EEC Syndrome and Other TP63-Related Disorders

An allelic family of ectodermal dysplasias, limb malformations and orofacial clefts caused by heterozygous variants in the TP63 gene: EEC3 syndrome, AEC syndrome (Hay-Wells, which includes Rapp-Hodgkin syndrome), ADULT syndrome, limb-mammary syndrome, split-hand/foot malformation type 4, isolated orofacial cleft type 8 and premature ovarian insufficiency type 21.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

TP63-related disorders form a syndromic class: a single gene, seven phenotypes with their own OMIM (Online Mendelian Inheritance in Man) number and a clinical overlap so extensive that the same variant can produce differently named phenotypes within one family [1–3].

1. Introduction

1.1. Historical overview

The association between split hand or foot and cleft lip was observed long before its common basis was understood. The first description is attributed to Eckhold and Marten in 1803, and in 1936 Cockayne published a family with cleft palate, harelip, dacryocystitis and split hands and feet [5, 21]. In 1963 Walker and Clodius described three pedigrees combining split hand/foot and cleft lip/palate, suggesting irregular dominant inheritance [12]. In 1970 Rüdiger, Haase and Passarge recognised that some of these patients also had ectodermal dysplasia and proposed the name EEC syndrome, from the initials of ectrodactyly, ectodermal dysplasia and clefting, in a girl with ectrodactyly of both hands and one foot, ectodermal dysplasia with severe keratitis and cleft lip/palate [12, 22]. Bixler and colleagues added cases in 1972, and the Brazilian series of Rodini and Richieri-Costa (1990), with 20 patients, contributed to the clinical and genetic delineation of the syndrome [5]. In 1995 Buss and colleagues gathered 24 cases in a national study in the United Kingdom, and in 1996 Roelfsema and Cobben analysed 230 published cases, 116 familial and 114 sporadic, establishing reference frequencies for the manifestations and a penetrance between 93% and 98% [12, 23].

The line of ectodermal dysplasias with clefting followed a parallel path. In 1968 Rapp and Hodgkin described a mother and two children with anhidrotic ectodermal dysplasia, cleft lip and cleft palate, a narrow nose and a small mouth, a combination not previously recorded [24, 25]. In 1976 Hay and Wells published seven patients from four families with ankyloblepharon filiforme adnatum, ectodermal defects (partial or total hair loss, absent or dystrophic nails, pointed and widely spaced teeth, partial anhidrosis) and cleft lip/palate, with autosomal dominant transmission [26]. The overlap between the two entities was debated from 1994, when Cambiaghi and colleagues asked whether they were the same disease [27]. In 1993 Propping and Zerres described a German family with at least seven living affected members, hypodontia or early loss of permanent teeth, ectrodactyly, lacrimal obstruction, onychodysplasia and excessive freckling, for which they coined the acronym ADULT (acro-dermato-ungual-lacrimal-tooth) [28]. In 1999 van Bokhoven and colleagues described limb-mammary syndrome in a large nine-generation Dutch family, with severe anomalies of the hands and feet and hypoplasia or aplasia of the mammary gland and nipple, and mapped it to 3q27 with a maximum lod score of 12.01 [29, 30].

1.2. Milestones of molecular discovery

The mapping of limb-mammary syndrome to 3q27 was the starting point. In 1999 Celli and colleagues, in Nijmegen, showed that five families with EEC syndrome were linked to the same 3 cM interval and identified, in the p63 gene, a p53 homologue located in that interval, heterozygous variants in nine unrelated families: eight amino acid substitutions predicted to abolish DNA binding and one frameshift affecting the α isoform but not the β and γ isoforms; six of the nine were C>T transitions at CpG dinucleotides, and transactivation studies explained the dominant character [2, 31]. In 2000 Ianakiev and colleagues demonstrated p63 variants in families with isolated split-hand/foot malformation (SHFM4) [32]. Three decisive publications followed in 2001: van Bokhoven and colleagues found p63 variants in 40 of 43 patients or families with EEC, concentrated at codons 204, 227, 279, 280 and 304 of the historical numbering, but in only 4 of 35 cases of isolated split hand/foot, and described frameshifts in exons 13 and 14 in two families with limb-mammary syndrome [33]; McGrath and colleagues identified missense variants in the SAM (sterile alpha motif) domain in eight families with Hay-Wells syndrome [34]; and Amiel and colleagues described the first TP63 variant in ADULT syndrome [35]. Propping and colleagues had shown in 2000 that the original ADULT family was linked to 3q27 (lod score 4.82), which made the two syndromes allelic [36].

Rapp-Hodgkin syndrome was linked to TP63 in 2003 by Kantaputra and colleagues, with the de novo variant S545P (historical numbering, = NM_003722.5:c.1738T>C p.(Ser580Pro); ClinVar 6545, pathogenic) in the SAM domain in a Thai boy, and in the same year by Bougeard and by Dianzani, the latter in a family in which the mother had had mild ankyloblepharon corrected at birth [25, 37, 38]. In 2006 Leoyklang and colleagues found the variant R313G (historical numbering, = NM_003722.5:c.1054A>G p.(Arg352Gly); ClinVar 6547, classified as of uncertain significance) de novo in a Thai child with non-syndromic cleft lip, the first evidence of TP63 in isolated clefting [38–40]. In 2006 Rinne and colleagues published the update on 227 patients with p63 variants, which established at least six allelic syndromes and showed that five recurrent variants accounted for almost 90% of patients with EEC [41]. Isolated premature ovarian insufficiency was associated with TP63 in 2019 by Tucker and colleagues, with nonsense variants in the last exon [42], and became OMIM entry 620311 after work published in 2022 and 2023 [11, 43, 44].

1.3. Nomenclature and reclassifications

The nomenclature of this class has accumulated historical designations that are worth knowing in order to read the literature. The abbreviation EEC1 (OMIM 129900) designates the form linked to 7q11.2–q21.3, proposed on the basis of eight reports of EEC syndrome with chromosome 7 anomalies and a Japanese family with a t(7;9)(q11.21;p12) translocation; the gene for this form remains unidentified and the region coincides with the SHFM1 locus (DLX5/DLX6) [1, 12]. The abbreviation EEC2 designated a Dutch family linked to chromosome 19 by O'Quinn and colleagues in 1998; van Bokhoven and colleagues later found the TP63 variant R227Q in that family, the linkage to chromosome 19 was considered fortuitous and OMIM entry 602077 was moved to 604292 [45, 46]. The abbreviation EEC3 (604292) designates the form caused by TP63. The Bone Dysplasias atlas places the EEC2 family at 9p13–q13, which matches neither the original publication nor OMIM; the 9p12 location appears in the t(7;9) translocation associated with EEC1 [12, 47].

Hay-Wells and Rapp-Hodgkin syndromes are now treated as variable expressions of a single disease, AEC syndrome, because they share variants (three identical among 42 variants described by 2010, for example I510T (historical numbering, = NM_003722.5:c.1646T>C p.(Ile549Thr)), found in one patient with AEC and in another with RHS) and because ankyloblepharon, the feature that distinguished them, is often subtle, transient and lyses before it is recognised [1, 25, 48, 49]. In 2010 Clements and colleagues proposed abandoning the eponyms in favour of “AEC syndrome” [48]. Orphanet followed this merger: code ORPHA:3022 (Rapp-Hodgkin syndrome) and ORPHA:1888 (ectodermal dysplasia with ectrodactyly without clefting, OMIM 129810) were listed as inactive when consulted in October 2026, whereas ORPHA:1071 (AEC) and ORPHA:1072 (ankyloblepharon filiforme adnatum with cleft palate, a clinical subtype) remain active [50–52]. Some sources contain errors that should not be reproduced: the Oxford Desk Reference places TP63 at 7q21–22, which confuses the gene with the EEC1 locus [53]; the founding publications use 3q27, whereas the current cytoband in OMIM and NCBI is 3q28 [2, 31]; GeneGuidance assigns orofacial cleft type 8 to number 129400, which belongs to Rapp-Hodgkin syndrome [14]; and some case reports assign number 129900 (EEC1) to EEC caused by TP63 [7].

1.4. Definition of the entities

EEC3 syndrome is defined by the combination, in variable proportions, of malformation of the central rays of the hands and feet (from syndactyly to tetramelic split hand/foot), ectodermal dysplasia, cleft lip with or without cleft palate and anomalies of the lacrimal system, in a patient with a pathogenic TP63 variant; no single sign, including ectrodactyly, is mandatory [1, 5, 47]. AEC syndrome is defined by the triad of ankyloblepharon filiforme adnatum, ectodermal defects and cleft lip and/or palate, with neonatal and scalp skin erosions as its own distinctive feature [1, 6]. ADULT syndrome combines ectrodactyly or syndactyly, excessive freckling, breast hypoplasia and other ectodermal changes, without orofacial cleft [8, 54]. Limb-mammary syndrome combines severe anomalies of the hands and feet with breast and nipple hypoplasia, ectodermal changes mainly of the teeth and nails and variable cleft palate, without skin and hair changes [9, 30]. SHFM4 is isolated split-hand/foot malformation due to TP63, in which ectodermal dysplasia and orofacial cleft are exclusion criteria [1]. Orofacial cleft type 8 is cleft lip with or without cleft palate without other signs of TP63 disease [1, 55]. Premature ovarian insufficiency type 21 is loss of ovarian function before the age of 40 years, with amenorrhoea and raised follicle-stimulating hormone (FSH), due to variants that constitutively activate the oocyte TAp63α isoform [11, 43, 44].

1.5. Current classifications

Four classification systems coexist. GeneReviews groups six overlapping phenotypes (AEC with RHS, ADULT, EEC3, limb-mammary, SHFM4 and orofacial cleft type 8) and does not include ovarian insufficiency, which it regards as absent from the list of known germline phenotypes [1]. OMIM records eight phenotypes linked to the gene, counting AEC and RHS separately and including POF21 [2]. GeneGuidance notes that POF21 has a strong or moderate GenCC classification, which makes the omission in GeneReviews a matter of being out of date rather than a scientific divergence [14]. The classification of ectodermal dysplasias agreed at the 2017 international panel at the NIH (National Institutes of Health) defines these conditions as genetic disorders affecting the development or homeostasis of two or more ectodermal derivatives (hair, teeth, nails, certain glands) and catalogues them by molecular pathway, the p63 pathway being one of the three main ones, alongside the EDA/NF-κB and WNT pathways [56]. The first five-yearly update, in 2022, added the attribute “congenital” to the definition and lists ADULT, EEC, limb-mammary syndrome and AEC with RHS under the p63 pathway, together with ectodermal dysplasia, ectrodactyly and macular dystrophy caused by CDH3 [57]. The clinical classification of Freire-Maia, developed in Brazil in the 1970s, separated group A (at least two of hair, teeth, nails and sweat glands) from group B (one of these plus another ectodermal tissue, such as the mammary gland), and is still cited as a historical antecedent [56]. Lamartine's functional classification of 2003 placed p63 in the subgroup of transcription regulators [58].

2. Molecular Genetics and Pathophysiology

2.1. The TP63 gene, its promoters and isoforms

The TP63 gene (OMIM 603273) lies at 3q28 and encodes the p63 protein, a transcription factor of the p53 family [2, 14]. Its organisation explains much of the clinical diversity of the class. Two alternative promoters produce isoforms with different amino termini: the TA isoforms, with a complete transactivation domain, and the ΔN isoforms, which start at an alternative exon and lack that domain; alternative splicing of the carboxy terminus generates, in each, the α, β and γ variants (as well as δ and ε) [14]. The MANE Select transcript is NM_003722.5 (transcript variant 1, TAp63α), which encodes the protein NP_003713.3 of 680 amino acids; NM_001114980.2 encodes ΔNp63α (NP_001108452.1), of 586 amino acids, 94 fewer than TAp63α [13]. GeneReviews describes ΔNp63α as “39 amino acids shorter” and cites transcript NM_001114982.1; checking the RefSeq databases shows that NM_001114982.1 corresponds to variant 6 (393 amino acids) and that the 39-amino-acid difference is the one separating the two historical TA sequences (GenBank AF075430 and AF091627), not TA from ΔN [1, 13, 59]. This 39-residue difference is the source of almost all numbering discrepancies in the literature.

