *KRT10*-nEDD-epidermolytic has milder palmoplantar involvement.1 Patients with *KRT2*-nEDD present with mild scaling without erythroderma.53 Other less common nEDDs caused by variants in *KRT1*, *KRT10*, *KRT2* and *KRT16* are listed in Table 2.52,54–67

*CDSN*-nEDD shows generalized superficial skin peeling with erythema and, as in *FLG*-nEDD, a predisposition to atopic dermatitis (Figure 2).14 In contrast, *CSTA*-nEDD features generalized or acral superficial skin peeling without erythema (Figure 2).16 *FLG2*-nEDD also shows superficial skin peeling without erythema but mainly on the extremities (Figure 2).15 *SERPINB8*-nEDD can manifest as superficial skin peeling on the extremities, with or without erythema.68 *KRT83*-nEDD, *PERP*-nEDD, *KDSR*-nEDD, *GJB3*-nEDD, *GJB4*-nEDD, *GJA1*-nEDD, *TRPM4*-nEDD and *ABCA12*-nEDD – previously named erythrokeratodermia variabilis et progressive – are characterized by well-demarcated, thickened and erythematous plaques that expand and regress, although the location and movement of the plaques varies widely among these nEDD types (Figures 2–4).3–13 Autosomal recessive *KRT83*-nEDD with its keratoderma and normal hair is phenotypically distinct from heterozygous, dominant missense variants in *KRT83* causing monilethrix. Among the nEDDs, hair alterations also include yellow hair in *PERP*-nEDD-autosomal recessive (AR).11 In *TGM1*-nEDD and *ABCA12*-nEDD, alopecia is not uncommon.69,70 AR EDD due to *ST14* variants is classified as a syndromic EDD (sEDD) because of prominent ocular involvement, but many individuals with *ST14* variants have only skin and hair involvement.71

It can be difficult to separate nEDDs from sEDDs. Thus, in the new nomenclature, for a given EDD, if most patients

exhibited extracutaneous symptoms, the disease was classified as sEDD, and if most patients did not exhibit extracutaneous symptoms, the disease was classified as nEDD. *KDSR*-nEDD presents with a variety of clinical manifestations, ranging from thickened scaly plaques localized to the face and genitalia to severe generalized scaling at birth.12,39 Approximately half of patients with *KDSR*-nEDD have haematological symptoms, including thrombocytopenia.39,72 However, because haematological symptoms are usually transient and many patients have skin symptoms as their main complaint, we included patients with *KDSR* variants in the nEDD classification (Table 1).73

In contrast, given that *STS* deletions leading to EDD are common, and also that a large percentage of affected boys have learning disabilities (ranging from mild to attention-deficit disorder to autism), *STS*-sEDD (previously named X-linked ichthyosis) was kept a syndromic disorder (not because of the previous association with genital region abnormalities, which are uncommon).74,75 Clinical overlap between *STS*-sEDD, with its large, thick polygonal, usually darker scales, and *FLG*-nEDD, can lead to misdiagnosis, especially in children.76 Although patients with *SLC27A4* variants, previously known as ichthyosis prematurity syndrome, show prematurity and neonatal asphyxia, these symptoms are likely to be secondary to the massive desquamation *in utero* that eventually transforms into generalized mild scaling.77–79 Thus, in the new nomenclature, patients with *SLC27A4* variants are included as *SLC27A4*-nEDD in the nEDD group.

In cases in which the disorder is limited to skin and adnexae (a nEDD), but the morphological features are not conclusive for a gene-specific disorder and genetic results are unavailable or inconclusive, a presumed diagnosis can be based on clinical features or a preliminary diagnosis made of 'unspecified nEDD' (followed by an optional probable diagnosis based on clinical features in parentheses). For patients who have relevant pathogenic variants in more than one gene (e.g. concurrent *FLG*-nEDD and *STS*-sEDD), a combination of names can be used (*FLG*-nEDD, *STS*-sEDD), preferably with the most penetrant gene listed first.

Eleven AR nEDDs (*SULT2B1*-nEDD, *ALOX12B*-nEDD, *ALOXE3*-nEDD, *CYP4F22*-nEDD, *CERS3*-nEDD, *PNPLA1*-nEDD, *SDR9C7*-nEDD, *TGM1*-nEDD, *CASP14*-nEDD, *ABCA12*-nEDD and *NIPAL4*-nEDD) typically show generalized scaling or result in encasement in a collodion-like membrane at birth with subsequent desquamation (Figures 3–5).1,26,29,32–34,36,37,41–43,49,80–86 The severity of scaling, degree of erythroderma and presence or absence of a collodion membrane at birth in these nEDDs are described in Table 2. *LIPN*-nEDD shows noncongenital, late-onset generalized scaling.31,43 Patients with *TGM1*-nEDD present with highly variable clinical features, including self-healing or self-improving collodion membrane (sometimes limited to acral areas), bathing suit patterning of scale or temperature-sensitive manifestations (worst on scalp and trunk) (Figure 3).87–89 Furthermore, ectropium and eclabium are common in *TGM1*-nEDD and *ABCA12*-nEDD. Phenotypic features of *ABCA12*-nEDD can vary from mild to very severe, including thick fissured plate-like truncal scales, severe ectropion and eclabium (Figure 4).41,42,83,84 In severe cases with *ABCA12*-nEDD (formerly known as harlequin ichthyosis), deformed nose, ears, hands and feet, and joint
<table><caption>**Table 2** Modes of inheritance of nonsyndromic epidermal differentiation disorders (nEDDs), age of onset and clinical clues</caption><thead><tr><th>Gene-based name</th><th>Inheritance</th><th>Age of onset</th><th>Clinical clues</th></tr></thead><tbody><tr><td>FLG-nEDD</td><td>AD (autosomal semi-dominant)</td><td>Infancy to childhood</td><td>Generalized fine scaling and palmoplantar hyperlinearity, variable keratosis pilaris, atopic diathesis, PPK</td></tr><tr><td>KRT1-nEDD-epidermolytic</td><td>AD from an affected parent or germline (gonadal) mosaicism from an unaffected parent</td><td>Birth</td><td>Blistering/erosions and erythema at birth, progressive development of corrugated, localized or diffuse thickening and scaling, severe PPK</td></tr><tr><td>KRT1-nEDD-nonepidermolytic</td><td>AD</td><td>Birth to infancy</td><td>Diffuse erythema, scaling and erosions, PPK</td></tr><tr><td>KRT1-nEDD-spiny</td><td>AD</td><td>Infancy</td><td>Very severe dark, spiky or verrucous plaques, severe PPK</td></tr><tr><td>KRT1-nEDD-annular</td><td>AD</td><td>Childhood</td><td>A cyclic history of annular erythematous plaques with peripheral scale</td></tr><tr><td>KRT10-nEDD-epidermolytic</td><td>AD from an affected parent or germline (gonadal) mosaicism from an unaffected parent; AR (rare)</td><td>Birth</td><td>Blistering/erosions and erythema at birth, progressive development of corrugated, localized or diffuse skin thickening and scaling, usually mild or absent PPK</td></tr><tr><td>KRT10-nEDD-nonepidermolytic</td><td>AD</td><td>Childhood</td><td>Multiple well-defined scaly plaques on the trunk and extremities</td></tr><tr><td>KRT10-nEDD-spiny</td><td>AD</td><td>Infancy</td><td>Widespread verrucous lesions; the face, palms and soles are unaffected</td></tr><tr><td>KRT10-nEDD-annular</td><td>AD</td><td>Childhood</td><td>A cyclic history of annular erythematous plaques with peripheral scale</td></tr><tr><td>KRT2-nEDD</td><td>AD from an affected parent or germline (gonadal) mosaicism from an unaffected parent</td><td>Birth to infancy</td><td>Blistering/erosions and erythema at birth, mild scaling without erythroderma, superficial erosion ('moulting', superficial denuded areas), flares with large bullae</td></tr><tr><td>KRT1-nEDD-mosaic</td><td rowspan="4">Postzygotic mosaicism</td><td rowspan="4">Birth to infancy</td><td rowspan="4">Localized skin thickening, scaling and erosions following the lines of Blaschko</td></tr><tr><td>KRT2-nEDD-mosaic</td></tr><tr><td>KRT10-nEDD-mosaic</td></tr><tr><td>KRT16-nEDD-mosaic</td></tr><tr><td>KRT83-nEDD</td><td>AD</td><td>Birth</td><td>Symmetric plaques mainly on the extremities, expanding and contracting</td></tr><tr><td>KRT1-nEDD-revertant mosaic</td><td>AD</td><td>Infancy</td><td>Slowly enlarging round islands of normal skin upon generalized erythroderma, beginning in childhood; localized normal skin following the lines of Blaschko, appearing in early infancy</td></tr><tr><td>KRT10-nEDD-revertant mosaic</td><td>AD</td><td>Infancy</td><td></td></tr></tbody></table>

