Aplasia cutis congenita (ACC) is a congenital disorder that can be classified into nine types, with Type I ACC being the most common. Type V ACC associated with fetus papyraceus is a rare subtype of ACC. We report the case of a Type V ACC in a male newborn with extensive abdominal skin defects. The patient received conservative treatment using hydrogel foam and silicone foam dressings. Approximately five weeks later, the patient was discharged when more than 60% of the skin had completed epithelialization. After discharge from West China Second University Hospital, Chengdu , the patient continued to be followed up regularly at the Burns and Plastic Surgery Clinic at local hospital in Gansu. We followed up the child by telephone. After 4 months of follow-up, scar tissue formation was observed in the trunk area. The infant is 2 years and 5 months old now, physical examination did not reveal any organ problems.

BACKGROUND: The aim of this study was to analyse the differences in the phenotypes of missing teeth between a pair of brothers with hypohidrotic ectodermal dysplasia (HED) and to investigate the underlying mechanism by comparing the mutated gene loci between the brothers with whole-exome sequencing.
METHODS: The clinical data of the patients and their mother were collected, and genomic DNA was extracted from peripheral blood samples. By Whole-exome sequencing filtered for a minor allele frequency (MAF) ≤0.05 non-synonymous single-nucleotide variations and insertions/deletions variations in genes previously associated with tooth agenesis, and variations considered as potentially pathogenic were assessed by SIFT, Polyphen-2, CADD and ACMG. Sanger sequencing was performed to detect gene variations. The secondary and tertiary structures of the mutated proteins were predicted by PsiPred 4.0 and AlphaFold 2.
RESULTS: Both brothers were clinically diagnosed with HED, but the younger brother had more teeth than the elder brother. An EDA variation (c.878 T > G) was identified in both brothers. Additionally, compound heterozygous variations of WNT10A (c.511C > T and c.637G > A) were identified in the elder brother. Digenic variations in EDA (c.878 T > G) and WNT10A (c.511C > T and c.637G > A) in the same patient have not been reported previously. The secondary structure of the variant WNT10A protein showed changes in the number and position of α-helices and β-folds compared to the wild-type protein. The tertiary structure of the WNT10A variant and molecular simulation docking showed that the site and direction where WNT10A binds to FZD5 was changed.
CONCLUSIONS: Compound heterozygous WNT10A missense variations may exacerbate the number of missing teeth in HED caused by EDA variation.

UNASSIGNED: To explore the mechanism by which the Wnt/β-catenin pathway induces osteogenic differentiation of bone marrow-derived stem cells (BMSCs) in anhidrotic ectodermal dysplasia (AED) with an Ectodysplasin A (EDA)/EDA receptor (EDAR)/EDARADD mutation.
UNASSIGNED: An AED patient served as the AED group, whereas the other patients without AED were included in the normal group. Peripheral venous blood collected from the AED patient was subjected to whole-genome resequencing. BMSCs from the mandible of patients with AED and normal individuals were isolated and cultured in vitro. Cell proliferation assay was performed to compare the growth speed of BMSCs between the AED and normal groups. CHIR-99021, an activator of the Wnt/β-catenin pathway and XAV-939, an inhibitor, was used to manage BMSCs in an osteogenic environment in both groups. The expression of β-catenin was detected by quantitative polymerase chain reaction, while that of RUNX2 was detected by western blotting. Alizarin red was used for staining.
UNASSIGNED: A novel mutation (c.152T > A in EDA) and two known mutations (c.1109T > C in EDAR and c.27G > A in EDARADD) were identified. The growth rate in the normal group was higher than that in the AED group. In the normal group, the number and size of calcified nodes and the expression of RUNX-2 increased with CHIR-99021 treatment, which could be inhibited by XAV-939. In contrast, CHIR-99021 inhibited osteogenesis in the AED group and this effect was promoted by XAV-939.
UNASSIGNED: Activation of the Wnt/β-catenin pathway downregulates osteogenesis of BMSCs in AED patients with EDA/EDAR/EDARADD gene mutations. Further investigation in more AED patients is required, given the wide range of mutations involved in AED.

