Clouston syndrome is a rare autosomal dominant form of hidrotic ectodermal dysplasia that presents significant challenges due to its multisystemic manifestations and limited therapeutic options. This review explores the functional role of stem cells in the treatment and management of Clouston syndrome, highlighting advancements in regenerative medicine and stem cell therapy. Stem cell types such as mesenchymal stem cells (MSCs), epidermal stem cells (EpSCs), and induced pluripotent stem cells (iPSCs) have shown promise in regenerating ectodermal derivatives like skin, hair, and nails. Gene-editing technologies, including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR-Cas9), can correct pathogenic mutations in the GJB6 gene. Emerging techniques in tissue engineering and three dimensional (3D) bioprinting are also discussed, focusing on their potential to create patient-specific, bioengineered constructs. Clinical trials in related genetic disorders provide evidence for the feasibility of these approaches in improving patient outcomes. However, challenges such as immune rejection, ethical concerns, and stem cell production scalability remain barriers. Addressing these issues requires interdisciplinary collaboration, sustained funding, and targeted research. This review underscores the transformative potential of regenerative medicine. It highlights the need for continued efforts to develop curative strategies for treatment, integrating stem cell-based therapies, gene editing, and bioengineering. Clouston syndrome is a rare inherited condition that affects the skin, hair, and nails. People with this disorder often have thickened skin on the hands and feet, very brittle or misshaped nails, and sparse or fragile hair. Although the condition is lifelong, its symptoms can vary from person to person, which sometimes makes diagnosis difficult. Clouston syndrome is caused by a change in a gene called GJB6, which provides instructions for a protein that helps cells in the skin communicate with each other. When this gene is altered, the normal development of skin, hair, and nails is disrupted.In this review, we summarize what is currently known about the clinical features, genetic causes, and laboratory methods used to diagnose Clouston syndrome. We also discuss experimental advances that may improve future care, including stem cell-based treatments, gene therapy, and other regenerative approaches. Although these techniques are not yet available for patients, ongoing research may eventually lead to new treatment options.By bringing together knowledge from clinical reports, genetic studies, and emerging therapeutic strategies, this review aims to help clinicians, researchers, and families better understand Clouston syndrome and the potential for future medical advances.

Ellis-Van Creveld syndrome is a rare genetic disorder characterised by skeletal abnormalities, cardiac anomalies, and findings of hidrotic ectodermal dysplasia. Cardiac anomalies are common in this syndrome and usually include an atrial septal defect when present. The disorder is caused by homozygous or compound heterozygous pathogenic variants in the EVC and EVC2 genes. A small number of patients with Ellis-Van Creveld syndrome have also been found to have copy number variants associated with these two genes. A 13-year-old girl patient was referred to the paediatric genetic department with short stature, short extremities, operated post-axial polydactyly, nail hypoplasia, and severe mitral valve insufficiency. Chromosomal microarray analysis identified a 45 kb homozygous deletion encompassing exons 3-11 of the EVC gene at 4p16.2. Herein, we present a case with an intragenic deletion of the EVC gene and expand the clinical and genetic spectrum of Ellis-Van Creveld syndrome.

GJB2 and GJB6 variants, encoding Cx26 and Cx30 respectively, are the most frequently involved genes commonly contributing to hereditary hearing loss either isolated or in combination with skin abnormalities. GJB6 variations are classically associated with two distinct conditions: non-syndromic hearing loss and hidrotic ectodermal dysplasia, type Clouston, the latter typically not involving deafness. Whole genome sequencing (WGS) was used to find genetic variants after clinical features of a 13-year-old female patient were recorded. In this report, we describe the association of congenital hearing loss and ectodermal anomalies (palmoplantar keratoderma, knuckle pads, and nail dystrophy) in a female with the ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) GJB6 variant. As a result, we report on the third case of individuals showing this same missense variant and syndromic hearing loss. This study underscores the overlapping phenotypes observed in patients with the p.Gly59Arg variant in the GJB6 gene. The findings suggest a continuum of phenotypic presentations for this variant, with the key clinical features being the combination of congenital hearing loss and hyperkeratosis. Hidrotic ectodermal dysplasia 2, or Clouston syndrome (referred to as HED2 throughout this GeneReview) is characterized by a triad of major clinical features including partial-to-complete alopecia, nail dystrophy, and palmoplantar hyperkeratosis. Sweating is preserved and there are usually no dental anomalies. Sparse scalp hair and dysplastic nails are seen early in life. In infancy, scalp hair is fine, sparse, and brittle. Progressive hair loss may lead to total alopecia by puberty. The nails may be milky white in early childhood; they gradually become dystrophic, thick, and distally separated from the nail bed. Palmoplantar keratoderma may develop during childhood and increases in severity with age. Associated features may include cutaneous hyperpigmentation (particularly over the joints) and finger clubbing. The clinical manifestations are highly variable even within the same family. The diagnosis of HED2 is established in a proband with suggestive findings and a heterozygous pathogenic variant in GJB6 identified by molecular genetic testing. Targeted analysis for the four most common GJB6 pathogenic variants detects pathogenic variants in approximately 100% of affected individuals. Treatment of manifestations: Special hair care products to help manage dry and sparse hair; wigs; artificial nails; emollients and keratolytics to relieve palmoplantar hyperkeratosis. HED2 is inherited in an autosomal dominant manner. Most individuals with HED2 have an affected parent; de novo pathogenic variants have also been reported. Offspring of affected individuals have a 50% chance of inheriting the pathogenic variant and being affected. Once the causative GJB6 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for HED2 are possible.

Pathogenic variants in genes encoding connexins that cause skin diseases, such as keratitis-ichthyosis-deafness (KID) syndrome and hidrotic ectodermal dysplasia (HED) or Clouston syndrome, display increased hemichannel activity. Mechanistic insights derived from biophysical studies of the variant connexins support the hypothesis that inhibition of the acquired hemichannel activity could alleviate epidermal pathology. Use of pharmacological blockers and engineered mAbs in mouse models of HED and KID confirm that hemichannel inhibition is a promising target for new therapeutic approaches to KID and HED. Insights from this work could apply to other connexin-based genetic skin diseases in which hemichannel activity is elevated.

We aim to explore a potential treatment strategy for hair loss. A male 6-year-old child was diagnosed with hidrotic ectodermal dysplasia 2 (HED2) caused by GJB6 (p.G11R) mutations. He presented at our clinic with diffuse thinning and fine and brittle hair since birth. Additionally, the child exhibited abnormal development of teeth, fingernails, and toenails. The condition of the child's hair had not improved significantly with age. He was treated with botanical extracts combined with Minoxidil. After one and a half months of treatment, the patient showed remarkable hair growth. Our team has previously used botanical extracts in combination for the treatment of autosomal recessive wooly hair in children. In the present case, treatment with botanical extract combined with minoxidil was found to be equally efficacious. This case report provides valuable information for future studies on the use of botanical extracts in treating hair loss, as well as a safe and effective potential treatment strategy for children with congenital alopecia.