TYPE Perspective

PUBLISHED 06 September 2022

DOI 10.3389/fgene.2022.1000744

Ectodermal dysplasias: New

OPEN ACCESS perspectives on the treatment of
EDITED BY
Jordi Pérez-Tur,
Institute of Biomedicine of Valencia
so far immedicable genetic
(CSIC), Spain

REVIEWED BY
disorders
Izzet Yavuz,
Dicle University, Turkey
Holm Schneider*
*CORRESPONDENCE
Holm Schneider, Center for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen,
[email protected] Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

SPECIALTY SECTION
This article was submitted to Genetics of
Common and Rare Diseases,
a section of the journal
The past decade has witnessed an expansion of molecular approaches
Frontiers in Genetics
facilitating the differential diagnosis of ectodermal dysplasias, a group of
RECEIVED 22 July 2022
ACCEPTED 04 August 2022
genetic diseases characterized by the lack or malformation of hair, teeth,
PUBLISHED 06 September 2022 nails, and certain eccrine glands. Moreover, advances in translational
CITATION research have increased the therapeutic opportunities for such rare diseases,
Schneider H (2022), Ectodermal and new dental, surgical, and ophthalmic treatment options are likely to offer
dysplasias: New perspectives on the
treatment of so far immedicable
relief to many individuals affected by ectodermal dysplasias. In X-linked
genetic disorders. hypohidrotic ectodermal dysplasia (XLHED), the genetic deficiency of the
Front. Genet. 13:1000744. signaling molecule ectodysplasin A1 (EDA1) may even be overcome before
doi: 10.3389/fgene.2022.1000744
birth by administration of a recombinant replacement protein. This has been
COPYRIGHT
shown at least for the key problem of male subjects with XLHED, the nearly
© 2022 Schneider. This is an open-
access article distributed under the complete absence of sweat glands and perspiration which can lead to life-
terms of the Creative Commons threatening hyperthermia. Prenatal treatment of six boys by injection of an
Attribution License (CC BY). The use,
distribution or reproduction in other EDA1 replacement protein into the amniotic fluid consistently induced the
forums is permitted, provided the development of functional sweat glands. Normal ability to sweat has so far
original author(s) and the copyright
persisted for >5 years in the two oldest boys treated in utero. Thus, timely
owner(s) are credited and that the
original publication in this journal is replacement of a missing protein appears to be a promising therapeutic strategy
cited, in accordance with accepted for the most frequent ectodermal dysplasia and possibly additional congenital
academic practice. No use, distribution
or reproduction is permitted which does
disorders.
not comply with these terms.
KEYWORDS

ectodermal dysplasia, molecular therapy, ectodysplasin A, neonatal Fc receptor, stem

cell, prosthodontic rehabilitation, tissue-engineering

Introduction
The genetic basis of the prenatal development of vertebrates has been studied
extensively for almost five decades, leading to a more comprehensive understanding
of the interplay between the many genes involved and the developmental windows in
which their expression is required. In the field of medicine, this knowledge may have both
diagnostic and therapeutic implications.
The ectoderm, one of three germ layers in the early embryo, gives rise to the central
and peripheral nervous system, the neural crest cells, the tooth placodes, and the
epidermis with its appendages. Impaired ectodermal development, thus, can result in

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Schneider 10.3389/fgene.2022.1000744