The ΔNp63α isoform predominates in stratified epithelia: the ΔN promoter is the only one active in epidermal cells throughout stratification and in many epithelia, including skin, oral tissues and mammary gland [1]. The TA isoform is expressed at low levels in other tissues: in oocytes, where it eliminates cells with DNA damage; in the cochlea, where it regulates the Notch pathway; in late myogenesis; and in cardiomyocyte development [1, 14]. From amino to carboxy terminus the protein has a transactivation domain (absent from the ΔN forms, which have their own alternative transactivation domain), the DNA-binding domain (DBD), an oligomerisation region that allows the formation of dimers and tetramers, the SAM domain, which mediates protein-protein interactions, and the transactivation inhibitory domain (TID), present only in the α isoforms, which keeps TAp63α in an inactive dimer [1, 11, 18, 43].

2.2. Role in ectodermal and limb development

p63 is a master regulator of ectodermal cell commitment and differentiation and maintains the stem and progenitor cell compartments of epithelia [1, 57]. Mice lacking p63 are born with limb truncation, craniofacial defects and absence of all squamous epithelia and their derivatives, including the mammary, lacrimal and salivary glands; limb truncation results from failure to maintain the apical ectodermal ridge of the limb bud [2]. In the apical ridge, p63 activates DLX5, DLX6 and FGF8; DBD variants associated with EEC and SHFM4 reduce activation of the DLX5 and DLX6 promoters, which mechanistically links SHFM4 to SHFM1, caused by DLX5 itself [2, 60]. p63 also regulates IRF6, the Van der Woude syndrome gene, in a feedback loop relevant to cleft lip, and directly or indirectly induces RIPK4 and EDAR, which explains the interconnection with the EDA/NF-κB pathway of the hypohidrotic ectodermal dysplasias [56, 57, 60].

In the epidermis, ΔNp63α maintains cell adhesion, favours early and inhibits late markers of differentiation, modulates Notch1-dependent transcription and determines epidermal identity [18]. Its direct targets include FRAS1 (extracellular matrix and basement membrane), IKKα (terminal differentiation), PERP (a desmosomal protein whose absence in mice causes postnatal lethality above 95% in the first week, oral and cutaneous blisters and severe infections in survivors) and ZNF750, KLF4 and GRHL3, factors of epidermal differentiation [2, 18, 61]. The SAM domain of p63 interacts with ABBP1, a protein that favours epithelial K-SAM splicing of FGFR2, and with SCAF4; AEC variants abolish these interactions [18]. In eroded and intact skin of patients with AEC, expression analysis showed reduced FRAS1, collagen VII, cornified envelope proteins (SPRR1A, SPRR4, LCE5A, hornerin), lipid transporters such as ALOX15B and several hair keratins, reflecting simultaneous defects of adhesion, barrier and hair follicle [62]. In the cornea, ΔNp63α sustains the proliferative potential of limbal epithelial stem cells, and its defect explains the progressive limbal insufficiency of EEC [59, 63].

2.3. Molecular mechanisms by phenotype

The mechanisms differ according to the domain affected, and it is this difference that underpins the separation of the entities. In EEC3, all causal variants known to GeneReviews are missense variants in the DBD that disrupt DNA binding; splicing changes and frameshifts have also been described [1, 31, 64]. The mutant protein interferes with the normal protein in dimeric and tetrameric complexes, with a dominant-negative effect [1]. Among DBD variants, the residues affected in EEC3 contact DNA directly or coordinate zinc, whereas those affected in SHFM4 serve mainly the structural maintenance of the domain [32, 65].

In AEC syndrome, about 82% of variants lie in the SAM domain and 18% in the amino-terminal domain specific to ΔNp63; the SAM domain and the TID of exon 14 account for most [1, 66]. SAM variants destabilise the domain and cause misfolding and aggregation of p63, which drags the normal protein and other p53 family members into aggregates, reducing DNA binding and the activating and repressive functions; reducing the tendency to aggregate restores transcriptional activity, which defines AEC as a protein aggregation disease [2, 67]. AEC variants repress ZNF750, KLF4 and GRHL3 and impair epidermal differentiation without altering proliferation; exogenous expression of ZNF750 in model tissue rescues most target genes [2, 61]. Knockdown of ΔNp63 in murine epidermis produces erosions with suprabasal proliferation, delayed terminal differentiation and basement membrane anomalies, a phenotype indistinguishable from AEC [18, 68]. Induction of PERP is impaired with some AEC mutants and not with others, which may explain part of the variability [69]. In amino-terminal variants with a premature stop codon (for example p.Gln11Ter), translation reinitiates at the next methionine and produces a slightly shortened ΔNp63α isoform, lacking a non-canonical transactivation domain; this is not a null allele, and the effect remains dominant [70].

In ADULT syndrome, the classic variants affect arginine 337 of the current numbering (arginine 298 of the historical numbering) in the DBD but, unlike EEC variants, confer gain of function by unmasking a second transactivation domain active on the ΔNp63γ isoform [1, 2, 54]. In limb-mammary syndrome, the variants lie between the transactivation domain and the DBD or are truncating in exons 13 and 14 (SAM domain and TID), with a probably dominant-negative effect [1, 33]. In orofacial cleft type 8, deletions of a large part of TP63 and loss-of-function variants indicate haploinsufficiency, a mechanism distinct from that of the syndromes [1, 71]. In POF21, variants that compromise the TID undo the inactive TAp63α dimer and generate a constitutively active tetramer, which increases transcription of pro-apoptotic targets and accelerates oocyte loss even without DNA damage; the conserved core of the TID (residues 643 to 655) and truncations upstream of it concentrate the variants [11, 43]. Mice with TID deletion rapidly lose their oocytes after birth, and carriers of p.Arg647Cys lose them more slowly [11].

2.4. Variant spectrum and normalisation of nomenclature

In October 2026 ClinVar listed 199 TP63 variants classified as pathogenic or likely pathogenic; the conditions most cited in submissions were “not provided” (78), “TP63-related spectrum disorders” (70), “TP63-related disorder” (31), EEC3 (25), RHS (22), AEC (16), ADULT (16), SHFM4 (15), orofacial cleft type 8 (10), POF21 (9) and limb-mammary syndrome (10), counts of submissions and not of patients [38]. Most variants are amino acid substitutions; the five recurrent EEC variants are C>T transitions at CpG islands and account for almost 90% of patients [2, 41].

The founding literature uses the numbering of the original TAp63α sequence (AF075430), which lacks the 39 amino-terminal amino acids of the current sequence; hence, at confirmed positions, the current numbering on NM_003722.5 corresponds to the historical one plus 39 [40, 59]. This rule applies only to variants actually confirmed; other conversions require verification. The table gathers, in HGVS (Human Genome Variation Society) nomenclature, the correspondences confirmed in ClinVar (alternative names field) and in VariantValidator (GRCh38) [38, 40].

Other variants cited in the following sections were normalised in VariantValidator: c.1681T>C p.(Cys561Arg), c.1927C>T p.(Arg643Ter), c.1445T>C p.(Ile482Thr), c.1037C>G p.(Ala346Gly) and c.925A>G p.(Asn309Asp), the last assuming that the authors used the MANE transcript [40, 60, 72–75]. The variant c.1568T>C, described as p.(Leu523Pro) in a patient with AEC, does not validate on NM_003722.5 (the reference base at that position is A), so the authors' c. notation belongs to another numbering and cannot be used as current HGVS [40, 59]. The variant described as c.1198_1208delACCATTCCTGAinsTGT p.(Thr400fs) in twin girls with AEC has not been normalised and is kept in the authors' notation [76]. For ADULT syndrome, the GeneReviews text refers to arginine 337 and the title of Rinne's 2006 article to arginine 298: the two designations refer to the same codon in different numberings, as confirmed by ClinVar and VariantValidator [1, 38, 54].

2.5. Genotype-phenotype correlations

The distribution of variants by domain is the basis of the molecular classification, although it is not absolute.

This table describes trends. The same variant produces different phenotypes: p.(Arg243Trp) causes EEC and ADULT, p.(Arg319His) causes classic EEC and isolated split hand/foot, and p.(Arg266Gln) caused EEC3 in a son and ADULT in his father [3, 60, 79]. p.(Arg266Gln) is associated with severe voiding difficulties, nasolacrimal obstruction, sparse hair and eyebrows, dystrophic nails, hypodontia and a lower frequency of clefting: four of six cases or families with EEC and this variant had the urological abnormality [3, 80]. Arginines 318 and 343 (historical R279 and R304) are associated with the most severe eye disease [59, 81]. In SHFM4, variants that spare the DNA-contact and zinc-coordinating residues tend to cause limb malformation only, whereas those affecting them cause dual SHFM4/EEC3 phenotypes, along a gradient EEC3 > SHFM4/EEC3 > SHFM4 only [65]. Nonsense variants of the carboxy-terminal subdomain of the TID (Q673*, W658*, R655*, K671*, Q672*) produce a variable EEC3-like spectrum, and the sumoylation motif variants p.(Glu678Gln) and p.(Glu678Ter) are the most reliable “SHFM4-only” variants [65]. In AEC, the 2006 symposium cohort did not allow genotype-phenotype correlations to be identified [18, 82].

2.6. Inheritance, penetrance, expressivity and mosaicism

All disorders of the class have autosomal dominant inheritance [1, 2]. About 30% of patients with AEC have an affected parent and about 70% have a de novo variant; the same proportion appears to apply to the other TP63 disorders, according to unpublished data from the GeneReviews authors [1]. Expressivity varies within and between families, and partial manifestations are frequent [47, 49]. The penetrance of EEC was estimated at between 93% and 98% in the analysis of 230 published cases [12], and Alves and colleagues described it as practically complete, with rare debatable cases of non-penetrance [60]. In SHFM4, the review of 72 families with 182 carriers found non-penetrance in 7.7% (14/182), 9.4% in families with “SHFM4-only” variants (6/64) and 6.8% in families with the dual SHFM4/EEC3 phenotype (8/118); the non-penetrance rate in isolated EEC3 is not documented [65]. Reduced penetrance has also been described in ADULT, in a father whose only sign was freckling of the back and shoulders, and in a Chinese family with p.(Arg319His) in which a sister and the grandfather, both carriers, had normal limbs [35, 79].

Mosaicism is a constant factor in this class. Barrow and colleagues detected germline mosaicism in the founder of a family with EEC [64]. Enriquez and colleagues described two sibling fetuses with urogenital anomalies, split hand/foot and bilateral cleft lip/palate, both with c.1051G>A p.(Asp351Asn), born to clinically normal parents without the variant in lymphocyte DNA [83]. Kosaki and colleagues described a Japanese infant with split hand/foot and cleft lip/palate due to p.(Arg243Trp) (historical R204W) whose father had split hand/foot, no cleft, whorled pigmentation along the lines of Blaschko, grey hair over one half of the scalp and mosaicism for the variant in blood and hair, whereas most of his spermatozoa carried it [46, 47, 84]. In AEC, some clinically normal parents have had more than one affected child, and in one family the variant of the dizygotic twins was present in the mother without phenotype [1]. Two sisters with AEC and p.Leu523Pro (authors' notation) were daughters of unaffected parents with germline mosaicism demonstrated by the same group [59]. In POF21, transmission also occurs through the father: the Danish p.(Arg643Ter) and the Chinese p.(Arg647Cys) and p.(Arg643Gln) were inherited from male parents without an ovarian phenotype, which makes male carriers transmitters [11, 43, 73].