(Continued)

contractures are seen.⁹⁰,⁹¹ Some patients with ABCA12-nEDD show GJB3-nEDD-like phenotypic features, such as well-demarcated noncongenital thickened erythematous plaques (Figure 4).¹³,⁹²,⁹³

Patients with two autosomal dominant (AD) nEDDs (NKPD1-nEDD and ASPRV1-nEDD) also have generalized

scaling from birth.⁴⁰,⁵⁰ KLK11-nEDD is another AD nEDD and presents with thickened scaly plaques and patchy scaling on the trunk, diffuse scaling on the extremities and PPK (Figure 3).⁹⁴,⁹⁵

Six nEDDs result from the combination of germline variants and somatic second-hit variants in the mevalonate/
<table><caption>**Table 2** (Continued)</caption><thead><tr><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>PERP-nEDD-AR</td><td>AD, AR</td><td>Infancy</td><td>PPK extending to the dorsal surface of the hands and feet (transgrediens), thickened erythematous plaques on the trunk, yellow hair and nail dystrophy. Recessive cases affect whole body. Susceptibility to cutaneous fungal infection</td></tr><tr><td>CDSN-nEDD</td><td>AR</td><td>Birth</td><td>Generalized superficial skin peeling with erythema, intractable pruritus, atopic diathesis</td></tr><tr><td>FLG2-nEDD</td><td>AR</td><td>Infancy</td><td>Superficial skin peeling without erythema, mainly involving the limbs, sparing the face and palmoplantar skin</td></tr><tr><td>CSTA-nEDD</td><td>AR</td><td>Infancy</td><td>Generalized or acral superficial skin peeling without erythema, rare reports of erythroderma at birth</td></tr><tr><td>SULT2B1-nEDD</td><td>AR</td><td>Birth</td><td>Collodion membrane, generalized desquamation with large dark scales</td></tr><tr><td>MVD-nEDD</td><td></td><td></td><td></td></tr><tr><td>MVK-nEDD</td><td>AD (all lesions result from combination of germline variants and somatic or postzygotic second-hit variants)</td><td>Birth, infancy to adolescence</td><td>Lesions presenting at birth are linear, pink-to-red and scaly; disseminated lesions present in adolescence or later, primarily on sun-exposed areas and featuring round-to-oval flat lesions with characteristic double-edge scales</td></tr><tr><td>PMVK-nEDD</td><td></td><td></td><td></td></tr><tr><td>FDPS-nEDD</td><td></td><td></td><td></td></tr><tr><td>SLC17A9-nEDD</td><td></td><td></td><td></td></tr><tr><td>FDFT1-nEDD</td><td></td><td></td><td></td></tr><tr><td>ALOX12B-nEDD</td><td>AR</td><td>Birth</td><td>Generalized mild scaling, collodion membrane at birth in some patients, prominent erythema, anterior overfolded ear deformity can be present at birth, sometimes self-improving</td></tr><tr><td>ALOXE3-nEDD</td><td>AR</td><td>Birth</td><td>Generalized mild scaling, collodion membrane at birth in some patients, sometimes self-improving</td></tr><tr><td>CYP4F22-nEDD</td><td>AR</td><td>Birth</td><td>Generalized mild scaling, but some cases are severe, can present with collodion membranes, sometimes self-improving</td></tr><tr><td>LIPN-nEDD</td><td>AR</td><td>Late-onset</td><td>Noncongenital generalized scaling</td></tr><tr><td>CERS3-nEDD</td><td>AR</td><td>Birth</td><td>Collodion membrane at birth, generalized fine scales and erythroderma</td></tr><tr><td>PNPLA1-nEDD</td><td>AR</td><td>Birth</td><td>Collodion membrane at birth, generalized mild scaling; more severe lamellar scaling is rare</td></tr><tr><td>SDR9C7-nEDD</td><td>AR</td><td>Birth</td><td>Fine semi-adherent greyish-white scales on the trunk and extremities, scaling over the knees and dorsal hands, PPK</td></tr><tr><td>NKPDI-nEDD</td><td>AD</td><td>Birth</td><td>Generalized mild lamellar scaling and mild PPK</td></tr></tbody></table>

(Continued)

cholesterol biosynthesis pathway genes (MVD-nEDD, MVK-nEDD, PMVK-nEDD, FDPS-nEDD, SLC17A9-nEDD and FDFT1-nEDD). Two distinct phenotypes may occur: (i) linear pink-to-red scaly lesions that appear at birth or in early infancy; and (ii) multiple flat disseminated round-to-oval lesions with characteristic double-edged scales that appear during adolescence or later, often on sun-exposed areas.²⁰⁻²² Generally, patients with what was formerly called porokeratosis have one germline variant in one of the disease-associated genes. If a second-hit variant occurs in that gene during embryonal development, it will cause localized lesions that can be seen from childhood. If second-hit

variants occur after adulthood, multiple disseminated small round-to-oval lesions appear, mainly on sun-exposed areas.