a variety of congenital disorders, including 189 conditions produce heat. In response, heat sensors in the hypothalamus send
initially classified as ectodermal dysplasias (Freire-Maia, 1971; a signal to the sweat glands that induces perspiration. The sweat
Pagnan and Visinoni, 2014). Three molecular pathways, namely subsequently evaporates from the skin, and this evaporation
ectodysplasin A, Wnt/β-catenin and tumor protein 63 (p63) cools the body. Sweating is essential for our thermoregulation
signaling, have been found to play major roles in the budding particularly during outdoor activities on sunny days, in cases of a
and morphogenesis of ectodermal derivatives (Mikkola and febrile virus infections, or in hot environments. Young infants
Thesleff, 2003; Mikkola, 2007; Harris et al., 2008; Cui et al., exposed to heat are at highest risk of developing a heat-related
2014). Almost all genes known to regulate the position, shape, or illness. If you place a newborn who cannot sweat in an incubator,
number of teeth or hairs have important functions in the his head will soon become red and warm to the touch, the
mediation of cell communication, which is generally respiratory rate will go up dramatically, but his body temperature
considered the most important mechanism driving embryonic will rise despite panting. Within a few hours a life-threatening
development (Thesleff, 2003). Integration of genomics has been situation may develop (Blüschke et al., 2010). An older child at
instrumental in explaining complex sequential interactions risk of overheating will intuitively search for water, shade, or cold
between epithelium and mesenchyme that direct ectodermal surfaces to cool himself down, but such opportunities may not be
differentiation. This brought about a new classification system as readily available as needed. Being unable to sweat is life-
for ectodermal dysplasias (Wright et al., 2019; Peschel et al., threatening—from the hour of birth! Apart from hypo- or
submitted) based on the molecular pathways rather than just the anhidrosis there are other cardinal symptoms of XLHED,
anatomical structures affected. Grouping rare diseases according such as missing or misshapen teeth which do not erupt on
to shared characteristics of pathogenesis is expected to facilitate time. Oligodontia and heat intolerance are usually more
differential diagnosis as well as genetic counselling and becomes severe in boys with XLHED than in affected girls because
even more important with molecular therapies on the horizon. male patients have a single copy of the X chromosome that
Several research groups have used animal models to establish carries the disease-causing mutation, while in females the two X
successful approaches to treating disorders of ectodermal chromosomes most often differ in genetic content and the variant
development (e.g., Gaide and Schneider, 2003; Hermes et al., is usually expressed in only about half the cells. The absence of
2014; Watanabe et al., 2015; Jia et al., 2017a; Jia et al., 2017b). multiple teeth, however, allows non-invasive prenatal diagnosis
Although the pharmaceutical industry has remained reluctant to as early as 5 months before birth by tooth bud counting during a
invest in such strategies, one of them, namely the prenatal routine fetal ultrasound scan (Wünsche et al., 2015; Hammersen
replacement of missing EDA1 in children with the most et al., 2019).
prevalent ectodermal dysplasia, the X-linked hypohidrotic
form (XLHED), is currently being evaluated in a worldwide
clinical study (ClinicalTrials.gov identifier: NCT04980638). Clinical trials of postnatal protein
This trial constitutes the first attempt to investigate a replacement
pharmacotherapy of genetic disease in patients in utero. If
successful, knowledge transfer to the treatment of other Individuals with XLHED lack functional EDA1, a
congenital disorders will be facilitated. For ectodermal heterotrimeric transmembrane protein of the TNF family, the
dysplasias caused by variants of the gene TP63 (encoding the signaling part of which is released by the protease furin leading to
transcription factor p63), the typical skin and corneal lesions may its circulation with the blood stream. For more than 15 years an
be amenable to cell therapy using genetically corrected international research consortium has been investigating a
autologous stem cells. Last but not least, small molecule drugs recombinant replacement protein that resembles natural
are being increasingly used to improve the outcome of EDA1. In this molecule named Fc-EDA, the receptor binding
prosthodontic treatment, the longevity of dental implants, domains are linked by Fc fragments of immunoglobulins. It binds
results of the surgical repair of orofacial clefts, or ocular to the natural EDA1 receptor (EDAR) and activates the signaling
surface regeneration. Similar small molecule therapies might cascade inducing the formation of sweat glands, hair, and teeth.
also be developed for the treatment of other manifestations of Fc-EDA has been evaluated in clinical trials: first in a Phase I
ectodermal dysplasias. study in adults with XLHED who received five doses of the drug
intravenously (ClinicalTrials.gov identifier: NCT01564225). Two
dose cohorts were investigated, in which no relevant side effects,
Molecular therapy before birth except for the formation of anti-drug antibodies, were observed.
Then we conducted a Phase 2 dose-escalation study in infants
In hypohidrotic forms of ectodermal dysplasia, such as with XLHED who were treated within 28 days after birth
XLHED, the congenital absence of most if not all sweat (ClinicalTrials.gov identifier: NCT01775462), and we assessed
glands (Schneider et al., 2011) causes the main clinical safety, pharmacokinetics, and efficacy of Fc-EDA. Unfortunately,
problem. Why is that? While exercising, for example, muscles almost no sweat ducts could be detected by confocal laser-

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Schneider 10.3389/fgene.2022.1000744

FIGURE 1
Eccrine sweat gland development. In the human fetus, eccrine sweat glands begin to form in palmoplantar skin and a bit later (around
gestational week 20) across the rest of the body. At 30 weeks of gestation most sweat glands have already completed the critical portion of
development but still lack sympathetic innervation.