MBTPS1 (NM_003791.4) encodes Site-1 protease, a serine protease that functions sequentially with Site-2 protease regulating cholesterol homeostasis and endoplasmic reticulum stress response. MBTPS1 pathogenic variants are associated with spondyloepiphyseal dysplasia, Kondo-Fu type (MIM:618392; cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, and Silver-Russell-like syndrome). In this report, we describe a 14-year-old female with a complex medical history including white matter volume loss, early-onset cataracts, retrognathia, laryngomalacia, inguinal hernia, joint hypermobility, feeding dysfunction, and speech delay. Additionally, features of ectodermal dysplasia that she has include decreased sweating, heat intolerance, dysplastic nails, chronically dry skin, and abnormal hair growth issues. Exome sequencing analysis identified compound heterozygous variants in the MBTPS1 gene: c.2255G > T p.(Gly752Val) predicted to affect important function of the protein, which was inherited from the mother, and a splice site variant c.2831 + 5G > T, which was inherited from the father. The RNA-seq analysis of the splice variant showed skipping of exon 21, predicted to result in frameshifting p.(Ser901fs28*) leading to non-sense mediated decay. To our knowledge, only eight studies have been published that described the MBPTS1-related disorders. Interestingly, we observed the features of ectodermal dysplasia in our patient that further expands the phenotypic spectrum of MBTPS1 gene-related disorders.

BACKGROUND: Aplasia cutis congenita (ACC) is a rare genetic disorder characterized by the localized or widespread absence of skin in humans and animals. Individuals with ACC may experience developmental abnormalities in the skeletal and muscular systems, as well as potential complications. Localized and isolated cases of ACC can be treated through surgical and medical interventions, while extensive cases of ACC may result in neonatal mortality. The presence of ACC in pigs has implications for animal welfare. It contributes to an elevated mortality rate among piglets at birth, leading to substantial economic losses in the pig farming industry. In order to elucidate candidate genetic loci associated with ACC, we performed a Genome-Wide Association Study analysis on 216 Duroc pigs. The primary goal of this study was to identify candidate genes that associated with ACC.
RESULTS: This study identified nine significant SNPs associated with ACC. Further analysis revealed the presence of two quantitative trait loci, 483 kb (5:18,196,971-18,680,098) on SSC 5 and 159 kb (13:20,713,440-207294431 bp) on SSC13. By annotating candidate genes within a 1 Mb region surrounding the significant SNPs, a total of 11 candidate genes were identified on SSC5 and SSC13, including KRT71, KRT1, KRT4, ITGB7, CSAD, RARG, SP7, PFKL, TRPM2, SUMO3, and TSPEAR.
CONCLUSIONS: The results of this study further elucidate the potential mechanisms underlying and genetic architecture of ACC and identify reliable candidate genes. These results lay the foundation for treating and understanding ACC in humans.

Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome is a rare autosomal dominant inherited disease caused due to mutations in the TP63 gene. More commonly, mutations in the TP63 gene result in ectodermal dysplasia and/or orofacial cleft. ADULT syndrome is a type of ectoderm-related tissue dysplasia. This case report describes a patient with chronic tearing, congenital atresia, and obstruction of the lacrimal ducts, which are the main clinical manifestations of ADULT syndrome. This patient also presented with some clinical manifestations that were different from those of ADULT syndrome, namely, mild eyelid fusion and abnormal development of the fifth finger (a stiff fifth finger with camptodactyly that was shortened in length). The gene mutation in this patient was also at a site different from those usually reported in the literature. In this patient, c.518G > T resulted in p. G173V (accession number: NM_003722; exon4). We performed successful dacryocystorhinostomy and artificial lacrimal duct implantation. As shown above, we discussed the clinical characteristics and genetics of the disease in detail. In sharing this case, we aim to contribute to the current understanding of the genes and clinical manifestations of ADULT syndrome and to assist clinicians in the clinical diagnosis of TP63 mutation-related diseases.

