A Causal Treatment for X-Linked Hypohidrotic Ectodermal Dysplasia: Long-Term Results of Short-Term Perinatal Ectodysplasin A1 Replacement.

X-linked hypohidrotic ectodermal dysplasia (XLHED), caused by a genetic deficiency of ectodysplasin A1 (EDA1), is a rare developmental disorder of ectodermal derivatives such as hair, sweat glands, and teeth. The absence of sweat glands and perspiration can evoke life-threatening hyperthermia. As molecular genetic findings are not always conclusive, the concentrations of circulating EDA1 may help to distinguish between total and partial EDA1 deficiencies. We previously treated nine male patients with obvious signs of XLHED with a recombinant EDA1 replacement protein, Fc-EDA, either shortly after birth (n = 3) or by prenatal administration in gestational week 26 and beyond (n = 6). Here, we present the long-term follow-up for up to six years. In patients who had received Fc-EDA after birth, neither sweat glands nor sweating ability were detected at the age of 12-60 months. In contrast, prenatal EDA1 replacement resulted in ample sweat gland development and pilocarpine-inducible sweating in all treated subjects, who also attained more permanent teeth than their untreated affected relatives. Normal perspiration has persisted for six years in the two oldest boys treated repeatedly with Fc-EDA in utero. When they had a sauna, adequate thermoregulation was evidenced. Lower sweat production after single prenatal dosing may indicate a dose-response relationship. The absence of circulating EDA1 in five prenatally treated subjects proved that these children would have been unable to perspire if they had been left untreated. The sixth infant was shown to produce an EDA1 molecule that, albeit interacting with its cognate receptor, cannot activate EDA1 signaling. In conclusion, a causal treatment of XLHED before birth is feasible.

X-linked hypohidrotic ectodermal dysplasia management with removable prosthesis in a pediatric patient: case report / Manejo de displasia ectodérmica hipohidrótica ligada al cromosoma X con prótesis removible en un paciente pediátrico: reporte de caso

Introduction: Ectodermal dysplasia is a rare genetic disorder that affects structures derived from ectoderm such as teeth, hair, nails, and sweat glands. Oligodontia is a common finding that affects the chewing, smiling and self- esteem of these pediatric patients. Case Report: We present a case report of a 7-years-old pediatric patient who consulted with his mother, showing the same condition. The intervention consisted of a removable prosthesis with satisfactory results. Conclusion: The X-linked hypohidrotic ectodermal dysplasia represents a challenge for a pediatric dentist who offers rehabilitation to the patient according to craniofacial development, age, socioeconomic status, and the number of missing teeth.

Introducción: La oligodoncia es un hallazgo común que afecta la masticación, la sonrisa y la autoestima de estos pacientes pediátricos. Case Report: Presentamos un reporte de caso de un paciente pediátrico de 7 años que consultó con su madre presentando la misma condición. La intervención consistió en una prótesis de remoción con resultados satisfactorios. Conclusión: La displasia ectodérmica hipohidrótica ligada al cromosoma X representa un desafío para un odontopediatra que ofrece rehabilitación al paciente de acuerdo con el desarrollo craneofacial, la edad, el nivel socioeconómico y el número de dientes faltantes.

Emerging therapies in genodermatoses.

The human genome project yielded a compendium of genetic material that has allowed rapid advancement both in the technique of whole exome sequencing and also in the ability to identify single gene defects. The next generation of genetics has investigated how these genes interact in the development of disease, identifying pathways of illness and end organ tissue abnormal development. From the knowledge of single genes and pathways of genodermatosis development arises the opportunity to produce genetic therapies. This contribution reviews some of the exciting, emerging genetic therapies in genodermatoses.

Attenuation of Mammary Gland Dysplasia and Feeding Difficulties in Tabby Mice by Fetal Therapy.

Hypohidrotic ectodermal dysplasias (HED) are hereditary differentiation disorders of multiple ectodermal structures including the mammary gland. The X-linked form of HED (XLHED) is caused by a lack of the secreted signaling molecule ectodysplasin A1 (EDA1) which is encoded by the gene EDA and belongs to the tumor necrosis factor (TNF) superfamily. Although male patients (hemizygous) are usually more severely affected by XLHED, heterozygous female carriers of an EDA mutation may also suffer from a variety of symptoms, in particular from abnormal development of their breasts. In Tabby mice, a well-studied animal model of XLHED, EDA1 is absent. We investigated the effects of prenatal administration of Fc-EDA, a recombinant EDA1 replacement protein, on mammary gland development in female Tabby mice. Intra-amniotic delivery of Fc-EDA to fetal animals resulted later in improved breastfeeding and thus promoted the growth of their offspring. In detail, such treatment led to a normalization of the nipple shape (protrusion, tapering) that facilitated sucking. Mammary glands of treated female Tabby mice also showed internal changes, including enhanced branching morphogenesis and ductal elongation. Our findings indicate that EDA receptor stimulation during development has a stable impact on later stages of mammary gland differentiation, including lactation, but also show that intra-amniotic administration of an EDA1 replacement protein to fetal Tabby mice partially corrects the mammary gland phenotype in female adult animals.

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia.

Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.).

Bone defects and future regenerative nanomedicine approach using stem cells in the mutant Tabby mouse model.