scanning microscopy after postnatal dosing and the subjects were corrected the development of hair, teeth, and sweat glands in the
unable to perspirate (Körber et al., 2020). Hence, the most presence of intact FcRn, proving that the therapeutic route of the
important aim had not been achieved. We reasoned that, if drug is systemic rather than through a direct effect on the skin
there was any chance of success, we would need to administer and oral epithelia (Schneider et al., 2018). In dogs with XLHED,
the drug within the natural time window of sweat gland minimally invasive delivery of Fc-EDA into the amniotic fluid
formation. also rescued the formation of skin appendages and teeth
(Margolis et al., 2019).
During this time we were approached by a pregnant
Treatment with Fc-EDA in utero woman with a family history of XLHED who was
concerned that the twins she was carrying would be
In humans, eccrine sweat gland development starts around affected. Her older son had the disease and showed a
gestational week 20 with the formation of a placode in the complete absence of sweat glands and perspiration.
epidermis. This placode soon undergoes solid cylindrical Prenatal tooth germ counting led to the diagnosis of
downgrowth into the mesenchyme (Figure 1). Once long XLHED in both male twins. We investigated the functional
enough, a lumen develops, the duct end begins to coil and impact of the EDA variant identified in the family, c.911A>G
becomes surrounded by myoepithelial cells. All these events (p.Y304C), which was demonstrated to result in an insoluble
take place in gestational weeks 20–30 (Ersch and Stallmach, EDA1 protein with complete loss of function and, thus,
1999). Sympathetic innervation of the gland, however, is only represents a null mutation. The parents requested
completed postnatally. Thus, in order to rescue sweat gland compassionate use of Fc-EDA to treat the affected
formation, delivery of Fc-EDA at the end of the second dichorionic twins in utero. This request was considered by
trimester of pregnancy appeared to be the most rational our team and finally approved by the ethics committee of our
approach. That brings us back to an essential component of university hospital. Using ultrasound guidance, we
our replacement protein, the Fc fragments, which allow a new administered two doses of the drug into each amniotic
drug-delivery method using the neonatal Fc receptor (FcRn). In cavity at gestational weeks 26 and 31. Postnatally, an
mammals, including human babies, FcRn is situated in gut intriguing finding was the rise in the number of tooth
epithelia and mediates the uptake of maternal antibodies from germs. After treatment in utero we detected 10 and 8 tooth
breast milk. It binds the Fc portion of such antibodies and buds, respectively, whereas prenatal sonography and MRI had
transports them across the intestinal epithelium into the revealed no more than two tooth germs in either twin
baby’s blood (Martins et al., 2016). FcRn-mediated (Schneider et al., 2018). The untreated older brother had
transcytosis is already operational in the fetus in the third three teeth and one additional tooth bud in total. Even
trimester of pregnancy when a fetus regularly swallows more impressive was the normal sweat-duct density on the
amniotic fluid. In Tabby mice, a naturally occurring animal soles of the feet, while we did not observe any sweat ducts in
model of XLHED, prenatal administration of Fc-EDA into the the untreated older brother. The twins’ ability to perspire,
amniotic cavity of affected embryos was shown to prevent the quantified by measuring pilocarpine-induced sweat
disease completely (Hermes et al., 2014). This treatment only production, also proved to be normal. To date pilocarpine-

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FIGURE 2
Oral rehabilitation in a woman with ectodermal dysplasia missing 14 permanent teeth. (A), affected female adolescent before multidisciplinary
dental treatment. (B), results of prostodontic rehabilitation. (Photos: Prof. Dr. Stephan Eitner, Department of Prosthodontics, and Dr. Dr. Ines
Willershausen, Department of Orthodontics and Orofacial Orthopedics, University Hospital Erlangen).