Two nEDDs, ATP2C1-nEDD and ATP2A2-nEDD, are due to abnormal differentiation and cell-cell adhesion of epidermal keratinocytes resulting from reduced function of keratinocyte Ca²⁺ pumps. Patients with ATP2C1-nEDD present with erythema, vesicles and erosions, mainly in intertriginous areas; disease often flares during bacterial, viral or fungal infections, which are common (Figure 4).¹⁷,¹⁸ Patients with ATP2A2-nEDD have follicular keratotic papules that often coalesce into plaques, usually begin during later childhood and are most commonly localized to the neck, forehead,
<table><caption>**Table 2** (Continued)</caption><tr><td>KDSR-nEDD</td><td>AR</td><td>Birth</td><td>Localized facial and genital thickened and scaly plaques with mild erythematous PPK, or severe collodion presentation at birth and subsequent generalized adherent scales. Intermittent thrombocytopenia and/or anaemia can be present</td></tr><tr><td>ABCA12-nEDD</td><td>AR</td><td>Birth</td><td>Phenotype can vary from mild to very severe, including – at birth – truncal fissured plate-like scales, severe ectropion and eclabium, resolving to severe scaly erythroderma. There can be shortening and webbing of the digits. Milder phenotypes can present at birth with collodion phenotypes or scaly erythroderma. Mild-to-severe ear deformities, hypercurvature of the nail plate and alopecia can be present. Some cases show a GJB3-nEDD-like phenotype, such as relatively fixed, well-demarcated, thickened and erythematous plaques that expand and contract in area, and transient erythematous, polycyclic macular patches</td></tr><tr><td>NIPAL4-nEDD</td><td>AR</td><td>Birth</td><td>Moderate-to-severe generalized scaling with no, mild or moderate erythema and PPK. Rarely presents with collodion membrane</td></tr><tr><td>SLC27A4-nEDD</td><td>AR</td><td>Birth</td><td>Thick, vernix-like covering at birth, especially on scalp, prematurity, neonatal respiratory distress, eosinophilia, persistent pruritus</td></tr><tr><td>SERPINB8-nEDD</td><td>AR</td><td>Childhood</td><td>PPK with skin peeling most prominent over the hands, feet and lower extremities</td></tr><tr><td>TGM1-nEDD</td><td>AR</td><td>Birth</td><td>Collodion presentation frequent at birth, mild fine scaling or severe dark-coloured large scaling, varying degrees of erythroderma. Some cases are self-improving and temperature-sensitive variants can manifest with bathing suit and scalp distribution. Ectropion and/or alopecia can be present</td></tr><tr><td>CASP14-nEDD</td><td>AR</td><td>Childhood</td><td>Generalized fine whitish scales, similar to FLG-nEDD</td></tr><tr><td>ASPRV1-nEDD</td><td>AD</td><td>Birth</td><td>Generalized large and plate-like scales with PPK, absent or mild erythema; some milder cases resemble FLG-nEDD</td></tr><tr><td>KLK11-nEDD</td><td>AD</td><td>Birth</td><td>Thickened scaly plaques and patchy scaling or diffuse scaling, PPK</td></tr><tr><td>GJB3-nEDD</td><td>AD, AR (rare)</td><td>Infancy</td><td></td></tr><tr><td>GJB4-nEDD</td><td>AD</td><td>Infancy</td><td>Relatively fixed well-demarcated thickened and erythematous plaques that expand and contract in area, and transient erythematous, polycyclic macular patches</td></tr><tr><td>GJA1-nEDD</td><td>AD</td><td>Infancy</td><td>Normal skin at birth, periorificial and intertriginous darkening, leuconychia, generalized or localized thickened erythematous plaques that expand and contract; most have PPK, some patients have hypotrichosis of scalp and eyebrows</td></tr></table>

(Continued)

scalp, central chest and intertriginous areas such as the axillae (Figure 4).¹⁹

CARD14-nEDD is commonly diagnosed as pityriasis rubra pilaris type V or psoriasis but occasionally has features (prominent facial involvement, ectropion and generalized involvement) that allow inclusion of this disorder as an nEDD.⁹⁶⁻⁹⁸ Patients with POMP-nEDD often present with generalized or localized skin thickening and erythema, linear keratotic papules on the antecubital and popliteal areas, and PPK.⁹⁹

## From new nomenclature to pathological and laboratory characteristics

Biopsied skin from individuals with nEDDs often shows nonspecific thickening of the stratum corneum in histological sections.¹ However, some nEDDs have distinctive histopathological findings that provide clues to diagnosis (Table 3). An example is the absence or thinning of granular layers, which is a characteristic pathological feature of FLG-nEDD.⁴⁷ Suprabasal epidermolysis and granular
<table><caption>**Table 2** (Continued)</caption><thead><tr><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td>ATP2C1-nEDD</td><td>AD</td><td>Late onset</td><td>Erythema, vesicles and erosions favouring skin folds but also present on other sites; susceptible to flares due to bacterial, viral and mycotic infections</td></tr><tr><td>ATP2A2-nEDD</td><td>AD</td><td>Typically onset childhood or later</td><td>Follicular keratotic papules coalescing into plaques, mainly localized on folds or seborrhoeic areas, palmar pitting, oral papules, papules on the dorsal hands, nail changes include red and white linear stripes, distal detachment from the nailbed with subungual hyperkeratosis, vegetations of the inguinal folds (especially in male patients), recurrent bacterial or viral infections</td></tr><tr><td>TRPM4-nEDD</td><td>AD</td><td>Infancy</td><td>Erythematous thickened plaques beginning on the distal extremities and progressing to involve the face, wrists and ankles, with sparing of the volar surfaces; slowly progressive, spontaneous remission after puberty</td></tr><tr><td>CARD14-nEDD</td><td>AD, AR (rare)</td><td>Infancy</td><td>Prominent facial involvement in children, pink-red coalescing plaques with areas of sparing, localized or generalized scaling and erythema; some individuals have joint pain and pustules can appear within plaques. Can have ectropion when severe</td></tr><tr><td>POMP-nEDD</td><td>AR</td><td>Birth</td><td>Generalized or localized skin thickening and erythema, PPK and keratotic papules in a linear arrangement, knee and elbow folds have thickening with a cerebriform appearance</td></tr></tbody></table>

See Table 1 for colour coding (the three rarest nEDDs are in bold). Important features used to define the disease are also highlighted in bold. AD, autosomal dominant; AR, autosomal recessive; PPK, palmoplantar keratoderma.

degeneration are observed in nEDDs associated with keratin gene variants (*KRT1*-nEDD-epidermolytic, *KRT1*-nEDD-annular, *KRT10*-nEDD-epidermolytic, *KRT10*-nEDD-annular, *KRT1*-nEDD-mosaic, *KRT10*-nEDD-mosaic, *KRT16*-nEDD-mosaic).⁵¹,⁵⁴⁻⁵⁷,⁵⁹⁻⁶¹ Some patients carrying classical *KRT1* or *KRT10* variants do not show epidermolytic changes on histology (*KRT1*-nEDD-nonepidermolytic and *KRT10*-nEDD-nonepidermolytic).¹⁰⁰ Two other keratinopathies (*KRT1*-nEDD-spiny and *KRT10*-nEDD-spiny) show extensive serrated thickening of the stratum corneum and prominent papillomatosis without epidermolysis.¹⁰¹,¹⁰² In *KRT2*-nEDD and *KRT2*-nEDD-mosaic, epidermolysis and granular degeneration are limited to the superficial epidermis.⁵³,⁵⁸ In *KRT1*-nEDD-revertant mosaic and *KRT10*-nEDD-revertant mosaic, perinuclear vacuolation and compact thickening of the stratum corneum are seen in lesional skin, with almost normal skin histologically in revertant spots.⁶³⁻⁶⁷

In these entities, bacterial and mycotic superinfections of the epidermis and thickened stratum corneum are common. Several other nEDDs are accompanied by microbiome changes with recurrent dermatophytosis. In particular, patients with *ATP2A2*-nEDD are susceptible to bacterial (staphylococcal and streptococcal) and viral (herpes simplex virus) infections.¹⁰³,¹⁰⁴

*CDSN*-nEDD often exhibits a psoriasiform histology, but sometimes superficial detachment of the horny layer and subcorneal erythrocytes are seen. *SERPINB8*-nEDD shows disadhesion of keratinocytes and widening of intercellular spaces in the basal and suprabasal layers of the epidermis.⁶⁸ In both *ATP2C1*-nEDD and *ATP2A2*-nEDD, acantholysis and

dyskeratosis are prominent in lesional epidermis.¹⁷⁻¹⁹ Six nEDDs are associated with variants in genes encoding proteins of the mevalonate pathway (*MVD*-nEDD, *MVK*-nEDD, *PMVK*-nEDD, *FDPS*-nEDD, *SLC17A9*-nEDD and *FDFT1*-nEDD); skin from patients with these disorders shares the histopathological feature of a parakeratotic column-cornoid lamella at the edge of lesions.²⁰⁻²²

Ultrastructurally, absence or defective formation of the cornified cell envelope and extracellular clefts are observed in the stratum corneum of patients with *TGM1*-nEDD.⁸¹,¹⁰⁵ In *ABCA12*-nEDD, lamellar granules without normal lamellar structures and prominent lipid vacuoles are seen in the granular layer cells and cornified cells, respectively.⁴¹,⁴²

## From the new nomenclature to diagnosis

From the data reviewed above, we have created a schematic diagnostic algorithm for each nEDD based on skin morphology and disease onset (congenital/noncongenital) (Figure 6).