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that affects skin, hair, teeth, eyes and central nervous system. We present the case of a female patient with mild IP caused by a hypomorphic pathogenic variant of the inhibitor of the kappa light polypeptide gene enhancer in B cells, kinase gamma (IKBKG) gene. This is the first report of a female IP patient with the hypomorphic variant, NM_001099856.6: c.1423dup, which is causative of anhidrotic ectodermal dysplasia with immune deficiency in males.

Cardio-facio-cutaneous (CFC) syndrome is a RASopathy subtype that presents with unique craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. This study describes the phenotypic spectrum of CFC in China and its association with CFC syndrome gene variants.
Twenty Chinese CFC patients, aged 0.6-9.5 years old, were included in this study and their clinical phenotypic spectrum was compared with that of 186 patients with CFC from non-Chinese ethnicities. All 20 Chinese patients with CFC carried de novo heterozygous BRAF, MAP2K1, and MAP2K2 variants. Two novel variants were detected and consistently predicted to be deleterious using bioinformatic tools. The clinical features of CFC in the Chinese patients included hypertrophic cardiomyopathy (2/20, 10%), pulmonary valve stenosis (2/20, 10%), curly or sparse hair (7/20, 35%), epilepsy (1/20, 5%), and hypotonia (10/20, 50%); these features were less frequently observed in Chinese patients than non-Chinese patients (p < 0.05). In contrast, feeding difficulties (19/20, 95%) were more frequently observed in the Chinese patients. Absent eyebrows and severe short stature were more common in patients with BRAF variants than in those with MAP2K1/2 variants. Facial recognition software was used to recognize most CFC patients using artificial intelligence.
This study identified novel and common variants in our cohort of 20 Chinese patients with CFC. We uncovered differences in clinical features between Chinese and non-Chinese patients and detected genotype-phenotype correlations among the BRAF and MAP2K1/2 variant subgroups. This is the largest cohort of Chinese CFC patients to our knowledge, providing new insights into a subtype of RASopathy.

In this study, we retrospectively analyzed the clinical data of a newborn with aplasia cutis congenita (ACC) to provide insights for diagnosing and treating the disease. It is believed that ACC with an intact skull and a skin defect diameter of less than 2 cm can be treated conservatively. The main strategies include local disinfection and regular dressing changes to promote epithelial regeneration. The lesion can heal over weeks or months through epithelization adjacent to the defect tissue, resulting in a healed contracture scar with a smooth, hairless surface that can be surgically removed later. For children with large scalp defects or skull defects, skin transplantation, free flap, and cranioplasty can be performed to repair the wound and restore the tissue structure. It is worth mentioning that although this child had a scalp defect larger than 2 cm, conservative treatment still had a significant effect. This suggests that conservative treatment can be considered as the first choice for ACC neonates without skull defects, and surgical treatment can be considered when necessary.

OBJECTIVE: The purpose of this study was to identify a pathogenic mutation located in TP63 in a nuclear Han Chinese family.
METHODS: Whole-exome sequencing and Sanger sequencing were performed to identify candidate variants. The AlphaFold and PyMOL predicted the three-dimensional structure of the protein. Single-cell RNA-sequencing data and spatiotemporal transcriptomic atlas were used to generate the dissection of candidate gene expression at single-cell resolution. Significant genes (Pearson\'s coefficient ≥0.8 and P < 0.05) were identified for Gene Ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathways analysis.
RESULTS: A heterozygous missense variant at TP63 exon 8 (c.1010 G>A:p.Arg337Gln) was identified in the proband. This variant was predicted deleterious and likely to impair the local stability of the protein. In addition, single-cell RNA-sequencing indicated that TP63 was highly expressed in skin tissues. Furthermore, spatial transcriptome data of mice embryos showed TP63 was mainly enriched in the mucosal epithelium, thymus, epidermis, mesenchyme, and surface ectoderm. GO and KEGG pathway annotation analysis revealed that TP63 played a positive role in the process of ectoderm via the TGF-beta signaling pathway.
CONCLUSIONS: The missense variant of TP63 (c.1010 G>A:p.Arg337Gln) was associated with ectodermal dysplasia.