2.7. Allelic disorders, modifiers and associations under study

The class is by definition a set of allelic disorders, and the boundaries between them are partly artificial: Alves and colleagues consider the distinction between EEC and ADULT “somewhat artificial”, and Valenzise and colleagues described the ADULT variant p.(Arg337Gln) in a 17-year-old boy with ectodermal dysplasia and arrhythmogenic right ventricular cardiomyopathy, without skin or limb signs, whose carrier mother had only hypodontia and athelia [60, 85]. In a family with SHFM6 due to a homozygous WNT10B variant, all affected members but one also had an insertion polymorphism in the TP63 promoter (rs34201045), suggesting a modifier effect not yet confirmed [1, 2]. OMIM also lists, as an association awaiting confirmation, TP63 variation in lung cancer risk [2]. The possibility of predisposition to epithelial neoplasms in germline carriers rests on isolated cases (oral squamous cell carcinoma in an ADULT carrier, cutaneous squamous cell carcinoma in a man with a TID variant, diffuse large B-cell lymphoma in a Japanese girl with EEC3 and historical p.Asp312Gly), with no study demonstrating an increased risk [46, 54, 78].

3. Clinical Spectrum and Manifestations by System

3.1. Manifestations common to the class

TP63-related disorders combine, in variable proportions, three groups of manifestations: ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, dental anomalies), orofacial cleft and split-hand/foot malformation or syndactyly [1, 31]. To these are added lacrimal duct obstruction, hypopigmentation, hypoplasia of the breasts and nipples and hypospadias. Three findings each belong to a single entity: ankyloblepharon filiforme adnatum (strands of tissue that totally or partially fuse the upper and lower eyelids) and scalp skin erosions with scarring and alopecia, both specific to AEC, and excessive freckling, specific to ADULT [1]. The GeneReviews comparative table summarises the distribution of features.

Source: adapted from GeneReviews, Table 2 [1]. POF21 does not appear in the original table; it presents with ovarian insufficiency with or without subtle signs of LMS [11, 73].

3.2. EEC3 syndrome

The manifestations are present at birth [1, 47]. Published figures vary with the method of ascertainment, and it is worth knowing where each comes from.

Sources: [1, 5, 12, 23, 41, 65].

Smith's Recognizable Patterns gives 84%, 68%, 59% and 52% for limbs, cleft, lacrimal and genitourinary anomalies, respectively; the first three values coincide with the Roelfsema and Cobben series, and the fourth appears to result from reading the 52 patients with urogenital anomalies in that series as a percentage [5, 12]. The denominators of the original series are what allow the frequencies to be compared. Isolated cases were more severe than familial ones, and variability between families was greater than within each family [12]. In the comparison in the 2025 review, EEC3 (Rinne's 2006 series) had ectrodactyly in 68%, ectodermal dysplasia in 50% and clefting in 37%, and changes of hair, lacrimal gland, nails and teeth reached 51–55%, those of skin and breast 34% each [65].

Limbs. The spectrum ranges from mild cutaneous syndactyly to monodactyly; typically there is ectrodactyly with syndactyly of the remaining digits, sometimes polysyndactyly and preaxial polydactyly and digital duplication [1, 47]. Intra-individual asymmetry and variation between relatives are the rule [86].

Skin, hair, nails and teeth. The skin is dry and fair, with mild hyperkeratosis and no erosions; the hair is silvery blond, coarse, dry and sparse, with sparse eyebrows and eyelashes; the nails are thin, brittle and ridged; the teeth are conical and small, with hypodontia and susceptibility to caries [1, 5, 53]. Light microscopy of the hair is normal, but scanning electron microscopy shows bulb distortion and longitudinal grooves of the shaft [1, 5]. In the Dutch family with EEC3 followed since 1996, most affected members had blond, sparse, slow-growing hair, periorbital hyperpigmentation and caries, and eight were edentulous at examination, which led the authors to recommend systematic dental examinations [46]. Hypohidrosis is uncommon in EEC3, unlike AEC and ADULT [1, 87].

Eye. Absence of the lacrimal puncta, present in about 90%, causes epiphora, blepharitis, dacryocystitis, keratoconjunctivitis and photophobia, with corneal ulceration and scarring [1, 23]. The main ocular problem, according to Smith, is meibomian gland deficiency with an unstable tear film [5]. In the series of 23 patients from 19 families in the United Kingdom, Ireland and Italy, all had ocular involvement, and 61% (14/23) developed limbal stem cell deficiency (LSCD), related to age and not to the overall severity of the syndrome or to the variant, with progressive keratopathy, dense vascularised pannus and visual loss [63]. In the 2023 Venice series, eye disease deteriorated rapidly between the third and fifth decades, with transparency, neovascularisation and pannus worsening with age, up to total ocular surface failure at 61 years in one patient [59]. A review of published cases found lacrimal drainage anomalies in 87% and lacrimal duct atresia in 59%, figures subject to publication bias [21].

Genitourinary tract. Genitourinary anomalies include megaureter, duplex collecting system, vesicoureteric reflux, ureterocele, bladder diverticula, renal agenesis or dysplasia, hydronephrosis, urethral stenosis, micropenis, cryptorchidism, hypospadias and transverse vaginal septum [5, 47]. Obstructive uropathy may begin before birth and, in severe forms, cause intrauterine hydronephrosis, oligohydramnios, pulmonary hypoplasia and perinatal death [12, 47]. Voiding difficulties with thin, atrophic bladder epithelium, described in the Dutch family, improved with a synthetic sulphated glycosaminoglycan and tended to improve with age; in other patients they required urethrotomy, self-catheterisation or ureteric reimplantation [46, 80].

Other manifestations. Conductive hearing loss and chronic or recurrent respiratory infections (6%) are occasional; intellectual disability occurs in about 7%, and most patients have normal intelligence [5, 47]. Choanal atresia, anal atresia and omphalocele, growth hormone deficiency, hypogonadotrophic hypogonadism and central diabetes insipidus have been described; the last three, when associated with holoprosencephaly, may correspond to misclassified Hartsfield syndrome [5, 12]. Alves and colleagues described bilateral sensorineural hearing loss and hypothyroidism in a Brazilian female proband [60], and Bothra and colleagues multiple bone fractures in an adolescent [21]; these are isolated observations.

3.3. AEC syndrome (Hay-Wells, including Rapp-Hodgkin)

The manifestations are present at birth. The best systematic description comes from the 2003 Workshop on skin erosions (12 patients, 6 boys and 6 girls, aged 1 month to 15 years, born at term with weight appropriate for gestational age, 11 with a family history) and from the 2006 International Symposium in Houston (23 affected individuals from 13 families, 18 evaluated in the Baylor College of Medicine protocol), small and selected samples [17, 18, 82]. In the literature review accompanying the Workshop report, ankyloblepharon filiforme adnatum appears in about 70% of cases, congenital erythroderma in 90%, extensive scalp erosions in 70% and cleft palate, with or without cleft lip, in 80%; heat intolerance and hypohidrosis were reported in up to 50%, without objective demonstration of eccrine dysfunction [17].

Sources: [1, 17, 18, 88–92].

Eyes and eyelids. Ankyloblepharon filiforme adnatum is present in about 70% of newborns; partial adhesions may be subtle and lyse spontaneously before being recognised, so the sign cannot be used to separate AEC from RHS [1, 48]. Absence or atresia of the lacrimal puncta causes chronic conjunctivitis and blepharitis, often unrecognised in early childhood [1, 93]. Blepharitis is disproportionately greater than conjunctivitis, the eyelid sweat glands appear absent, the lacrimal duct openings extrude debris and concretions, and the eyelashes and eyebrows are misaligned, thin and sparse [17, 18]. In the Venice series, the two sisters with AEC had absent meibomian glands, recurrent epithelial defects and neovascularisation from adolescence [59].

Skin. Almost all newborns have superficial erosions, ranging from very limited to life-threatening total body involvement, typically on the scalp [1]. Congenital erythroderma, with diffuse erythema and erosions, occurs in 70–90% of infants, and the skin may appear shiny and membranous; one of the sisters in the Venice series was born as a collodion baby [1, 59]. GeneReviews describes this collodion membrane appearance in the text and, in the differential diagnosis table, states that AEC is not associated with a collodion membrane or ichthyosis; the appearance exists, but without ichthyotic evolution [1]. Erosions are recurrent and intermittent in childhood and adulthood, on the head and neck, palms, soles, skin folds and ear canals [1, 18]. Severe scalp erosions cause scarring alopecia and hypotrichosis, a finding that does not occur in the other TP63 disorders [1]. Scalp infections may progress to severe chronic granulomas, and exuberant granulation tissue is favoured by occlusive dressings [1, 49, 94]. Infants with dark skin may have mask-like facial hypopigmentation that improves with age; in fair skin, reticulate hyperpigmentation of the neck and skin folds appears and evolves into cribriform, reticulate, stellate or punctate scars on the shoulders, back and chest [1]. Histology of non-lesional skin shows mild atrophy, focal orthokeratosis, superficial perivascular lymphocytic dermatitis and scattered melanophages, with no pathognomonic findings [95]. There is palmoplantar keratoderma with erosions and, in patients with the RHS phenotype, palmar biopsy showed detachment of keratinocytes in the upper layers and apoptotic keratinocytes [37, 49]. According to GeneSkin, the disease is not progressive and scalp erosions improve with age in most patients [93].

Hair, nails and sweat glands. The hair is light, coarse, wiry and brittle, with a fibreglass-like or uncombable appearance; microscopy shows pili torti, pili trianguli et canaliculi, grooves and pigment loss [1, 95]. Nails are altered in all: dystrophic, thin, soft or absent, with characteristically absent proximal nail folds, pterygium and longitudinal ridging; the hyperconvex appearance previously described is not the most frequent, and nail changes may vary over time [17, 18, 96]. Some patients have fewer pores and reduced sweating, but without the hyperthermia of hypohidrotic ectodermal dysplasia; hyperthermia is rare and limited to early childhood [1, 49, 87].

Face, oral cavity, ear and voice. A cleft is present in all, in the form of submucous cleft, cleft of the soft and/or hard palate, cleft lip only or cleft lip/palate, and mixed clefting (cleft lip/palate in one relative and isolated cleft palate in another) occurs in this syndrome, unlike most syndromes with clefting [1, 49, 88]. The face becomes more characteristic with age: maxillary hypoplasia, micrognathia, broad nasal root, underdeveloped alae nasi, thin upper vermilion, short philtrum and small, sometimes cupped, ears [1, 49]. Trismus is present in 35% [91]. Adults have on average 4.75 permanent teeth (0 to 12), mainly first molars, canines and upper incisors, and only 22% had prosthetic replacement of missing teeth [90]. All patients in Cole's series had a history of otitis, 93% of those tested had conductive hearing loss, seven with moderate to severe impairment (41–90 dB), 61% needed myringotomy with ventilation tubes, 69% had hoarseness or voice problems and 88% had speech below the level expected for age; oro-auditory problems persisted after cleft closure [88]. The deficient mucosal lining of the vocal cords may affect the voice [49].

Limbs and genitourinary tract. The limbs are more involved than previously thought: complete bilateral 2–3 toe syndactyly in 47%, 3–4 toe syndactyly in 18%, 3–4 finger webbing or syndactyly in 24% and hammer toes in 47% of Sutton's 17 patients; split hand/foot in 2 of 17 (12%) [1, 91, 92]. Hypospadias affects most boys [91]. In girls, the small perineal body gives the appearance of an anteriorly placed anus, and imperforate hymen has been described [17]. Micropenis, vaginal dryness and erosions have been described [49, 94].