## From new nomenclature to therapies

The new nomenclature is not only a naming system, but also a tool for advancing therapeutic strategies. Table 4 summarizes current and experimental therapies for nEDDs. Recent innovations include repurposed drugs, gene editing therapies and viral delivery systems.
<figure><img src="image_4.png" /><figcaption>**Figure 1** Neonatal appearance of different nonsyndromic epidermal differentiation disorders (nEDDs). (a) Translucent tight membrane causing ectropion and eclabium (formerly known as collodion baby). (b) A baby with erythroderma with fine desquamation (formerly known as congenital ichthyosiform erythroderma). This phenotype is observed in patients with several nEDDs, including *TGM1*-nEDD and *ABCA12*-nEDD. (c) A newborn baby presenting with large erosions in the perineal region, as is frequently seen in babies born with *KRT1*- and *KRT10*-nEDDs-epidermolytic. (d) Large plaques of thickened skin and deep fissures, ectropion and eclabium in a newborn baby with *ABCA12*-nEDD (formerly known as harlequin ichthyosis).</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 2** Representative clinical features of nonsyndromic epidermal differentiation disorders (nEDDs) due to anomalies/genetic variants in structural proteins of the epidermis. (a) *FLG*-nEDD: darker polygonal scaling is most pronounced on the lower leg in this patient with skin of colour. (b) *FLG*-nEDD: generalized fine scaling on the anterior aspect of the leg, which may appear slightly greyish on darker skin. (c) *FLG*-nEDD: keratosis pilaris. Folliculocentric keratotic papules on the outer aspect of the upper arm, frequently seen in patients with this disorder. (d) *FLG*-nEDD: palmoplantar hyperlinearity. Fine wrinkling (excessive skin lines) on the soles of the feet. (e) *FLG*-nEDD: palmoplantar hyperlinearity. Well-defined lines on the palm, which may appear more pronounced compared with healthy skin. The skin may also feel rough, with an overall thickened texture. (f) *PERP*-nEDD-AR: diffuse and rough thickening of the soles extending to the lateral aspects of the feet (classically referred to as *transgrediens*). Note the onychodystrophy of the first toenail on the left foot, as well as diffuse dark hyperpigmentation in the adjacent areas. (g) *CSTA*-nEDD: superficial peeling of the skin and erythema on the dorsum of the foot. (h) *FLG2*-nEDD: diffuse superficial skin peeling and erythema on the upper back and the shoulders. (i) *CDSN*-nEDD: diffuse erythema and superficial peeling of the skin leaving patchy areas of more pronounced erythema. AR, autosomal recessive.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Figure 3** Representative clinical features of nonsyndromic epidermal differentiation disorders (nEDDs) due to anomalies in structural proteins of the epidermis (continued). (a) *KRT10*-nEDD-epidermolytic: corrugated, dark scaling is seen on the arm, legs, feet and hand. (b) *KRT10*-nEDD-epidermolytic: corrugated thickening of the skin in the axillae. The skin in patients with this disorder can range in colour from pale to dark. (c) *KRT10*-nEDD-epidermolytic: diffuse thickening of the skin with a ridged or corrugated appearance on the antecubital folds, along with scattered erosions due to skin fragility. (d) *KRT10*-nEDD-epidermolytic: large corrugated dark scaling in a patient with skin of colour. (e) *KRT10*-nEDD-epidermolytic: corrugated thickening on the anterior wrist without palmar involvement. The absence of palmar thickening is typical in patients with *KRT10* variants. (f) *KRT10*-nEDD-annular: annular scaly plaque on the inner left ankle. These lesions show superficial epidermolysis and are often transient. (g) *KRT10*-nEDD-epidermolytic: warty focal thickening on the elbows. This morphology is also often present on the knees. Note the diffuse skin thickening in adjacent areas. (h) *KRT1*-nEDD-epidermolytic: diffuse erythema, severe skin thickening and scaling in the legs of a child. (i) *KRT1*-nEDD-epidermolytic: diffuse severe scaling and skin thickening on the thigh of an adult. (j) *KRT1*-nEDD-epidermolytic: severe thick scaling is seen in the soles and the lower legs. (k) *KRT1*-nEDD-epidermolytic: diffuse skin thickening and scaling with erythema in the neck and the shoulders of a child. (l) *KRT1*-nEDD-epidermolytic: rough diffuse thickening of the palm, commonly also present on the soles. (m) *KRT1*-nEDD-annular: annular superficial erythematous and scaly lesions on the lower abdomen, typically transient. (n) *KRT10*-nEDD-mosaic: severe grey skin thickening on the legs, following the lines of Blaschko. (o) *KRT2*-nEDD: mild greyish skin thickening on the trunk of a young boy. (p) *KRT2*-nEDD: diffuse thickening of the skin with areas of superficial detachment in a patient with a darker skin prototype. This typical appearance is due to the presence of epidermolysis in the upper layers of the stratum corneum. (q) *KRT2*-nEDD: close-up view of lesions showing patchy areas of superficial peeling (Mauserung phenomenon). (r) *KRT10*-nEDD-revertant (rev) mosaic: severe erythroderma with large, superficial scaling in a newborn baby with this condition (formerly known as ichthyosis with confetti). (s) *KRT10*-nEDD-revertant (rev) mosaic: severe erythroderma in a child with scattered lenticular areas of healthy-looking skin, reflecting revertant mosaicism. (t) *KRT10*-nEDD-revertant (rev) mosaic: multiple scattered normal-looking skin spots, reflecting revertant mosaicism, on severe erythroderma in an adult. (u) *KRT1*-nEDD-revertant (rev) mosaic: scattered normal-looking skin spots, reflecting revertant mosaicism are seen in the erythrodermic skin.</figcaption></figure>

## Repurposed drugs

Systemic retinoid is a current treatment of choice for several subtypes of nEDDs, particularly *TGM1*-nEDD and *ABCA12*-nEDD, during the neonatal period.¹⁰⁶ Topical high-dose vitamin D and calcipotriene have been used successfully in a number of nEDDs.¹⁰⁷⁻¹¹⁰ Topical cannabinoids, which mediate neuroendocrine responses in keratin expression, have shown promise in improving nEDD symptoms caused by *KRT1* variants.¹¹¹

Anti-inflammatory biologics have been investigated for the treatment of nEDDs, given the psoriasis-like immunophenotype in nEDDs.¹¹² To date, a double-blind randomized trial,