induced sweating has remained at roughly the same level. No efficacy endpoints will be compared to data of untreated affected
hyperthermic episodes or XLHED-related hospitalizations relatives.
have occurred. And there are good reasons to assume that
once sweat glands are normally formed they will work
permanently. Generation of replacement tissues for
Half a year later we treated another affected boy who therapies after birth
received, however, only one dose of Fc-EDA in utero. This
boy developed slightly fewer sweat glands and produced less Ectodermal dysplasias resulting from a dysfunctional
sweat than the treated twins, suggesting an advantage of repeated p63 protein, in particular ankyloblepharon-ectodermal
dosing (Schneider et al., 2018). Although the replacement protein dysplasia-cleft lip/palate (AEC) syndrome and ectrodactyly-
was detectable in cord blood samples, confirming an efficient ectodermal dysplasia-cleft lip/palate (EEC) syndrome, are
uptake from amniotic fluid into the fetal blood, Fc-EDA serum characterized by typical tissue defects. Most of the children
concentrations in the pregnant women always remained below with AEC syndrome suffer from painful skin erosions that
the detection limit, indicating minimal if any maternal drug can lead to infection, scarring, and hair loss (Siegfried et al.,
exposure. Anti-drug antibodies that had been found after 2005; Maillard et al., 2019). In patients with EEC syndrome,
intravenous administration in adult males and non-pregnant recurrent corneal lesions are frequently observed, culminating in
females did not appear to be elicited in the mother when Fc-EDA loss of vision (Felipe et al., 2012). The primary cause of the slow
was delivered intra-amniotically (Körber et al., 2020). corneal healing process appears to be a malfunction and later
Transillumination of the treated infants’ eyelids revealed a disappearance of limbal stem cells (Di Iorio et al., 2012).
larger amount of Meibomian glands than usually present in Orofacial clefts that are typical manifestations of both AEC
subjects with XLHED (Schneider et al., 2018). In all three and EEC syndrome require surgical treatment of soft tissue
treated boys, we observed increased, basically normal saliva and bone defects. Patients with many types of ectodermal
production. Thus, the prenatal therapy does not only rescue dysplasia, irrespective of the molecular pathway impaired, are
sweat gland development but also seems to have an impact on the afflicted with a lack of teeth. Preservation of oral function
function of other eccrine glands. Three more affected boys includes dental implant therapy, often associated with bone
received Fc-EDA on a named-patient basis repeatedly between augmentation prior to implant placement.
gestational weeks 25 and 31 and are now able to perspire as
efficiently as the infants we had treated before.
The efficacy and safety of Fc-EDA (now also called ER004) as Regenerative therapies for skin and
a prenatal pharmacotherapy for male subjects with XLHED is corneal lesions
currently being investigated in a multicenter clinical trial,
benefitting from the PRIME scheme of the European In patients with AEC syndrome, treatment of chronic skin
Medicines Agency and fast-track designation by the FDA. Up lesions based on the expansion and grafting of genetically
to 20 patients will be treated in utero with three injections of Fc- corrected autologous keratinocytes might be feasible and has
EDA, the first one at the beginning of gestational week 26. At the been discussed (Koch and Koster, 2021). This may involve the
age of 6 months, the pilocarpine-induced sweat volume and other generation of patient-specific induced pluripotent stem cells,