Growth and nutrition. Mean z-scores for birth weight and height-for-age are significantly lower than the reference; weight-for-age increases with age at the expense of body fat; at least a quarter of patients have nutritional or gastrointestinal problems (formula supplements, gastrostomy, gastro-oesophageal reflux, constipation), and short stature with preserved head circumference is present in almost all [89, 91]. Faltering growth is disproportionate compared with that of children with isolated clefts [18].

Immunity and infection. Some patients have neutropenia of undetermined cause, recurrent skin and ear infections, and there have been infants with bacteraemia and death from sepsis; one child had autoimmune lymphoproliferative syndrome [18]. One of the sisters in the Venice series had low B and T helper lymphocytes at birth and was admitted in the first year for interstitial bronchopneumopathy with severe dehydration [59]. Helenius and colleagues described immunodeficiency and mitral regurgitation secondary to left heart chamber dilatation in a preterm infant with EEC/AEC overlap [72]. Cultures of scalp lesions frequently grow community-acquired meticillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa [94].

Development and psychosocial impact. Cognitive development is generally normal, with mild language delay secondary to hearing loss and clefting in some patients [7, 94]. Family functioning is variable: some families report few effects, others reduced quality of life and a negative impact on the child and family [97].

Rare findings. Choanal atresia, atresia of the external auditory canals, supernumerary nipples, ventricular septal defect, patent ductus arteriosus, absent lingual frenulum, Wilms tumour and alveolar synechiae have been described [7, 49, 92]. In Rapp-Hodgkin syndrome with a TP63 variant, Groenouw-type corneal dystrophy and early menopause at 28 and 35 years in a mother and daughter have been described, anticipating the association with ovarian insufficiency [25].

3.4. ADULT syndrome

The manifestations are present at birth and may become more marked with age, except for the freckles, which appear in sun-exposed areas in a subgroup and progress with age and exposure [1]. Syndactyly of the fingers and toes is the most frequent limb anomaly, and ectrodactyly is present in some patients; the skin is dry without erosions, sometimes atrophic, photosensitive or with dermatitis; the hair is light and fine, with sparse eyebrows and eyelashes and frontal alopecia; the nails are dysplastic; there are conical teeth, hypodontia and early loss of permanent teeth [1, 85]. Subjectively reduced sweating is universal and reported as heat intolerance, without hyperthermia [1]. Lacrimal duct atresia causes chronic conjunctivitis and blepharitis; in a Chinese female patient with an atypical variant, the obstruction was corrected by dacryocystorhinostomy with implantation of an artificial lacrimal duct [1, 77]. Breast and/or nipple hypoplasia is frequent, especially in women [1]. ADULT is distinguished from EEC by the normal lip and palate and from LMS by the more marked ectodermal involvement [54]. A Brazilian family with p.(Arg337Gln) showed adermatoglyphia in all affected members, discovered through difficulties in obtaining fingerprints for identity documents [85, 98]. A patient with ADULT-AEC overlap was diagnosed at 60 years of age [99].

3.5. Limb-mammary syndrome

Limb anomalies (split hand/foot and syndactyly, as well as duplication and fusion defects) are present in 75–85%; nipple hypoplasia or aplasia is almost constant and aplasia or hypoplasia of the mammary gland affects 90% of women [1, 30]. Lacrimal duct atresia occurs in about half, nail dysplasia in 30%, hypodontia in 10–15% and clefting in 25–30%, in the form of isolated cleft palate, submucous cleft or bifid uvula; skin and hair changes are typically absent [1, 29]. According to van Bokhoven and Brunner, LMS is distinguished from EEC by constant breast hypoplasia, absence of skin and hair changes and isolated cleft palate, which does not occur in EEC [2]. Anteriorly placed anus and ear pits have been described [30]. A female patient previously described with LMS presented at 14 years with primary amenorrhoea, absent uterus and ovaries on magnetic resonance imaging and hypergonadotrophic hypogonadism, the first case of female gonadal dysgenesis in this group [30, 100]. Mathorne's Danish family, with six affected members in two generations and the variant c.1927C>T p.(Arg643Ter), had nipple anomalies in all (supernumerary, cleft, small, bean-shaped or widely spaced), lacrimal atresia in four and dental anomalies in three, without limb defects; the two sisters had ovarian agenesis and uterine hypoplasia [30, 73].

3.6. SHFM4

Malformation of the central rays of the autopod includes median clefts of the hands and feet, monodactyly, syndactyly and aplasia or hypoplasia of the phalanges, metacarpals and metatarsals [1, 65]. By definition, ectodermal dysplasia and orofacial cleft exclude a diagnosis of SHFM4; in practice, the 2025 review showed that, among 152 carriers classified as SHFM4, ectrodactyly was present in 91%, ectodermal dysplasia in 30% and clefting in 7%; the most frequent ectodermal signs were dental (25%), cutaneous (19%), hair (19%) and nail (18%), and, excluding carriers of p.(Arg337Gln), ectodermal dysplasia was present in 23% (32/137) [1, 65]. SHFM4 and EEC3 thus form a continuum, in which the classification of the proband depends on careful examination of the ectodermal derivatives of relatives. Reduced penetrance has been described since 1988 [101]. A p.(Arg319His) variant in a Chinese family was associated with overexpression of TP63, PERP, CDH3 and DLX5 on RNA-seq [79]. In a 2003 study, p63 variants were not a major cause of non-syndromic split hand/foot, and van Bokhoven found them in only 4 of 35 cases [33, 102].

3.7. Orofacial cleft type 8

A pathogenic TP63 variant was identified in three individuals with apparently non-syndromic cleft lip or cleft lip/palate: a 4-year-old Thai girl, among 100 patients screened (de novo variant R313G, = p.(Arg352Gly), absent in 500 controls), and a 3-year-old boy and his father with a 2 bp duplication, without other features of TP63 disease after evaluation [1, 2, 39, 103]. Partial gene deletions and loss-of-function variants have been described in three families with orofacial cleft and/or hypodontia, sometimes with minor skin and nail anomalies [71]. In 62 patients with non-syndromic clefts from Iowa, p63 screening found no variants [64]. The contribution of TP63 to isolated clefts is therefore small.

3.8. Premature ovarian insufficiency type 21

Premature ovarian insufficiency (POI) is defined by menstrual disturbance and raised FSH before the age of 40 years, and more than 80 potentially causal genes are known, with no cause identified in most individual patients [43]. The first patients with TP63 variants had isolated POI with primary amenorrhoea and de novo nonsense variants in the last exon [42]. Tucker and colleagues then described three missense variants in non-syndromic POI: p.(Arg97Pro), in one patient and an affected aunt, p.(Arg647Cys), inherited from the father, and p.(Tyr18Cys), with no demonstrated functional effect [43]. In the Chinese cohort of 1,030 women with isolated POI, nine heterozygous variants in 11 patients accounted for 0.78% (8/1,030) of cases, with primary or secondary amenorrhoea between 13 and 29 years of age; p.(Arg647Cys) was found in three unrelated patients [11]. Vanderschelden and colleagues found two point variants and an intragenic copy number change affecting the first exon of the ΔN isoforms in three women with isolated POI [104]. The spectrum includes sporadic, familial, isolated and syndromic POI, the latter with signs of LMS [73, 104]. In Portugal, Falcão Cardoso and colleagues, in Porto, described a 15-year-old girl with primary amenorrhoea, absent thelarche, hypergonadotrophic hypogonadism, a 46,XX karyotype, a hypoplastic uterus (14 × 9 × 10 mm) and ovaries not identifiable on magnetic resonance imaging, with a novel pathogenic TP63 variant [105].

3.9. Expanded phenotypes and manifestations in adulthood

The expression of TP63 disorders in adults continues to be described. A 68-year-old Asian man with c.1768C>T p.(Pro590Ser) in the TID had complete anodontia since exfoliation of the deciduous teeth, total alopecia at 30 years, hypohidrosis, severe palmoplantar keratoderma with haemorrhagic fissures, dystrophy of all nails and pubic cutaneous squamous cell carcinoma at 60 years, without limb malformations or cleft [78]. Rinne and colleagues discussed an oral squamous cell carcinoma in a carrier of the ADULT variant [54]. Kantaputra and colleagues described amelogenesis imperfecta, a supernumerary premolar and fused incisors in a family with the splice variant c.588-2A>C [106]. A Chinese family with a splice variant had an atypical, mild EEC3 [107]. Sodero and colleagues described a newborn with EEC3, tetralogy of Fallot, oesophageal atresia with fistula and penoscrotal hypospadias [108]. These isolated reports do not establish frequencies.

3.10. Natural history and effect of treatment

Natural history differs between entities. In EEC3, patients are cognitively normal and adapt after reconstruction of the cleft and limbs; long-term morbidity depends mainly on the eye and, in part, on the urinary tract [5, 63]. In AEC, mortality is concentrated in the neonatal period and early childhood (17% deaths in childhood in the 2003 series of 12 patients, from dehydration, electrolyte imbalance or sepsis), and after this phase the overall prognosis is described as good, with normal life expectancy, although without cohort survival data [7, 18, 94]. The available data come from treated patients, and the series do not compare outcomes with and without an intervention; the course of erosions, nutrition and hearing in each series reflects the care provided.

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

Prenatal period. Ultrasound may show cleft lip, split hand or foot and obstructive uropathy; EEC has been diagnosed by ultrasound from 14 weeks and, in known families, after 16 weeks through detection of the cleft [12, 47]. Fetal hydronephrosis in twin girls with AEC and fetal urogenital anomalies in siblings with EEC due to germline mosaicism show that the urinary finding may precede recognition of the syndrome [76, 83].

Newborn. The combination of orofacial cleft with split hand/foot, syndactyly, dysplastic nails or sparse hair should prompt a search for the lacrimal puncta and for ankyloblepharon [109, 110]. A newborn with cleft palate, erythroderma, superficial erosions (especially of the scalp) and strands of tissue between the eyelids has AEC until proven otherwise [1, 7]. Ankyloblepharon may lyse in the first hours or days, and its absence does not exclude AEC [1, 48]. Neonatal erosions frequently lead to an initial diagnosis of epidermolysis bullosa (25% in the 2003 series) or congenital ichthyosiform erythroderma [18, 74, 94].

Infant and child. Signs that should raise suspicion include recurrent scalp infection with scarring alopecia, recurrent conjunctivitis and blepharitis with epiphora, hypodontia with conical teeth, light, wiry and sparse hair, recurrent otitis media with hearing loss, faltering growth disproportionate to the cleft and hypospadias [1, 18, 88]. In a child with a cleft, examination of the lacrimal puncta and digital rays is the most useful step to distinguish EEC from isolated clefts, and examination of the parents (submucous cleft, bifid uvula, hands and feet, teeth, nails) may reveal a mild form [109]. Voiding difficulties, dysuria or straining in a child with ectodermal dysplasia should prompt investigation of the urinary tract, especially with p.(Arg266Gln) [46, 80].

Adolescent. Primary or secondary amenorrhoea with raised FSH, absent thelarche or breast hypoplasia, with or without nipple anomalies, lacrimal atresia or hypodontia in the patient or her relatives, suggest POF21 or LMS [11, 73, 105].

Adult. Progressive eye disease with pannus, corneal neovascularisation and symblepharon may be the reason for consultation: in the Venice series, two of eight patients had initially been diagnosed with cicatricial or ocular pemphigoid, at 29 and 59 years, and one patient with EEC had been treated as herpetic keratitis [59, 111]. The combination of severe palmoplantar keratoderma, anodontia and alopecia in an adult without malformations may correspond to a TID variant [78]. Excessive freckling with hypodontia and breast hypoplasia in a parent of an affected child suggests ADULT with minimal expression [35].