anecdotal reports and a large international series reporting the use of antibodies targeting interleukin (IL)-12/IL-23, IL-17A and IL-4/IL-13 receptor have shown limited-to-no value for *TGM1*-nEDD and *KRT10*-nEDD-epidermolytic, but they have shown promise for patients with more erythrodermic forms of nEDDs involving disruption of ceramide synthesis and transport, as well as several sEDDs.¹¹³ In a double-blind randomized placebo-controlled trial, secukinumab was not significantly more effective than placebo across the full spectrum of patients, half of whom had *TGM1*-nEDD or *KRT10*-nEDD-epidermolytic.¹¹⁴ More research is needed to determine which subtypes of nEDDs may benefit most from biologic therapies.⁸⁶,⁹⁸,¹¹³,¹¹⁵,¹¹⁶
<figure><img src="image_7.png" /><figcaption>**Figure 4** Representative clinical features of nonsyndromic epidermal differentiation disorders (nEDDs) due to anomalies in enzymes and molecules associated with cholesterol metabolism, ceramide synthesis and transport. (a) SULT2B1-nEDD: dry, scaly skin and postinflammatory hypopigmentation. (b) ALOX12B-nEDD: large adherent scales on the anterior aspects of the lower legs in a patient with a darker skin phenotype. (c) ALOX12B-EDD: erythema, smooth thickening and hyperlinearity (excessive wrinkling) on the palmar surface. (d) ALOXE3-nEDD: diffuse moderate scaling on the trunk. (e) CYP4F22-nEDD (mild involvement): skin thickening on the dorsal hands, with sparing of the trunk. (f) CYP4F22-nEDD: skin thickening and scaling on the dorsum of the hand. (g) CERS3-nEDD: erythroderma with minimal scaling. (h) NIPAL4-nEDD: reticulated scaling on the abdomen with a brownish hue, creating a pebblestone-like appearance. (i) PNPLA1-nEDD: sharply demarcated scaly erythema on the legs (formerly known as erythrokeratodermia variabilis et progressiva). (j) PNPLA1-nEDD: widespread scaling on the trunk and upper extremity, with mild underlying erythema. (k) SDR9C7-nEDD: brownish-hued scales on the anterior legs and knees. (l) ABCA12-nEDD: severe erythroderma with diffuse fine scaling in an infant. Visible signs of pruritus are evidenced by self-scratching. (m) ABCA12-nEDD: prominent erythema with extensive uniform scaling on the lower back and buttocks. (n) ABCA12-nEDD: joint deformity of the hand with lateral angulation of the wrist and visible restriction of the thumb mobility. Palms show diffuse thickening, scaling and superficial fissuring. (o) ABCA12-nEDD: ear deformity showing fusion of the retroauricular fold, resulting in an underfolded pinna accompanied by erythema and scaling. (p) SLC27A4-nEDD: this neonate was born prematurely weighing 1990g after ultrasound evaluation in the second trimester of pregnancy showed polyhydramnios. Severe respiratory distress was noted at birth and at day 1 of age, the thick caseous desquamating skin was noted on scalp, back and extremities.</figcaption></figure>
<figure><img src="image_8.png" /><figcaption>**Figure 5** Representative clinical features of nonsyndromic epidermal differentiation disorders (nEDDs) due to anomalies in miscellaneous enzymes and channels. (a) *TGM1*-nEDD: the large scales on the legs appear darker in a patient with a dark skin prototype compared with those seen in patients with lighter skin. (b) *TGM1*-nEDD: large, thickened adherent scales of a pale-brown hue in a patient with a light skin prototype (formerly referred to as lamellar desquamation). Underlying erythema of varying degrees is common. (c) *TGM1*-nEDD: a patient with a self-improving phenotype showing diffuse thickening of the dorsal hands with pronounced wrinkling. The texture is often rough and the fingers have a slight curvature due to poor skin elasticity. (d) *TGM1*-nEDD: in a patient with temperature-sensitive variants, large greyish scaling is confined to the bathing suit areas, corresponding to the warmer skin areas. (e) *TGM1*-nEDD: severe scaling and erythema on the fingers. (f) *TGM1*-nEDD: alopecia consisting of a recession of the hairline leaving a band of atrophic and shiny skin in a woman. (g) *ASPRV1*-nEDD: large lamellated scaling on the legs of a boy with skin of colour. (h) *ASPRV1*-nEDD: generalized large scales and erythema on the legs of a patient with a light skin phenotype. (i) *KLK11*-nEDD: diffuse erythema with scaling on the lower leg. (j) *CARD14*-nEDD: generalized scaling and erythema on the arm and the trunk. (k) *GJA1*-nEDD: young woman with variable inflamed or hyperpigmented plaques. (l) *GJB3*-nEDD: well-demarcated erythema with scaling on the lower extremities (formerly known as erythrotkeratodermia variabilis et progressiva). (m) *ATP2C1*-nEDD: Erythema and erosions in the inguinal skin folds. (n) *ATP2A2*-nEDD: follicular keratotic papules coalescing into plaques on the neck.</figcaption></figure>

## Treatment using revertant mosaic skin

This approach uses the patient's own naturally corrected cells to treat *KRT1*-nEDD-mosaic and *KRT10*-nEDD-mosaic. A recent study has shown that autografts of revertant epidermal keratinocytes can temporarily improve skin conditions in patients with *KRT1*-nEDD-revertant mosaic, offering a promising strategy.¹¹⁶ However, this approach has a number of limitations. Firstly, treatment using cultured epidermal autografts (CEAs) of revertant cells from mosaic normal-appearing skin regions can only be used in patients with mosaicism. Secondly, when CEAs from normal-appearing skin are grafted onto nEDD lesions, they may be replaced by cells carrying the original pathogenic variants if the latter have a selective survival advantage, as has been reported.¹¹⁶ Finally, because skin grafting is required, treatment is generally only applicable to limited areas.

## Gene editing therapy

CRISPR-Cas9 and other gene-editing techniques are being investigated for their potential to correct disease-causing variants.¹¹⁷ Animal models of gene-edited *FLG* have shown improvements in skin barrier function, offering hope for gene therapy in humans. Dang *et al.* describe the successful correction of the pathogenic variants in *TGM1* by adenine base editing in mutant embryos.¹¹⁸ However, significant challenges remain, particularly with regard to off-target effects and delivery of the gene editing machinery to target cells in the epidermis.

## Gene therapy delivered via viral vector

Gene therapy using viral vectors such as adenoviruses and lentiviruses has successfully corrected enzyme deficiencies in animal models of nEDDs. The hypothesis is that these
<table><caption>**Table 3** Distinctive pathological and laboratory features of the nonsyndromic epidermal differentiation disorders (nEDDs)</caption><thead><tr><td>Gene-based name</td><td>Pathological and laboratory features</td></tr></thead><tbody><tr><td>FLG-nEDD</td><td>Absence or thinning of granular layers, follicular plugging</td></tr><tr><td>KRT1-nEDD epidermolytic</td><td>Granular degeneration, perinuclear vacuoles, sometimes epidermolysis</td></tr><tr><td>KRT1-nEDD nonepidermolytic</td><td>Extensive serrated hyperkeratosis and prominent papillomatosis without epidermolysis</td></tr><tr><td>KRT1-nEDD-annular</td><td>Granular degeneration, perinuclear vacuoles, sometimes epidermolysis</td></tr><tr><td>KRT10-nEDD epidermolytic</td><td></td></tr><tr><td>KRT10-nEDD nonepidermolytic</td><td>Extensive serrated thickening of the stratum corneum and prominent papillomatosis without epidermolysis</td></tr><tr><td>KRT10-nEDD-annular</td><td>Granular degeneration, perinuclear vacuoles, sometimes epidermolysis</td></tr><tr><td>KRT2-nEDD-superficial</td><td>Granular degeneration and sometimes epidermolysis in superficial epidermis</td></tr><tr><td>KRT1-nEDD-mosaic</td><td>Granular degeneration, perinuclear vacuoles, sometimes epidermolysis</td></tr><tr><td>KRT2-nEDD-mosaic</td><td>Granular degeneration and sometimes epidermolysis in superficial epidermis</td></tr><tr><td>KRT10-nEDD-mosaic</td><td>Granular degeneration, perinuclear vacuoles, sometimes epidermolysis. Rare binuclear keratinocytes</td></tr><tr><td>KRT16-nEDD-mosaic</td><td></td></tr><tr><td>KRT1-nEDD-revertant mosaic</td><td>Perinuclear vacuolation, rare binucleate keratinocytes, compact thickening of the stratum corneum, with some cases showing parakeratosis; revertant spots show histological normal skin</td></tr><tr><td>KRT10-nEDD-revertant mosaic</td><td></td></tr><tr><td>CDSN-nEDD</td><td>If biopsied in the centre of the lesion: superficial detachment of the horny layer</td></tr><tr><td>MVD-nEDD</td><td>Thickening of the stratum corneum with a parakeratotic column, cornoid lamella, at the margin of lesions</td></tr><tr><td>MVK-nEDD</td><td></td></tr><tr><td>PMVK-nEDD</td><td></td></tr><tr><td>FDPS-nEDD</td><td></td></tr><tr><td>SLC17A9-nEDD</td><td></td></tr><tr><td>FDFT1-nEDD</td><td></td></tr><tr><td>KDSR-nEDD</td><td>Remarkable acanthosis, sparse-to-absent keratohyalin granules in the granular layer, parakeratosis</td></tr></tbody></table>