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correction of the disease-causing TP63 mutation with genome helpful. This is often accompanied by maxillofacial surgery
editing techniques, subsequent differentiation of corrected stem preparing the jawbone for dental implants. Alternatively,
cells into keratinocytes, and production of keratinocyte sheets to autogenous tooth transplantation may be considered.
be transplanted onto the chronic wound, a technically very Present-day prosthodontic rehabilitation concepts
challenging and time-consuming approach. Alternatively, such frequently include the replacement of at least some missing
keratinocyte sheets could also be produced from patient-derived teeth by endosseous implants. As a result of hypo- or even
epidermal stem stells, as shown recently by the successful anodontia, however, the bony ridge of the jaw that normally
regeneration of almost an entire, fully functional epidermis on holds the teeth in place fails to develop properly. Therefore,
a child with severe junctional epidermolysis bullosa (Hirsch et al., bone grafting is a common prerequisite for implant surgery in
2017; Kueckelhaus et al., 2021). In this respect, the CRISPR/Cas patients with ectodermal dysplasias (Chrcanovic, 2018).
genome editing system may hold a lot of promise. Novel Guided alveolar ridge augmentation involves the
engineered CRISPR-associated endonucleases allow for much transplantation of bone from another site of the body,
higher specificity and fewer off-target effects than previous donor bone, or synthetic bone substitute that is covered
systems, which has improved gene editing for autosomal with a semi-permeable membrane. Natural osteogenesis
dominant diseases that cannot be tackled by alternative allele- then leads to a new bony base for the implant (Chrcanovic,
specific gene therapy (Caruso et al., 2022). 2018). Stability and long-term survival of dental implants
Similar strategies might be used to treat non-healing corneal depend on their osseointegration. Various small molecules
abrasions in patients with EEC or AEC syndrome. Human limbal with osteoinductive activity have been investigated that
stem cells, which are crucial for corneal epithelial regeneration induce for example bone morphogenetic protein-2 signaling
and for the maintenance of a physical barrier between the clear, or the Wnt pathway. Such small molecule drugs can be
avascular cornea and the vascularized conjunctiva, can be administered together with biomaterials and direct the
cultured in vitro for transplantation (Rama et al., 2010). differentiation of target cells, improve survival of the newly
Autologous, ex vivo expanded epithelial cells containing limbal formed tissue in the body, or stimulate endogenous stem cells
stem cells were approved some years ago as an advanced-therapy to enhance tissue repair (Lu and Atala, 2014).
medicinal product to treat severe limbal stem cell deficiency Today the outcome of multidisciplinary dental care is usually
(Pellegrini et al., 2018). Regeneration of the cornea with this satisfactory and sometimes astonishing (Figure 2). This has
method has led to the recovery of vision in numerous patients contributed to increased self-esteem of children, adolescents,
and is one of the first examples of a successful stem cell therapy and adults with ectodermal dysplasias.
(Pellegrini et al., 2018; De Luca et al., 2019). Considering the
healthy marriage of gene and stem cell therapy in other fields
(Nogrady, 2019), I see sense in merging the two also for the Conclusion
treatment of p63-associated syndromes.
In addition, the small molecule drug PRIMA-1MET, a Therapeutic perspectives for individuals affected by
p53 reactivator which has been tested in clinical trials for the ectodermal dysplasias have become exciting. Drug targeting
treatment of malignant neoplastic disease, was recently shown to via the neonatal Fc receptor may cure a so far immedicable
rescue epidermal differentiation and to improve wound healing genetic deficiency: the life-threatening inability to sweat
in patients with AEC syndrome when applied topically to associated with XLHED. Such treatment is efficient in
affected regions of the skin (Aberdam et al., 2020). Its utero, but without significant therapeutic effects if
mechanism of action, however, has remained unclear. performed after birth. A pivotal clinical trial of fetal
therapy that could lead to an approval of the new drug is
now recruiting patients. In this study, Fc-EDA will be
New dental treatment options administered to XLHED-affected male fetuses, trying to
confirm the clinical improvements we have seen in the first
Dental care of individuals with ectodermal dysplasias is six boys treated in utero. Last but not least, the same drug
challenging, but may profit tremendously from novel delivery route might be usable for the treatment of other
biomaterials and oral rehabilitation strategies. Treatment disorders of early development. Translational research is also
during childhood ranges from tooth shape corrections using paving the way to more effective regenerative therapies for
composite build-ups to removable partial or complete dental skin and corneal lesions using patient-derived epidermal or
prostheses and orthodontic appliances. Presurgical infant limbal stem stells. Furthermore, dental treatment options
orthopedics and maxillofacial surgery are required for cleft based on novel biomaterials, replacement of missing
palate repair (in case of p63-associated syndromes). If many jawbone, and prosthodontic rehabilitation exist that will
secondary teeth are absent, orthodontic space closure as well as help improve oral function in almost all individuals with
teeth distribution to improve prosthetic restoration will be ectodermal dysplasias.

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Data availability statement Acknowledgments

Access to the original data of clinical trials is restricted to I would like to express my deep gratitude to all my
protect confidential or proprietary information. The data that colleagues at the Center for Ectodermal Dysplasias
support the findings reported here are available from the author Erlangen (CEDER), to the many collaborators involved in
upon reasonable request. Requests to access these datasets should this work, to our public funders (Deutsche
be directed to Holm Schneider, [email protected]. Forschungsgemeinschaft, Care-for-Rare Foundation,
German Federal Ministry of Education and Research,
German-Swiss-Austrian ectodermal dysplasia patient
Ethics statement organization, National Foundation for Ectodermal Dysplasias,
Forberg Foundation, EspeRare Foundation) as well as to our
The studies involving human participants were reviewed industry partners (Edimer Pharmaceuticals, Inc., Pierre Fabre
and approved by Ethics Commission, University of Medicament), and particularly to the patients and their families
Erlangen-Nürnberg, or Clinical Ethics Committee, who have supported every step of our research.
University Hospital Erlangen. Written informed consent
to participate in this study was provided by the
participants’ legal guardian/next of kin. Written informed Conflict of interest
consent was obtained from the individual(s) for the
publication of any potentially identifiable images or data HS is inventor on a patent related to the prenatal treatment of
included in this article. XLHED. He signed, however, a Remuneration Waiver
Agreement with the Free State of Bavaria to relinquish any
personal financial gain from this invention.
Author contributions
HS wrote the manuscript. Publisher’s note
All claims expressed in this article are solely those of the
Funding authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
This work has been funded by the German Federal Ministry reviewers. Any product that may be evaluated in this article, or
of Education and Research (grant 01KG2008 to HS) and by the claim that may be made by its manufacturer, is not guaranteed or
EspeRare Foundation (Switzerland). endorsed by the publisher.

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