4.2. Warning and emergency signs

4.3. Newborn screening

There is no biochemical newborn screening for TP63 disorders. Universal newborn hearing screening is useful, but the hearing loss of AEC is mainly conductive and acquired through otitis, so a normal newborn screen does not obviate audiological surveillance [7, 88].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal clinical criteria for any of the TP63 disorders [1]. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic variant in TP63; a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [1]. The designation of the entity (EEC3, AEC, ADULT, LMS, SHFM4) is clinical and rests on the combination of features in the comparative table, bearing in mind that no sign is mandatory and that the same family may have members with different labels [3, 5, 47]. In practice, the designation “TP63-related disorder”, followed by a description of the phenotype, avoids artificial classifications and is used by ClinVar in most submissions [38, 60].

5.2. Targeted clinical evaluation

The evaluation includes photographic documentation and systematic examination of the ectodermal derivatives (hair, nails, teeth, skin, glands), the lacrimal puncta and eyelids, the palate (submucous cleft, bifid uvula), the hands and feet with radiography, the breasts and nipples and the genitalia [47, 109, 110]. Examination of the parents is part of the diagnosis, given mosaicism and minimal expressivity [1, 84]. Supporting tests are non-specific: skin biopsy in AEC shows mild atrophy, focal orthokeratosis and perivascular dermatitis without a pathognomonic finding; hair microscopy shows pili torti and pili trianguli et canaliculi, findings shared with other ectodermal dysplasias; the starch-iodine test of palmar sweat rarely helps [14, 93, 95]. The 2003 Workshop report concludes that light microscopy of the skin does not establish the diagnosis of AEC, because no histological finding is constant, and that biopsy serves mainly to exclude other diagnoses, in particular epidermolysis bullosa [17]. There is no biochemical biomarker. When POF21 is suspected, hypergonadotrophic hypogonadism (raised FSH), a 46,XX karyotype and pelvic ultrasound or magnetic resonance imaging document the ovarian insufficiency [43, 105].

5.3. Genetic tests and algorithm

5.4. Performance and limits of the tests

According to HGMD (Human Gene Mutation Database) data cited by GeneReviews, sequencing detects 99% of known pathogenic TP63 variants; this figure is the proportion of described variants that the method can detect, not the clinical sensitivity, which depends on the accuracy of the clinical diagnosis and has not been measured [1]. In EEC3, van Bokhoven found variants in 40 of 43 patients or families (93%) [33]; in AEC, the symposium cohort confirmed variants in 21 of 24 participants tested, and the three without a variant included two unaffected relatives and one patient with a slightly different phenotype [2, 66]; in isolated split hand/foot, the rate was 4 in 35 [33]. Deletion/duplication analysis has a low yield: a four-exon deletion in a person with EEC3 and partial deletions in families with orofacial cleft [1, 71, 113]. The limits to be aware of are low-level mosaicism in blood, deep intronic and non-canonical splicing variants, variants in alternative exons (3' exon of the ΔN isoforms, TA* exon) that may be missed by panels analysing only the canonical transcript, and structural rearrangements, such as the t(3;15)(q28;q21) translocation described in a family with SHFM4 [1, 65, 84, 104]. A negative result excludes neither a TP63 disorder nor a genetic cause of another kind.

5.5. Report content and interpretation

The report should state the gene, the transcript and its version (NM_003722.5 by default, MANE Select), the variant in HGVS nomenclature (c. and p.), the genomic coordinate with the genome build, the zygosity, the classification according to ACMG/AMP criteria (American College of Medical Genetics and Genomics / Association for Molecular Pathology) and, where useful, the correspondence with the historical numbering [38, 40]. Confusion between historical and current numbering is frequent in case reports and may generate notations that do not validate on the reference transcript [59]. To classify a novel variant, what counts is the domain affected, de novo occurrence with confirmed parentage, segregation, absence from gnomAD and published functional studies for the residue [1, 11]. De novo occurrence is confirmed only when maternity and paternity have been verified; otherwise it is presumed [1].

5.6. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal testing and preimplantation genetic testing (PGT-M) are possible [1]. Because the same variant can give very different phenotypes, identification of the variant in the fetus does not predict severity, and detailed ultrasound for clefts, split hand/foot and uropathy is more useful for estimating the phenotype than molecular testing alone [49, 114]. In the absence of a known variant, ultrasound allows suspicion, but the findings do not distinguish EEC from other causes of clefting and split hand/foot [114]. Proband-independent PGT-M, with direct detection of the variant and haplotyping using STR (short tandem repeat) markers linked to TP63, was used in a man with a de novo variant confirmed in sperm [75].

6. Differential Diagnosis

6.1. Comparative table

6.2. The newborn with erosions: AEC, epidermolysis bullosa and ichthyosis

The most urgent distinction is between AEC, epidermolysis bullosa and the congenital ichthyoses, because all three present with denuded skin, erythroderma or collodion membrane in the neonatal period. In AEC, erosions are more superficial, there are no blisters, and cleft palate, ankyloblepharon, dysplastic nails and sparse hair point to the diagnosis; dermatopathology helps to separate it from epidermolysis bullosa [1]. The 2003 Workshop report recommends including AEC in the differential diagnosis of the collodion baby and of epidermolysis bullosa and recognising the congenital features (facial cleft, ankyloblepharon, limb anomalies, marked scalp erosions without blisters, involvement of only the most superficial layers of the epidermis), to avoid unnecessary invasive investigations for epidermolysis bullosa [17]. The error is frequent: 25% of patients in the 2003 Workshop were first diagnosed with epidermolysis bullosa, and the diagnosis of AEC was reached at one year of age in a Chinese infant previously diagnosed with epidermolysis bullosa and congenital ichthyosiform erythroderma [17, 74]. CHANDS syndrome shares ankyloblepharon and the hair changes, but has no cleft or erosions, and cocoon syndrome 2 combines ankyloblepharon, cleft and ectodermal dysplasia with hypogammaglobulinaemia [1, 115]. Recessive CLPED1 (NECTIN1) is also in the differential diagnosis of AEC [34]. Ankyloblepharon filiforme adnatum, isolated or with cleft palate, also occurs in popliteal pterygium syndrome (IRF6) and trisomy 18, so the eyelid finding, without the ectodermal signs, is not exclusive to AEC [125].

6.3. Ectrodactyly with cleft or ectodermal dysplasia

Faced with split hand/foot, the presence of ectodermal, lacrimal or cleft signs points to TP63, and their absence to the other forms of split hand/foot, in particular the 10q24 duplication and DLX5 [1, 15]. The absence of ectodermal dysplasia does not exclude TP63, because SHFM4 is caused by the same gene and because 7.7% of carriers have no phenotype [65]. Hartsfield syndrome shares ectrodactyly and cleft lip/palate, and patients previously classified as EEC with holoprosencephaly, central diabetes insipidus, growth hormone deficiency and hypogonadotrophic hypogonadism probably had Hartsfield syndrome due to loss of function of FGFR1; in fetal cases confusion is easy, and neuroimaging is the discriminating test [5, 47, 121]. Ectodermal dysplasia with ectrodactyly and macular dystrophy, due to CDH3, is distinguished by fundoscopy [57]. Split hand/foot with long bone deficiency is distinguished by tibial aplasia or hypoplasia and the absence of ectodermal dysplasia [120]. Focal dermal hypoplasia and Adams-Oliver syndrome combine skin or scalp changes with distal limb defects, with skin lesions of their own pattern [123, 124].

6.4. Ectodermal dysplasia with cleft, without ectrodactyly

Among the ectodermal dysplasias, orofacial cleft points to TP63 and away from hypohidrotic ectodermal dysplasia, in which clefting is not typical and hypohidrosis compromises thermoregulation, which does not happen in the TP63 disorders [1]. AEC and EEC3 without limb defects may be indistinguishable from Zlotogora-Ogur syndrome (NECTIN1), which has recessive inheritance and partial syndactyly [47, 57]. In ectodermal dysplasia-syndactyly due to NECTIN4 there is neither ectrodactyly nor cleft [47].

6.5. Breast and nipple hypoplasia with limb anomalies

Ulnar-mammary syndrome (TBX3) shares breast and nipple hypoplasia with LMS and ADULT, but the limb defects are postaxial and ulnar, and there may be cardiac conduction defects and male hypogonadism [118]. An ADULT patient with ulnar ray hypoplasia and imperforate anus illustrates the overlap between the two [85]. Scalp-ear-nipple syndrome overlaps with ulnar-mammary syndrome and EEC [122].

6.6. Isolated cleft

In a child with an apparently isolated cleft, the probability of TP63 is low, and the most frequent monogenic causes are others, such as IRF6 (Van der Woude, the most common syndromic form of clefting), TBX22 (X-linked cleft palate with ankyloglossia) and MSX1 (about 2% of non-syndromic cleft lip, to be considered when there are co-segregating dental anomalies) [109]. Examination of the lacrimal puncta, teeth, nails, hands and feet of the child and the parents is the discriminating clinical test [109].

6.7. Ocular surface disease in adults

In an adult with symblepharon, conjunctival scarring and corneal neovascularisation, mucous membrane pemphigoid is the diagnosis most often considered, and two of the eight patients in the Venice series were treated as pemphigoid before EEC was recognised [59]. Herpetic keratitis was the initial diagnosis in a patient with bilateral pannus [111]. Searching for clefts, nail, tooth and hair changes and malformations of the hands and feet, even mild ones, guides the diagnosis.

7. Treatments and Risk Management Strategies

7.1. Principles and status of guidelines

There is no cause-directed treatment and no formal clinical guideline for the TP63 disorders; GeneReviews records that no guideline has been published, and a 2026 search of ERN-Skin, the French FIMARAD network and the literature found no later document [1, 19, 126]. Management relies on a multidisciplinary team bringing together clinical genetics, dermatology, ophthalmology, otorhinolaryngology, audiology, dentistry and prosthodontics, plastic surgery, hand surgery, urology, nutrition and gastroenterology, endocrinology and psychology [1, 18]. The available consensus documents are the following.

The GeneReviews treatment table, supplemented by the other sources, summarises the measures by manifestation.

7.2. Neonatal period in AEC syndrome

The newborn with AEC and extensive erosions needs admission to neonatal intensive care, with monitoring of temperature, electrolytes and infection, and with intravenous hydration while transepidermal losses are significant [1, 7, 76]. In the newborn girl from Palermo, intravenous hydration in the first days, topical antibiotics and antifungals and emollient and re-epithelialising creams led to resolution of the body erosions, with scalp lesions persisting [7]. In the twins described by Caceres, the approach included broad-spectrum antibiotics and aciclovir until infection was excluded, a humidifier with gradual weaning, cleansing with a mild synthetic detergent and abundant white petrolatum [76]; the empirical antibiotic therapy in that approach diverges from the GeneReviews recommendation, which reserves antibiotics for culture-proven infection [1]. Sepsis and dehydration explain the childhood mortality described in the 2003 series [17, 18]. The Workshop report recommends, in infants with severe erosions, an incubator with added water vapour to maintain high ambient humidity, prolonged admission with surveillance for secondary infections by gram-positive and gram-negative bacteria and yeasts, and prolonged home nursing care after discharge; although case reports describe normalisation of eroded skin in the first weeks, several infants presented at the Workshop had chronic wounds with life-threatening infections, which healed with atrophic scars [17]. Cleft palate and feeding difficulties may require a nasogastric tube; 58% (7/12) of the 2003 patients were tube-fed in the neonatal period [17, 18].