(Continued)

vectors will deliver functional copies of the mutated gene to keratinocytes, leading to the restoration of skin appearance and function. We consider the U.S. Food and Drug Administration's approval of B-VEC for treating dystrophic epidermolysis bullosa a milestone in the treatment of genodermatoses with promise for recessive forms of nEDDs.¹¹⁹ This platform incorporates the normal gene into a truncated inactivated herpes simplex viral vector, which is able to enter superficial keratinocytes to produce the full-length normal protein. The same viral platform (KB105) is being used to deliver full-length human *TGM1* to keratinocytes. In preclinical studies, KB105-infected, *TGM1*-deficient human

keratinocytes produced transglutaminase 1 (TGM1) protein and rescued enzyme function.¹²⁰ This *in vivo* approach showed no toxicity and restored TGM1 activity after topical application of KB105.¹²¹ However, the long-term safety and efficacy of viral gene therapy requires further investigation.

## Conclusion

We have comprehensively described the new classification and nomenclature of nEDDs based on a dyadic approach focusing on disease-associated gene defects. This new
<table><caption>**Table 3** (Continued)</caption><tr><td>ABCA12-nEDD</td><td>Ultrastructurally, malformed lamellar granules and lipid vacuoles are seen in the granular layer cells and in the corneocytes, respectively</td></tr><tr><td>SERPINB8-nEDD</td><td>Acanthosis, thickening of the stratum corneum, disadhesion of keratinocytes in the basal and suprabasal layers of the epidermis with intercellular space widening</td></tr><tr><td>TGM1-nEDD</td><td>Ultrastructurally, malformation of cornified cell envelope and cholesterol clefts within the stratum corneum are seen</td></tr><tr><td>ATP2C1-nEDD</td><td>Acantholysis and dyskeratosis</td></tr><tr><td>ATP2A2-nEDD</td><td></td></tr></table>

Only disorders with distinct pathological and laboratory features important for diagnosis are included in this table. See Table 1 for colour coding.

classification and nomenclature will promote recognition of these genetic disorders and potential therapeutic approaches by incorporating advanced understanding about the pathogenesis and pathophysiology of nEDDs. Adoption of the updated classification and nomenclature by patients, medical professionals and research scientists may facilitate consistent data gathering to understand the natural history of nEDDs, promote better communication and collaboration in the optimization of care, and lead to new treatment

strategies targeting causative genes, molecules and cellular dysfunction.

## Acknowledgements

We thank our patients for educating us about epidermal differentiation disorders and for those who consented to the use of their images. The authors acknowledge Pierre

<figure><img src="image_9.png" /><figcaption>**Figure 6** Diagnostic algorithm for nonsyndromic epidermal differentiation disorders (nEDDs): from key clinical and histopathological features to differential diagnoses. The various nEDDs are indicated by the gene symbol (red). A small number of exceptional cases of patients with nEDDs that fall outside this algorithm. <sup>a</sup>KRT2-nEDD is not always present at birth, but frequently manifests in infancy. N, no; pEDD, palmoplantar epidermal differentiation disorder; PPK, palmoplantar keratoderma; sEDD, syndromic epidermal differentiation disorder; Y, yes.</figcaption></figure>
<table><caption>**Table 4** Pathogenesis-driven approaches to therapies for nonsyndromic epidermal differentiation disorders (nEDDs)</caption><thead><tr><th>Gene-based name</th><th>Pathogenic mechanism and relevant new therapy or therapy expected in the future, if any</th></tr></thead><tbody><tr><td>FLG-nEDD</td><td>FLG deficiency: readthrough therapy for FLG nonsense variants<sup>a</sup></td></tr><tr><td>KRT-nEDDs</td><td>Disrupted normal keratin network: removal of variant proteins using small molecules, siRNA and repurposed drugs<sup>a</sup></td></tr><tr><td>PERP-nEDD</td><td>Defective desmosome formation</td></tr><tr><td>CDSN-nEDD</td><td>Defective corneodesmosomes due to corneodesmosin deficiency</td></tr><tr><td>FLG2-nEDD</td><td>Deficiency of FLG2 resulting in abnormal cell-cell adhesion in cornified cell layers</td></tr><tr><td>CSTA-nEDD</td><td>Deficiency of cystatin A, a cysteine protease inhibitor and also one of the precursor proteins of cornified cell envelope</td></tr><tr><td>SULT2B1-nEDD</td><td>SULT2B1 deficiency leads to absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol</td></tr><tr><td>MVD-nEDD</td><td>Reduction of end products of the mevalonate pathway, including cholesterol, and accumulation of toxic mevalonate metabolites:</td></tr><tr><td>MVK-nEDD</td><td>cholesterol and HMG-CoA reductase inhibitor topical therapy improve disease; there are reports of HMG-CoA reductase inhibitor therapy models<sup>a</sup></td></tr><tr><td>PMVK-nEDD</td><td></td></tr><tr><td>FDPS-nEDD</td><td></td></tr><tr><td>SLC17A9-nEDD</td><td></td></tr><tr><td>FDFT1-nEDD</td><td></td></tr><tr><td>ALOX12B-nEDD</td><td>Defective binding of esterified ω-hydroxyceramide to outer surface protein of cornified cell envelope, resulting in malformation of corneocyte lipid envelope</td></tr><tr><td>ALOXE3-nEDD</td><td></td></tr><tr><td>CYP4F22-nEDD</td><td>Defective formation of ultra-long-chain acylglucosylceramide</td></tr><tr><td>LIPN-nEDD</td><td>LIPN encodes lipase N, an acid lipase involved in triglyceride metabolism in the epidermis</td></tr><tr><td>CERS3-nEDD</td><td>Defective formation of ultra-long-chain acylglucosylceramide</td></tr><tr><td>PNPLA1-nEDD</td><td>Defective formation of ultra-long-chain acylglucosylceramide</td></tr><tr><td>SDR9C7-nEDD</td><td>Defective binding of esterified ω-hydroxyceramide to outer surface protein of cornified cell envelope, resulting in malformation of corneocyte lipid envelope</td></tr></tbody></table>

(Continued)

Fabre for supporting the in-person meeting to finalize the classification.

## Funding sources

ERN-Skin funded an early in-person meeting for the initial planning group in 2023. Pierre Fabre funded a multiday in-person meeting for the authors to finalize the classification in 2024, which included an honorarium for C.G.T. to support compilation of references and illustrations. Pierre Fabre did not participate in the discussions or otherwise influence the classification. Comitato UFFI United Fighting for Ichthyosis provided a grant of support to G.T.