X-linked Hypohidrotic Ectodermal Dysplasia (XLHED) is associated to a large spectrum of ectodermal and extra-ectodermal symptoms, especially craniofacial bone morphological, structural and metabolic anomalies. This skeletal phenotype described in affected patients and in the Ta mutant mouse model leads to craniofacial dysmorphies, endosseous implants and jaw bone grafts complications. Bone tissue bioengineering based on the use of PCL synthetic nanofibrous membrane and BMP nanoreservoirs appears as an original and promising approach to prevent such complications in the context of dysfunctional bone. Use of osteoblasts or stem cells seeded biomembranes appears as another strategy developed on the Tabby (Ta) model of XLHED. The Ta mouse experimental model is used to study the jaw bone response during the post-operative period after bone lesion and placement of synthetic PCL membrane functionalized with nanoreservoirs embedding different BMPs dimers or seeded with living cells.

Implant-supported fixed prosthesis in a hypohidrotic ectodermal dysplasia patient: a case report with 3 years follow-up and review of the literature.

INTRODUCTION: Ectodermal dysplasia (ED) is a rare inherited disorder that affects structures derived from embryonic ectoderm. Due to associated ridge deficiency, and anodontia found in these patients, multiple surgeries are often indicated before replacement of missing teeth with implants, resulting in increased morbidity and treatment time. MATERIALS AND METHODS: In this case report, a 31-year-old woman was transitioned from failing tooth-supported fixed restorations to a fully implant-supported fixed prosthesis using immediate implants and narrow diameter implants (NDI). By using some of her existing dentition to support the provisional restorations while osseointegration took place, the patient was able to retain function during treatment. Full-fixed implant-supported prostheses were delivered, providing an esthetic and functional outcome that has been maintained for 3 years. CONCLUSION: In ED patients, NDI together with immediate implant placement can be used successfully to support a complete fixed restoration and should be considered as an alternative to major reconstruction surgeries. Key factors associated with increased predictability are discussed together with a review of the literature.

Repeated salicylic acid peels for the treatment of hyperplastic sebaceous glands in hypohidrotic ectodermal dysplasia.

Hypohidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome) is the most common type of ectodermal dysplasia. Hypertrophic sebaceous glands (HSGs) are rarely present but they cause an aesthetic problem. We report a case of a patient suffering from hypohidrotic ectodermal dysplasia, treated with salicylic acid peels for the hyperplastic sebaceous glands.

Hypohidrotic ectodermal dysplasia, osteopetrosis, lymphedema, and immunodeficiency in an infant with multiple opportunistic infections.

Osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-HED-ID) is a rare X-linked disorder with only three reported prior cases in the English-language literature. We describe a case of OL-HED-ID in a male infant who initially presented with congenital lymphedema, leukocytosis, and thrombocytopenia of unknown etiology at 7 days of age. He subsequently developed gram-negative sepsis and multiple opportunistic infections including high-level cytomegalovirus viremia and Pneumocystis jiroveci pneumonia. The infant was noted to have mildly xerotic skin, fine sparse hair, and periorbital wrinkling, all features suggestive of ectodermal dysplasia. Skeletal imaging showed findings consistent with osteopetrosis, and immunologic investigation revealed hypogammaglobulinemia and mixed T- and B-cell dysfunction. Genetic testing revealed a novel mutation in the nuclear factor kappa beta (NF-KB) essential modulator (NEMO) gene, confirming the diagnosis of OL-HED-ID. Mutations in the NEMO gene have been reported in association with hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID), OL-HED-ID, and incontinentia pigmenti. In this case, we report a novel mutation in the NEMO gene associated with OL-HED-ID. This article highlights the dermatologic manifestations of a rare disorder, OL-HED-ID, and underscores the importance of early recognition and prompt intervention to prevent life-threatening infections.

Hypohidrotic ectodermal dysplasia: a multidisciplinary approach.

Hypohidrotic ectodermal dysplasia (HED; Christ-Siemens-Touraine syndrome) is a genetic disorder characterized by sparse hair, oligodontia with peg-shaped teeth, reduced sweating, and defects in a number of other ectodermal organs. A partial or complete absence of eccrine glands can lead to recurrent severe overheating that may cause seizures and neurological deficits. This clinical report presents a 14-year-old male patient with hypohidrotic ectodermal dysplasia, including the clinical and radiographic findings, and multidisciplinary treatment. The Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL) was administered to patient along with mother to assess for any psychiatric disorders. The screening and rating scales completed by mother and two teachers to evaluate the severity of attention deficit hyperactivity disorder (ADHD) symptoms, and other behavioral problems. Patient's academic performance, adaptive functioning, and problem behavior was evaluated using. The Teacher Report Form. Mental capacity was assessed with the Wechsler Intelligence Scale for Children (WISC-R). Illness Perception Questionnaire Revised was used to systematically assess illness representation attributes and emotional representations of illness. On the psychiatric diagnosis assessment using K-SADS-PL sub-threshold attention deficits and anxiety symptoms were determined. In this case we established a multidisciplinary approach in his treatment with pediatric, dermatological, and dental examinations, beside his psychiatric evaluation. The prosthetic rehabilitation included restoring upper teeth with copings and fabrication of upper and lower complete dentures. Metal framework was not incorporated in the partial denture design allowing modifications as the oral and maxillofacial development continued. Removable complete or partial dentures without metal framework is a treatment of choice until the completion of facial growth at which definitive treatment is considered.