7.3. Skin and scalp

The AEC-specific skin care recommendations are those of the 2003 Workshop on erosions and wound healing, published in 2005; the authors state that they rest on limited collective experience and not on evidence data, and that treatment may fail [17]. In the newborn with extensive erosions, the aim is to reduce the high risk of infection and of toxicity from percutaneous absorption: daily bathing, as tolerated, with gentle cleansing using a cotton swab, with plain water, dilute bleach or chlorhexidine, preceded by analgesia when needed; application of plain petrolatum and petrolatum-impregnated gauze, dispensed from single-use packaging; and, between dressing changes, a very dilute Dakin's solution of 0.025% hypochlorite [17]. Irritants and potential causes of inflammation should be avoided. Extensive debridement, traditional skin grafts and artificial skin substitutes were unsuccessful in the infants of the series; punch or pinch grafts were suggested as an alternative, without experience in AEC [17]. In older children, the dominant problems become pain, the time consumed by wound and skin care and pruritus, and the risk of secondary infection is lower than in infants; surveillance for infection should be balanced against restrained use of empirical antimicrobials, maintaining an intact skin barrier is the safest way to avoid infection, and a positive culture accompanied by increasing pain, redness, oedema and systemic symptoms is treated as specifically as possible [17]. The 2009 symposium report reiterates the rejection of aggressive measures and the preference for gentle cleansing and simple emollients [18]. GeneReviews adds periodic dilute bleach baths (Dakin's solution) to prevent secondary infection, advises against occlusive dressings, which favour granulation tissue, and reserves antibiotics for culture-proven infection [1]. For comparison, the European multicentre consensus on skin care in epidermolysis bullosa, the erosive genodermatosis with which AEC is confused in the neonatal period, proposes for extensive or colonised lesions baths of 15–20 minutes a day with a mild antiseptic — sodium hypochlorite at 5–10 mL per 5 L of water, acetic acid up to 0.25%, chlorhexidine 0.1% or polyhexanide —, also preceded by analgesia, with a sample taken for culture after washing with normal saline when infection is suspected [127]. The two recommendations agree on analgesia, mild antiseptics and targeted sampling for culture, but the AEC recommendation uses 0.025% Dakin's solution between dressing changes and does not set a bath duration; the epidermolysis bullosa dilutions have not been studied in AEC. In chronic erosive and pustular dermatitis of the scalp, refractory to conventional wound care, two patients with the Rapp-Hodgkin form improved markedly with high-potency topical corticosteroids; the authors liken this inflammation to erosive pustular dermatosis of the scalp of the elderly, and the evidence is limited to those two cases [128]. Scalp erosion is perhaps the most disabling manifestation: stepwise management ranges from daily baths, light debridement and emollients to extensive skin excision; grafts have had limited success, and an attempt with acellular dermal matrix in a patient with severe scalp disease failed [129]. In the boy from Botucatu, scalp exulcerations with exuberant granulation tissue and colonisation by meticillin-resistant S. aureus and P. aeruginosa did not improve in the first years with local care and antimicrobials; gentle removal of crusts, non-adherent dressings, several superficial debridements of the granulation tissue under topical anaesthesia and silver hydropolymer foams, changed every four days, were followed by the absence of new exulcerations from the age of seven [94]. These single-case measures are not presented as routine; superficial debridements under topical anaesthesia are closer to the gentle cleansing accepted by the Workshop than to the extensive debridement that failed in the infants of the 2003 series [17]. GeneSkin summarises the measures as emollients, antiseptics, appropriate dressings and antibiotic therapy for secondary infections [93]. Sun protection of hypopigmented areas and freckles completes the care [1].

Tetracyclines, particularly doxycycline, were recommended by the symposium participants for their dual antimicrobial and matrix metalloproteinase-inhibiting action [18, 92]. The 2003 Workshop went further: it considered that a risk-benefit assessment may justify a trial of doxycycline in children under 8 years with persistent scalp erosions, despite the risk of tooth discoloration, and attributed the observed success to possible inhibition of angiogenesis, which would make these erosions similar to ulcers with deficient re-epithelialisation [17]. This is off-label use, and none of the consensus sources gives a dose or duration. In Portugal, the SmPC (summary of product characteristics) of Vibramicina® (doxycycline 100 mg, dispersible tablet) indicates for infections, in adults and adolescents aged 12 to 17 years, 200 mg on the first day and 100 mg per day thereafter; between 8 and 11 years use must be justified, with 4.4 mg/kg on the first day and 2.2 mg/kg per day thereafter in children weighing 45 kg or less (up to 4.4 mg/kg in severe infections); and it contraindicates use before 8 years, because of the risk of permanent tooth discoloration [130]. This dosing is the label dosing for infections, and its use for AEC erosions is an extrapolation. The age restriction weighs heavily in this disease, whose most severe erosions occur in the first years of life, and this is where the sources diverge: the SmPC contraindicates doxycycline before 8 years, whereas the Workshop accepted a trial at that age for persistent scalp erosions [17, 130]. The photosensitivity described in the SmPC adds to the sun vulnerability of hypopigmented skin [1, 130].

7.4. Eye and lacrimal drainage

Ophthalmological assessment should be early and continuous [1, 5]. Absent lacrimal puncta and nasolacrimal obstruction are treated by probing, intubation or surgery; in complex EEC cases, with punctal stenosis, abnormal nasal anatomy, septal deviation and turbinate hypertrophy, probing, external dacryocystorhinostomy and conjunctivodacryocystorhinostomy with a Jones tube repeatedly failed, and combined endoscopic surgery (septoplasty, turbinoplasty and dacryocystorhinostomy with monocanalicular intubation) improved about 75% of the epiphora in an adolescent, with stent prolapse in the third week [21]. Surgical reconstruction of lacrimal drainage improves the ocular outcome [5]. Punctal plugs were used in one eye of a patient in the Venice series [59].

Dry eye and meibomian gland dysfunction are treated with lubricants, eyelid hygiene and warm compresses [1, 59]. The Venice centre's scheme consists of a topical corticosteroid at a concentration adjusted to each patient, with intentional omission of non-steroidal anti-inflammatory drugs, eyelid hygiene and warm compresses every night and daily hyaluronic acid eye drops; the authors stress that these measures relieve symptoms but did not halt the progression of limbal insufficiency [59]. Custom scleral lenses, worn for ten years by an adolescent with severe dry eye, neovascularisation, pannus and limbal insufficiency, were associated with minimal progression of ocular signs and better comfort and acuity, with interruptions due to the difficulty of insertion and removal caused by ectrodactyly [131]. In advanced disease, cataract surgery, keratoplasty and amniotic membrane grafting had infectious complications and ended in ocular surface failure in one patient [59]. Medical and surgical treatments of limbal insufficiency in EEC have limited benefit, which motivates the experimental approaches described in 7.11 [81]. Removal of the eyelashes in distichiasis was necessary in two sisters with AEC [59].

7.5. Cleft, ear, speech and airway

The cleft is treated by the cleft team according to general protocols, with palatoplasty between 6 months and 3 years in the cases described [1, 7, 59, 94]. In AEC, conductive hearing loss due to chronic otitis media is treated with myringotomy and ventilation tubes, and voice, speech and feeding problems frequently persist after cleft closure, which justifies speech therapy [1, 88]. Pierre Robin sequence, present in one of Caceres's twins, required surgery because of feeding difficulties linked to retrognathia [76]. Trismus (35% in AEC) and micrognathia are factors to consider in airway planning [49, 91]. Choanal atresia has been described in EEC and AEC and should be sought in neonatal nasal obstruction [5, 92].

7.6. Oral health and dental rehabilitation

Hypodontia and conical teeth require early caries prevention, preservation of the primary and mixed dentitions and prosthetic rehabilitation: removable dentures in childhood and implants in adolescence or early adulthood, with bridges and implants in adults [1, 93, 132]. The 2023 scoping review of oral management in EEC included 15 studies, almost all case reports, with no randomised trials, and assigns the main role to the paediatric dentist [132]. The international Delphi consensus published in 2013 addressed the rehabilitation of children with ectodermal dysplasia, especially implants in growing patients [133]. Eleven teams of paediatric dentistry, prosthodontics and orthodontics from Sweden, France, the United Kingdom, the USA, Hong Kong and Australia answered a 90-question questionnaire in 19 clinical areas; consensus covered 61% of questions in the first round, a further 21% in the second and a further 8% in the third, and the remaining 9 questions (10%) were resolved at a face-to-face meeting in London, funded by the British Dental Association and an implant manufacturer [133]. The consensus does not grade the evidence; the authors state that the available clinical data did not answer all the questions and that the final wording is therefore conservative [133]. The answers agreed for questions without prior consensus were as follows: radiographs are taken only when clinically justified for diagnostic assessment, with no justification for routine use in young patients (it was stated that orthopantomography should not precede 6 years of age to clarify agenesis and that 10 intraoral radiographs are an alternative); the indication for sedation of a child not yet able to cooperate depends on the ethical and legal requirements of each country, and a conservative approach with training of the child is preferred, for example prior familiarisation with alginate and the impression tray; orofacial function is assessed as an individual problem, with the help of parents or carers, and the Nordic Orofacial Test–Screening, used in 46 Swedish centres, is a quick but not mandatory instrument; at 2–3 years, a removable partial denture is a possible option, rarely indicated at that age; and from 6 to 11 years the options are a removable partial denture and/or mandibular implants [133]. On implants in growing bone without alveolar bone, the consensus concluded that clinical and experimental data are insufficient to recommend implants in the maxilla in this group, in whom the end of growth is awaited and removable partial dentures have given good results, and that, from 7–8 years, implants may be placed in the anterior mandible when clinically justified [133]. The data discussed included a 20-year Swedish follow-up of 40 implants in 6 patients, with complications in 52% of implants, more in the maxilla than in the mandible, fracture in 11% and loss in 15%; another study with 36% prosthetic complications; a French series of maxillary bone grafts in ectodermal dysplasia, with 50% failures of unexplained cause, in specialised teams; and six edentulous maxillae treated at one centre with overdentures at 6–9 years, without complications but without long-term follow-up [133]. The consensus added that there is no evidence for using implant configurations different from those used in patients without the disease, that cantilevers should be as short as possible, that there is no evidence for mini-implants, and that the choice when vertical dimension is lost through ankylosis of primary molars depends on the evidence (as yet non-existent), the opinion of the patient and carers, resources and the experience of the team, with immediate post-extraction implants and tooth autotransplantation, the latter highly operator-dependent, both being acceptable [133]. The group agreed on a multicentre crossover trial in children aged 8 to 15 years with mandibular anodontia, to compare an overdenture on two implants with a fixed prosthesis on four implants [133]. The 2025 systematic review summarises the same position (implants in the anterior mandible from 7–8 years in necessary cases) and contrasts it with several systematic reviews that propose a minimum age of 10 years and with historical recommendations that deferred implants until the end of growth (16–18 years) [134]. The Jönköping consensus conferences (1996 and 1998) had set about 6 years as the minimum age for implants in the anodontic mandible of hypohidrotic ectodermal dysplasia, with a removable overdenture on one implant in each canine region; in the face of early implant losses in Swedish children, attributed to the reduced size of the jaws and the hardness of the bone, the Swedish national centre for rare oral diseases came to recommend deferring surgery until about 8 years in children without teeth in the mandible, placing additional implants and a fixed prosthesis from 18 years and, in children with some teeth, using tooth-supported prostheses until the end of growth [135]. These recommendations derive mainly from hypohidrotic ectodermal dysplasia, and their application to the TP63 disorders, in which cleft palate and surgical repair condition the maxillary bone, is an extrapolation. The 2025 systematic review (23 studies from 1994 to 2024, almost all reports and series; 46 patients aged 3 to 18 years, 192 implants, all with mandibular implants) found implant survival of 97.9% at 3 to 7 years (12 patients, mean follow-up 5.7 years), 100% at 8 to 12 years (21 patients, 4.2 years) and 91.3% at 13 to 18 years (5 patients, 8 years), with complications in 66.7%, 23.8% and 20% of patients, respectively; the complications (implants submerged or rotated by growth, remaking or relining of the prosthesis) were resolved with surgery or prosthetic adjustment, and maxillary implants had lower survival (3 losses in 32) [134]. The heterogeneity of the studies and the small number of patients per age group preclude an evidence-based minimum age [134]. In a 12-year-old girl with AEC and total edentulism, implants were considered contraindicated because of craniofacial growth and the limits of cleft repair, and complete bimaxillary removable dentures improved chewing, speech, aesthetics and confidence [136]. In AEC, only 22% of patients had prosthetic replacement of missing teeth, which the authors attribute to cleft palate treatment and to failure to recognise oral defects as part of the disease [90]. An ongoing Egyptian crossover trial is comparing 3D-printed overdentures with conventional acrylic overdentures in patients with ectodermal dysplasia aged 10 to 35 years [137].