## Conflicts of interest

A.G. holds stock in GSK, Novo Nordisk, Novartis, UCB and Sandoz; has been a paid consultant/advisory board member/speaker for LEO Pharma, Sanofi, Novartis, UCB, AbbVie, BMS, Pfizer and Almirall; has received grants from La Roche Posay and the LEO Foundation; and has been a patient advisor for the Pachyonychia Congenita (PC) Project. A.H. has provided consultancy/been on advisory boards for Boehringer Ingelheim and Kamari Pharma; has received research grants from Daiichi-Sankyo, Sixera Pharma, CureEB, EB Research Partnership, the PC Project and Association Ichtyose France (AIF); and has been a
<table><caption>**Table 4** (Continued)</caption><tr><td>NKPDI-nEDD</td><td>Defective ceramide metabolism and skin barrier formation</td></tr><tr><td>KDSR-nEDD</td><td>Defective formation of dihydrospingosine, resulting in deficiency of ultra-long-chain acylglucosylceramide</td></tr><tr><td>ABCA12-nEDD</td><td>Defective glucosylceramide secretion via lamellar granules</td></tr><tr><td>NIPAL4-nEDD</td><td>Loss-of-function of NIPAL4, a putative Mg<sup>2+</sup> transporter, leads to a failure of differentiation-dependent gene expression in keratinocytes, resulting in a defective acylceramide synthesis</td></tr><tr><td>SLC27A4-nEDD</td><td>Loss-of-function of solute carrier family 27 member 4 (fatty acid transporter protein) leads to a failure of CoA addition to ultra-long-chain fatty acids, resulting in a defective ultra-long-chain ceramide synthesis</td></tr><tr><td>SERPINB8-nEDD</td><td>Deficiency of SERPINB8 leads to mechanical instability of intercellular adhesions in the epidermis: kallikrein inhibitors may be efficient<sup>a</sup></td></tr><tr><td>TGM1-nEDD</td><td>Malformation of cornified cell envelope: topical application of HSV type 1 vector encoding TGM1<sup>a</sup></td></tr><tr><td>CASP14-nEDD</td><td>Loss-of-function of CASP14 leading to defective degradation of FLG and aberrant maturation of saposin A, a sphingolipid activator, resulting in malformation of the skin barrier</td></tr><tr><td>ASPRV1-nEDD</td><td>Aberrant filaggrin processing due to defective ASPRV1, a stratified epithelia-specific protease</td></tr><tr><td>KLK11-nEDD</td><td>Secretion deficiency of KLK11, a kallikrein-related peptidase associated with skin desquamation by degrading corneodesmosomes</td></tr><tr><td>GJB3-nEDD</td><td>Dysfunction of gap junction: removal of causative variant connexin molecules using small molecules, siRNA or antibodies<sup>a</sup></td></tr><tr><td>GJB4-nEDD</td><td></td></tr><tr><td>GJA1-nEDD</td><td></td></tr><tr><td>ATP2C1-nEDD</td><td>Reduced function of keratinocyte Ca<sup>2+</sup> pump, resulting in abnormal differentiation and cell-cell adhesion of epidermal keratinocytes</td></tr><tr><td>ATP2A2-nEDD</td><td></td></tr><tr><td>TRPM4-nEDD</td><td>Gain-of-function of a Ca<sup>2+</sup>-activated monovalent cation channel, TRPM4</td></tr><tr><td>CARD14-nEDD</td><td>Hyperactivation of NFκB and MAPK leading to inflammation: ustekinumab and Th17 inhibitors work well<sup>a</sup></td></tr><tr><td>POMP-nEDD</td><td>Proteasome insufficiency</td></tr></table>

See Table 1 for colour coding. The three rarest nEDDs are in bold. Currently available or promising future treatments are also highlighted in bold. ASPRV1, retroviral-like aspartic protease 1; CoA, coenzyme A; CASP14, caspase 14; FLG, filaggrin; HMG-CoA, β-hydroxy β-methylglutaryl CoA; HSV, herpes simplex virus; KLK11, kallikrein-related peptidase 11; MAPK, mitogen-activated protein kinase; NIPAL4, magnesium transporter NIPA4 isoform 1; SERPINB8, Serpin family B member 8; siRNA, small interfering RNA; SULT2B1, Sulfotransferase family 2B member 1; Th, T helper cell; TRPM4, Transient receptor potential cation channel subfamily M member 4. <sup>a</sup>Relevant new therapy or therapy expected in the future.

patient advisor for the PC Project. A.H.-M. has been an investigator for Mayne Pharma and Celgene; has been a consultant/on advisory boards for Sanofi, Viatris, Almirall, Galderma and L'Oréal; and has been a speaker for Sanofi, Viatris, L'Oréal, Leti Pharma and Beiersdorf. A.S.P. has been an investigator for AbbVie, Applied Pharma Research, Biomendics, Dermavant, Eli Lilly, Incyte, Janssen, Krystal, Regeneron, Timber and UCB; has been a consultant/on advisory boards for Abeona, Apogee, Arcutis, ASLAN, BioCryst, Boehringer Ingelheim, Castle Creek, Bristol Myers Squibb, Dermavant, Incyte, Krystal, LEO Pharma, L'Oréal, Mitsubishi Tanabe, MoonLake Immunotherapeutics, Procter and Gamble, Regeneron, Sanofi, Seanergy and UCB; has been on data safety monitoring boards (DSMBs) for AbbVie, Abeona and Galderma; and has been a patient

advisor for the Foundation for Ichthyosis & Related Skin Types (FIRST; Chair, Medical and Scientific Advisory Board) and the International Pachyonychia Congenital Consortium. C.B. has been an investigator for Sanofi, Pfizer, AbbVie, Boehringer Ingelheim, Amryt, Reacell, Krystal, Novartis, Pierre Fabre and Timber Pharmaceuticals; has been a consultant/on advisory boards for Sanofi, AbbVie, Boehringer Ingelheim and Amryt (Chiesi); and has been a speaker for Boehringer Ingelheim, Amryt (Chiesi), Krystal and Alexion. C.G.T. received an honorarium for providing support for this paper. E.A.O.T. has been an investigator for Kamari Pharma and Palvella Therapeutics; a consultant/on advisory boards for Kamari Pharma, Palvella Therapeutics and Azitra; has received research grants from Unilever, the LEO Foundation and Kamari Pharma (all money paid to university/
hospital); and has been a patient advisor for the PC Project and Ichthyosis Support Group (ISG). E.S. has been a consultant/on advisory boards for Kamari Pharma, Amryt and SolGel (all money paid to hospital); and has been a patient advisor for the PC Project. G.T. received a grant from the UFFI Society (United for fighting Ichthyoses) relevant to this paper. J.M.-H. has been an investigator for Mayne and Timber Pharmaceuticals. J.S. is Executive Director of the PC Project. J.M.C.T. has been an investigator for Castle Creek, LEO Pharma, Novartis, Palvella Therapeutics, Pfizer, Regeneron, Syneos, Timber Pharmaceuticals and Twi Biotech; has been a consultant/on advisory boards for Abeona, AFT, Amryt, AUCTA, Biocryst, Bridge Bio, Castle Creek, Coterie, GLG, Guide Point, Innova, Kamari, KrystalBio, LEO Pharma, Lifemax Menlo Therapeutics, Mitsubishi, NobelPharm, Novartis, Palvella Therapeutics, Pfizer, Pierre Fabre, Regeneron, Syneos, Timber Pharmaceuticals, Topicals and Twi Biotech; has been a patient advisor for the Gorlin Syndrome Alliance, the TSC Alliance, FIRST and the PC Project; and has received royalties from GeneReview, UpToDate and Springer Publishing. K.C. has been an investigator for AbbVie, Boehringer Ingelheim and Regeneron; has been a consultant/on advisory boards for Mitsubishi Tanabe, Biocryst, Kamari Pharma, Resvita and Timber Pharmaceuticals; and has been a patient advisor for FIRST. M.A. has been a paid advisory board member/speaker for Boehringer Ingelheim, Maruho Co., Ltd. and Sanofi K.K.; and has received research grants from Boehringer Ingelheim, Novartis Pharma K.K. and Maruho Co., Ltd. M.A.-E. is an employee of ISG. M.S. has been an investigator for AbbVie, Clinuvel, Incyte and MSD; has received research grants from the Austrian Science Fund, the European Union, El Cure and the PC Project (all money to university/hospital); has been on a DSMB paid for by Biontech; and has been a patient advisor for El Cure and FIRST. A.I.-Y., J.F. and K.M. declare no conflicts of interest.