7.7. Limbs

Hand and foot surgery and occupational therapy aim to optimise function; correction of the cleft hand and the feet was performed in early childhood in the cases described [1, 59]. Severe malformations of the leg bones associated with split hand/foot led to amputation in a Brazilian patient [60]. Ectrodactyly limits fine tasks such as inserting contact lenses, which matters for ocular planning [131].

7.8. Genitourinary tract

Hypospadias is corrected by paediatric urology; glanular hypospadias required no intervention in one patient, and phimosis with balanopreputial adhesions was corrected at four years [94]. In EEC3, obstructive anomalies (urethral stenosis, ureterocele, megaureter, bladder diverticula) may require internal urethrotomy, repeated dilatations, intermittent self-catheterisation or ureteric reimplantation [46, 80]. In the Dutch family, voiding difficulties with atrophic bladder epithelium improved with a synthetic sulphated glycosaminoglycan, and in Maclean's patients the severe difficulties persisted into adulthood, with biopsy-proven interstitial cystitis, without response to the oral therapy attempted [46, 80].

7.9. Growth and nutrition

Most children with AEC have faltering growth and need nutritional supplementation; many have needed gastrostomy, which should be considered early when the child is not thriving [1, 18]. At least a quarter have nutritional or gastrointestinal problems, including gastro-oesophageal reflux and constipation, and weight improves with supplementation, although height remains below the reference [1, 89]. In the boy from Botucatu, intolerance and refusal of oral feeding led to a nasoenteric tube and then gastrostomy at three years, with oral tolerance only at seven [94]. No patient in the 2006 symposium had been evaluated by endoscopy, and the causes of faltering growth are unclear [18].

7.10. Ovarian function, breasts and puberty

In POF21 and in LMS with ovarian insufficiency, oestrogen replacement induces pubertal development: in the Portuguese girl, transdermal oestradiol in increasing doses led to Tanner 4 thelarche and growth of the uterus from 14 to 35 mm in length, and in the Danish sisters oestrogen treatment normalised uterine size and allowed menstruation, indicating that uterine hypoplasia was secondary to ovarian insufficiency [30, 73, 105]. The sources do not describe the dosing scheme, which follows general practice for pubertal induction. Huang and colleagues advocate early diagnosis of female carriers, to allow fertility intervention, and identification of male carriers, who transmit the variant [11]. Breast hypoplasia or asymmetry can be corrected by plastic surgery [1].

7.11. Therapeutic research and developments in the last twelve months

All research targeting TP63 is at the preclinical stage, and no interventional human trial was found on ClinicalTrials.gov in October 2026; this negative search does not prove the absence of trials in other registries [1, 16]. The approaches follow three lines.

The findings of the last twelve months (November 2025 to October 2026) are: the isoform-switch strategy by gene editing, published online in December 2025 [141]; the preprint on allele-specific disruption in the cornea [139]; the first proband-independent PGT-M with the birth of a child without the variant [75]; the first Portuguese case of POF21 [105]; the description of cutaneous squamous cell carcinoma in an adult with a TID variant [78]; an atypical EEC3 due to a splice variant [107]; an ADULT-AEC phenotype diagnosed at 60 years [99]; a report of AEC focused on clinical diagnosis [143]; a series of three Chinese families with SHFM4 [144]; and the prosthetic rehabilitation of an edentulous adolescent [136]. None has resulted in an authorisation, regulatory opinion or clinical trial.

7.12. Regulatory status

7.13. Registered studies and limits of the evidence

There are no randomised trials or comparative studies of any intervention in the TP63 disorders. The skin care recommendations derive from expert opinion gathered in 2003 and 2006, the oral health recommendations from case reports and a Delphi consensus without grading of evidence, and the ophthalmological recommendations from centre experience [17, 18, 59, 132, 133]. The results of isolated cases, such as the absence of new exulcerations after the use of silver dressings or ocular stability with scleral lenses, do not allow the effect of the intervention to be separated from the spontaneous improvement with age described in AEC [93, 94, 131]. The rarity and the clinical variability with the same variant make trials difficult, as the authors of the Venice series acknowledge [59].

7.14. Agents and circumstances to avoid

Prolonged sun exposure should be avoided, to prevent burns of hypopigmented areas and increased contrast between hyper- and hypopigmented patches in AEC and to limit freckling in ADULT [1]. Occlusive dressings should be avoided on erosions, because they stimulate granulation tissue [1]. Aggressive debridement and grafts should be avoided on the scalp [18, 129]. Empirical antibiotic therapy without proven infection is not recommended outside the context of suspected sepsis [1]. Tetracyclines should not be used before 8 years of age [130]. In the eye, the Venice centre intentionally avoids topical non-steroidal anti-inflammatory drugs [59].

7.15. Pregnancy, perioperative care and transition

The sources consulted do not describe series of pregnancies in women with TP63 disorders. Pregnancy in an affected woman raises two issues: the 50% probability of transmission, with the fetal ultrasound surveillance described in 8.3, and fertility, which may be compromised in carriers of variants that cause ovarian insufficiency [1, 11]. Doxycycline should not be used in pregnancy unless the benefit outweighs the risk, and is not advised during breastfeeding because of its effect on dental development [130]. Perioperatively, the skin fragility of AEC, trismus, micrognathia and cleft palate are the relevant factors described in the sources; no specific anaesthetic recommendations were found [1, 76, 91]. Transition to adult care should preserve ophthalmological follow-up, because ocular surface disease worsens between the third and fifth decades, and dental and prosthetic follow-up, because implants are planned at the end of growth [1, 59]. The voiding difficulties of EEC3 may persist into adulthood [80].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

All TP63 disorders have autosomal dominant inheritance [1]. Counselling must convey two ideas simultaneously: the risk of transmitting the variant is 50% for each child of a carrier, but the child's phenotype cannot be predicted from the parent's phenotype, because of variable expressivity and incomplete penetrance [1, 86]. A mother with mild ectrodactyly may have a child with tetramelic split hand/foot and cleft lip/palate, and the reverse also occurs; the same variant may receive different names in successive generations [3, 60, 86].

Germline mosaicism has been documented in several families: the founder of an EEC family from Iowa, the parents of two sibling fetuses with severe EEC, the parents of two sisters with AEC and the mother without phenotype of dizygotic twins with AEC [1, 59, 64, 83]. In the case described by Kosaki, the father had mosaicism in blood and hair, but most of his spermatozoa carried the variant, which illustrates the difference between the somatic and germline fractions [46, 84]. Hence a negative test in the parents' blood does not reduce the recurrence risk to zero, and a family with two affected children of apparently normal parents should be studied for mosaicism [1]. In the South African family of Spranger and Schapera, three unaffected siblings of normal parents had affected children, and an unaffected descendant transmitted the disease, demonstrating non-penetrance across generations [101, 112].

8.2. Cascade testing and relatives at risk

Relatives at risk should be clarified, even when asymptomatic, to allow early surveillance of teeth and hearing and reproductive counselling [1]. Testing the parents for the familial variant is the first step in any simplex case, and careful clinical examination of the parents (nails, teeth, nipples, lacrimal puncta, skin pigmentation, hands and feet) may reveal minimal expression or mosaicism [1, 35, 84]. An apparently negative family history can only be considered negative after both parents have been tested [1]. In families with POF21, testing men is of reproductive interest, because they are transmitters without phenotype, and testing female carriers allows the early fertility intervention advocated by the authors [11]. There is no indication for carrier testing in the recessive sense, because all the entities are dominant.

8.3. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal testing and PGT-M are possible, and counselling should address the differing perspectives on their use, in a context in which severity is not predictable [1]. Detailed ultrasound for cleft, split hand/foot and uropathy is the indispensable complement to molecular testing, and may be more useful for estimating the phenotype than the variant alone [49, 114]. EEC has been identified on transvaginal ultrasound from 14 weeks in a fetus of unaffected parents, and obstructive uropathy may arise before birth [12, 47]. In Taiwan, a 34-year-old man with EEC features and the de novo variant c.925A>G, confirmed in sperm DNA, underwent three cycles of in vitro fertilisation with PGT-M by direct detection and STR haplotyping, combined with aneuploidy testing; of 17 blastocysts, six were at low risk for the variant and two of these were euploid, and transfer of one embryo resulted in a healthy newborn without the variant [75]. Haplotyping from the embryos made it possible to circumvent the lack of relatives to define the risk haplotype [75].

8.4. Fertility and family planning

Family planning should ideally be discussed before pregnancy, and counselling should be offered to young adults who are affected or at risk [1]. In carriers of TID variants or other variants associated with ovarian insufficiency, fertility may be reduced, and Huang and colleagues advocate early intervention [11]. Early menopause at 28 and 35 years in a family with RHS, and gonadal dysgenesis in a patient with LMS, show that assessment of ovarian reserve is also relevant to the syndromic forms [25, 100].

8.5. Minors

Testing asymptomatic minors from affected families has direct clinical utility, because it guides dental, audiological and ophthalmological surveillance from childhood [1]. In families with POF21, testing girls before puberty makes it possible to anticipate pubertal assessment and discussion of fertility, and the decision should involve the family and, according to maturity, the child herself [11, 105].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

The prevalence of the TP63 disorders, individually and collectively, is unknown [1]. The available figures measure different things and should neither be added together nor converted into one another.

Comparison with X-linked hypohidrotic ectodermal dysplasia, whose molecularly confirmed prevalence was 1.6/100,000 in Denmark, shows the order of magnitude of the most common ectodermal dysplasias and suggests that the TP63 disorders are rarer, although no population estimate confirms this [56]. The absence of population prevalence data in the sources does not mean that unconsulted regional studies do not exist.

9.2. Geographical distribution and populations described

TP63 disorders have been described in all populations, with no known founder effect; the recurrent EEC variants are C>T transitions at CpG dinucleotides, which arise repeatedly de novo [2, 41]. The core literature comes mainly from Europe and the USA: the Dutch LMS and EEC3 families (with follow-up of 26 affected members in 2011), the German ADULT family, the Finnish, Italian and Danish families with variants at arginine 337, the British series of 24 patients with EEC, the series from the United Kingdom, Ireland and Italy on eye disease and the North American NFED symposium cohort [18, 23, 28, 29, 46, 63, 85]. In Asia, these include the R313G (= p.(Arg352Gly)) variant of isolated cleft in a Thai series of 100 patients, the Thai RHS with S545P (= p.(Ser580Pro)), the Chinese families with SHFM4 and the Chinese POI cohort [11, 37, 39, 65, 144]. In South Africa, the family of Spranger and Schapera and that of Ianakiev, both from the Cape province, were the first with SHFM4 [112].

9.3. Brazil and Portugal

Brazil has made a historical contribution to this class. Freire-Maia's clinical classification of the ectodermal dysplasias was developed in Brazil in the 1970s [56]. The series of Rodini and Richieri-Costa (1990), with 20 Brazilian patients with EEC, is one of the largest clinical series before the molecular era [5]. In 2000 Bertola and colleagues described a 5-year-old Brazilian boy with ectodermal dysplasia, ankyloblepharon and bilateral choanal atresia without cleft, and later found the same I510T (= p.(Ile549Thr)) variant in one patient with AEC and another with RHS, one of the arguments for unifying the two syndromes [25, 92]. De Almeida and colleagues, in Porto Alegre, described adermatoglyphia as a manifestation of ADULT and the ADULT phenotype in a family with R298Q (historical numbering, = NM_003722.5:c.1010G>A p.(Arg337Gln)) [98, 148]. Alves and colleagues, in São Paulo, described a three-generation family from the North region with the variant p.(Ala346Gly) [60], and Amorim and colleagues, in Botucatu, the nine-year follow-up of a boy with AEC [94]. In Portugal, the only case identified in the sources is that of the girl with POF21 followed in Porto [105]. The sources consulted do not describe Portuguese series of EEC or AEC, which does not demonstrate that none exist.

9.4. Special populations

Dark skin. In African American infants with AEC, mask-like facial hypopigmentation may dominate the picture and improves with age, whereas in fair skin reticulate hyperpigmentation of the neck and skin folds predominates [1]. A family of African descent with EEC, a mother and three of her four children, was described in 1972 [12].

Twins. Two pairs of monozygotic twins with AEC have been described; in Caceres's pair, Pierre Robin sequence and hearing loss were discordant, which shows that variability does not depend on genotype alone [49, 76].

Preterm infants. A very low birth weight preterm infant with EEC/AEC overlap had immunodeficiency and secondary mitral regurgitation [72].

Adults and older people. The diagnosis may be made late, at 29, 59 or 60 years, after diagnoses of pemphigoid or dermatological complaints, and eye disease, keratoderma and possibly skin neoplasms weigh more at this stage [59, 78, 99].

9.5. Reference networks and patient associations

In the European Union, ERN-Skin, coordinated from the Hôpital Necker in Paris, brings together 56 hospitals from 20 countries and has a thematic group dedicated to ectodermal dysplasias, including incontinentia pigmenti and p63-associated disorders; its guidelines page lists only documents on X-linked hypohidrotic ectodermal dysplasia [19]. Recent research on AEC has involved centres of this network [141]. By scope, ERN CRANIO (clefts and craniofacial anomalies), ERN-EYE (ocular surface disease) and ERN ITHACA (congenital malformations) are also relevant [19]. In France, the FIMARAD network has a national protocol for anhidrotic ectodermal dysplasia and none for p63 disorders [126]. The European GeneSkin portal provides fact sheets for professionals on AEC and EEC [93, 149].

In the USA, the NFED maintains the International Ectodermal Dysplasia Registry, funded the 2003 Workshop and the 2006 Symposium, and supports research and families [1, 18, 20]. Other associations cited by GeneReviews are the Ectodermal Dysplasia Society (United Kingdom), Selbsthilfegruppe Ektodermale Dysplasie e.V. (Germany, Austria and Switzerland), the American Cleft Palate-Craniofacial Association, the Children's Craniofacial Association and Face Equality International [1]. The sources consulted did not identify a Portuguese or Brazilian association specific to ectodermal dysplasias.

10. Illustrative Clinical Case

10.1. Neonatal AEC syndrome with a de novo variant (Palermo, 2021)

Serra and colleagues described a newborn girl, the first child of healthy non-consanguineous parents, born at term by vaginal delivery after a pregnancy with gestational hypertension treated with acetylsalicylic acid and controlled diabetes [7]. The Apgar score was 9 and 10, weight 2,780 g (21st centile), length 47 cm (16th centile) and head circumference 33 cm (29th centile). On the first day she was transferred to the neonatal intensive care unit because of cleft palate and dysmorphism. Examination showed erythroderma with fine lamellar scaling, extensive erosions on the back, hands and gluteal region, sparse and coarse hair, ankyloblepharon filiforme adnatum, cleft palate and nail dysplasia, together with cupped ears, maxillary hypoplasia, a broad nasal root, short philtrum, microstomia, thin lips, microglossia, hypoplasia of the distal phalanx of the left second finger and widely spaced nipples. Transdermal losses, mainly from the scalp, required intravenous hydration in the first days. With topical antibiotics and antifungals and emollient and re-epithelialising creams, the body erosions and nail dysplasia resolved, with seborrhoeic-type erythematous lesions persisting on the scalp. The eyelid adhesions were excised on day 10, without complications. Full blood count, electrolytes, liver, renal and thyroid function, transfontanellar, cardiac and abdominal ultrasound and hearing screening were normal.

TP63 sequencing identified the heterozygous missense variant c.1727T>C p.(Ile576Thr) in exon 13, which encodes the SAM domain, absent from the parents and therefore de novo; in ClinVar the variant is classified as pathogenic by several submitters, without conflict [7, 38]. The patient was discharged at one month with multidisciplinary follow-up in ophthalmology, dermatology, surgery, stomatology and neurodevelopment. She underwent palatoplasty at 15 months and speech therapy for abnormal tongue position. Repeated conjunctivitis led to the diagnosis of agenesis of the lacrimal puncta, with surgical reconstruction planned. At 17 months she weighed 8,400 g (6th centile), measured 74.5 cm (2nd centile) and had a head circumference of 44.6 cm (13th centile), according to the World Health Organization charts; she continued emollients and re-epithelialising creams, and had small areas of dermatitis with erosions, crusts and scarring alopecia on the scalp, sparse hair, eyebrows and eyelashes, thin dystrophic nails, oligodontia with conical teeth and mild cognitive and language delay, with regular neuromotor milestones. Figure 1 of the article shows the frontal and lateral views of the dysmorphism, hair and ears (https://pmc.ncbi.nlm.nih.gov/articles/PMC8479907/figure/Fig1/), and Figure 2 the scalp before and after prolonged treatment (https://pmc.ncbi.nlm.nih.gov/articles/PMC8479907/figure/Fig2/) [7].

The case brings together the elements that define AEC in the neonatal period: the triad of ankyloblepharon, ectodermal defects and cleft palate, acute skin failure with fluid and electrolyte risk, and progression to scarring alopecia, faltering weight and height and lacrimal obstruction recognised only after recurrent conjunctivitis [1, 18]. Excision of the adhesions on day 10 contrasts with the frequent autolysis of small strands described in GeneReviews, and the two approaches depend on the size of the adhesions [1]. The article assigns OMIM number 129900 to EEC and 603273 to RHS; the correct numbers are 604292 (EEC3) and 129400 (RHS), 603273 being the gene number [25, 46].

10.2. Nine-year follow-up in AEC syndrome (Botucatu, 2024)

A second, Brazilian, case shows the course throughout childhood. Amorim and colleagues followed from four months of age a boy born at term to non-consanguineous parents, with ulcerated lesions from birth on the trunk, scalp, face and upper limbs, onychodystrophy of all nails, ankyloblepharon corrected in the delivery room, cleft palate, pinna deformity and micropenis, initially referred as epidermolysis bullosa [94]. In the first three months he was admitted for transepidermal losses with fluid and electrolyte imbalance, skin infections, otitis and pneumonia. Food refusal led to a nasoenteric tube and gastrostomy at three years, the same age as cleft repair, and oral feeding was tolerated only at seven years. The scalp exulcerations, with exuberant granulation and colonisation by meticillin-resistant S. aureus and P. aeruginosa, stopped recurring only at seven years, after superficial debridements and silver foam dressings. At nine years he had scarring alopecia, madarosis, onychodystrophy, hypodontia with conical teeth, hypo- and hyperchromic and hypertrophic scars, generalised anhidrosis with heat intolerance, xerosis, short stature, mild psychomotor developmental delay and tympanic perforation from recurrent otitis. Molecular testing is not mentioned in the article. Figures 1 (exulcerations of the scalp, face, back and upper limbs at four months; https://pmc.ncbi.nlm.nih.gov/articles/PMC11551266/figure/fig0005/) and 4 (scarring alopecia and onychodystrophy at nine years; https://pmc.ncbi.nlm.nih.gov/articles/PMC11551266/figure/fig0020/) document this course [94]. The authors state that only cleft palate occurs in AEC and that limb involvement is minimal; these statements do not match the published series, which describe cleft lip in 47–83% and toe syndactyly in almost half of patients [18, 89, 91].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Vital prognosis in AEC is dominated by the neonatal period: in the series of 12 patients from the 2003 Workshop, 2 (17%) died in childhood, and deaths from sepsis have been described in infants [17, 18]. After early childhood, the sources describe a good overall prognosis and normal life expectancy, with no survival studies to quantify it [7, 94]. Scalp erosions improve with age in most patients, and the disease is described as non-progressive [93]. In EEC3, cognition is normal in most (intellectual disability in about 7%), and long-term morbidity depends on the eye, with limbal insufficiency in 61% of a series of 23 patients and worsening between the third and fifth decades, and on urinary anomalies [5, 59, 63]. In ADULT and LMS, prognosis depends mainly on hand function, oral health and, in women, ovarian function [1, 73]. The association with epithelial neoplasms rests on isolated cases and, in the sources consulted, does not justify a specific cancer screening programme [46, 54, 78].

11.2. Initial evaluation after diagnosis

Renal and bladder ultrasound does not appear in the GeneReviews initial evaluation table; it is justified because genitourinary anomalies affect 45% of patients with EEC3 and may be obstructive from the fetal period [1, 47].

11.3. Surveillance

The sources do not set surveillance intervals: GeneReviews leaves the frequency of dental and audiological assessments to the specialist, and the Venice centre recommends regular monitoring of the ocular surface without defining the interval [1, 59]. The table gives, for each examination, the age at which to start and the action threshold supported by the sources.

12. Summary and Final Considerations

TP63-related disorders are a group of autosomal dominant diseases caused by variants of a transcription factor that governs the development of squamous epithelia, their appendages and the apical ectodermal ridge of the limbs. EEC3, AEC (with the former Rapp-Hodgkin syndrome), ADULT and limb-mammary syndromes, SHFM4, orofacial cleft type 8 and premature ovarian insufficiency type 21 result from different mechanisms depending on the domain affected: dominant-negative interference by DNA-binding domain variants in EEC3, protein aggregation with SAM domain variants in AEC, gain of function at arginine 337 in ADULT, haploinsufficiency in isolated clefting and constitutive activation of oocyte TAp63α in ovarian insufficiency. The boundaries between entities are porous, the same variant can give different phenotypes within the same family, penetrance is incomplete in some families and parental mosaicism is frequent, which complicates counselling and makes it necessary to examine and test the parents.

Diagnosis is molecular, based on clinical suspicion built from the combination of cleft, central ray malformation, ectodermal dysplasia and lacrimal anomalies or, in the newborn, cleft palate with skin erosions and ankyloblepharon, which distinguish it from epidermolysis bullosa and the ichthyoses. Reading the literature requires attention to variant numbering, because the founding works use a sequence lacking the first 39 amino acids of the current reference protein. Treatment remains symptomatic and multidisciplinary, supported by expert consensus rather than trials: gentle wound care and infection control in AEC, lifelong ophthalmological surveillance for the limbal insufficiency of EEC, rehabilitation of the cleft, hearing, teeth and hands, and attention to the urinary tract and ovarian function. The targeted therapies under study, from reactivation of mutant p63 to allele silencing and isoform switching by gene editing, remain at the preclinical stage.

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