## Data availability

No new data were generated or analysed in support of this research.

## Ethics statement

All clinical photographs were obtained with the written informed consent of the patients.

## Patient consent

Written patient consent for publication was obtained.

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# Appendix 1

## Complete list of author affiliations

Masashi Akiyama,¹ Keith Choate,² Ángela Hernández-Martín,³ Mandy Aldwin-Easton,⁴ Christine Bodemer,⁵ Antoni Gostyński,⁶,⁷ Alain Hovnanian,⁸,⁹ Akemi Ishida-Yamamoto,¹⁰ Kiril Malovitski,¹¹,¹² Edel A O'Toole,¹³ Amy S Paller,¹⁴ Matthias Schmuth,¹⁵ Janice Schwartz,¹⁶ Eli Sprecher,¹¹,¹² Joyce M C Teng,¹⁷ Céline Granier Tournier,¹⁸ Juliette Mazereeuw-Hautier,¹⁸ Gianluca Tadini¹⁹ and Judith Fischer²⁰

¹Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

²Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

³Department of Dermatology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain

⁴Ichthyosis Support Group, Earley, Reading, UK

⁵Department of Dermatology, Reference Centre for Genodermatoses, AP-HP, Hôpital Necker-Enfants Malades, Paris Cité University, Paris, France

⁶Department of Dermatology, Maastricht University Medical Center, Maastricht, the Netherlands

⁷GROW Research Institute for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands

⁸INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute of Genetic Diseases, University Paris Cité, Paris, France

⁹Department of Genomic Medicine of Rare Diseases, AP-HP, Hôpital Necker-Enfants Malades, Paris, France

¹⁰Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan

¹¹Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

¹²Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel

¹³Department of Dermatology, Royal London Hospital and Blizard Institute, Queen Mary University of London, London, UK

¹⁴Northwestern University Feinberg School of Medicine and Ann and Robert H. Lurie Children's Hospital, Chicago, IL, USA

¹⁵Department of Dermatology, Medical University Innsbruck and Karl Landsteiner Institute for Pediatric Dermatology and Rare Diseases, Innsbruck, Austria

¹⁶Pachyonychia Congenita Project, Holladay, UT, USA

¹⁷Department of Dermatology, Stanford University School of Medicine, Palo Alto, CA, USA

¹⁸Reference Center for Rare Skin Diseases, Dermatology Department, CHU Toulouse, Paul Sabatier University, Occitanie, Toulouse, France

¹⁹Center for Cutaneous Inherited Diseases, Pediatric Dermatology, Fondazione Ospedale Maggiore Policlinico Milano, University of Milan, Milan, Italy

²⁰Institute of Human Genetics, Medical Center, Faculty of Medicine and Center for Cornification Disorders, Freiburg Center for Rare Diseases, Medical Center, University of Freiburg, Freiburg, Germany
<figure><img src="image_10.png" /></figure>

NO COMPROMISE,
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Bimzelx®▼ (bimekizumab) offers
the opportunity for complete, fast,
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proven PsA efficacy ¹⁻⁷

<figure><img src="image_11.png" /></figure>

of patients
with PsO achieved
**PASI 100 at Week 16**

(vs 1.2% placebo [n=1/86], p<0.0001)***²

<figure><img src="image_12.png" /></figure>

of patients
with PsO achieved
**PASI 75 at Week 4**

(vs 1.2% placebo [n=1/86], p<0.0001)***²

<figure><img src="image_13.png" /></figure>

of patients
with PsO achieved
**PASI 100 at 5 years³**

<figure><img src="image_14.png" /></figure>

of biologic-naïve
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achieved **ACR 50 at
Week 104/100**, respectively¹,⁴⁻⁶

BIMZELX was well tolerated, the most frequently reported adverse reactions were: upper respiratory tract infections and oral candidiasis. Other common reported adverse reactions include tinea infections, ear infections, herpes simplex infections, oropharyngeal candidiasis, gastroenteritis, folliculitis, headache, rash, dermatitis, eczema, acne, injection site reactions, fatigue, and vulvovaginal mycotic infection (including vulvovaginal candidiasis).⁴

This promotional material has been created and funded by UCB Pharma Ltd and is intended for healthcare professionals in the UK.

BIMZELX is indicated for the treatment of: moderate to severe plaque PsO in adults who are candidates for systemic therapy; active PsA, alone or in combination with methotrexate, in adults who have had an inadequate response, or who have been intolerant, to one or more DMARDs, active nr-axSpA with objective signs of inflammation as indicated by elevated CRP and/or MRI, in adults who have responded inadequately, or are intolerant, to NSAIDs, active AS in adults who have responded inadequately or are intolerant to conventional therapy; and active moderate to severe HS (acne inversa) in adults with an inadequate response to conventional systemic HS therapy.⁴

Prescribing information for United Kingdom click here.
Please refer to the SmPC for further information.

These data are from different clinical trials and cannot be directly compared.

Co-primary endpoints PASI 90 and IGA 0/1 at Week 16 were met.**Secondary endpoints: 1N= mNRI, missing data were imputed with mNRI (patients with missing data following treatment discontinuation due to lack of efficacy or a TRAE were counted as non-responders; multiple imputation methodology was used for other missing data). †43.9% (n=189/431), and 43.4% (n=116/267) of biologic-naïve and TNFi-IR PsA patients achieved the primary endpoint of ACR 50 at Week 16 in BE OPTIMAL and BE COMPLETE, respectively (vs 10.0% [n=28/281] and 6.8% [n=9/133] placebo, p<0.0001); 54.5% (n=235/431) and 51.7% (n=138/267) maintained it at Week 52 (NRI).⁴⁻⁶

**ACR 50**, ≥50% response in the American College of Rheumatology criteria, **AS**, ankylosing spondylitis, **CRP**, C-reactive protein, **DMARD**, disease-modifying antirheumatic drug, **HS**, hidradenitis suppurativa, **IGA**, Investigator's Global Assessment, **(m)NRI**, (modified) non-responder imputation, **MRI**, magnetic resonance imaging, **nr-axSpA**, non-radiographic axial spondyloarthritis, **NSAID**, non-steroidal anti-inflammatory drug, **PASI 75/90/100**, ≥75/90/100% improvement from baseline in Psoriasis Area and Severity Index, **PsA**, psoriatic arthritis, **PsD**, psoriatic disease, **PsO**, psoriasis, **TNFi-IR**, tumour necrosis factor-α inhibitor – inadequate responder, **TRAE**, treatment-related adverse event.

**References:** 1. Gordon KB, et al. Lancet. 2021;397(10273):475-486. 2. Blauvelt. 2025. AAD Presentation 62275. 3. Mease PJ, et al. Rheumatol Ther. 2024;11(5):1363-1382. 4. BIMZELX SmPC. 5. Ritchlin CT, et al. Ann Rheum Dis. 2023;82(11):1404-1414. 6. Coates LC, et al. RMD Open. 2024;10(1):e003855. 7. Strober B, et al. AAD 2024;oral presentation.

▼This medicine is subject to additional monitoring. This will allow quick identification of new safety information. Adverse events should be reported.

Reporting forms and information can be found at www.yellowcard.mhra.gov.uk for the UK. Adverse events should also be reported to UCB Pharma Ltd at UCBCares.UK@UCB.com or 0800 2793177 for UK.

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Inspired by patients.
Driven by science.

Bimzelx®▼
(bimekizumab)