HELIX syndrome (Hypohidrosis-Electrolyte disturbances-hypoLacrimia-Ichthyosis-Xerostomia) (MIM#617671) (ORPHA:528105), described in 2017, is due to an abnormal claudin 10 b protein, secondary to pathogenic CLDN10 variants. So far, only ten families have been described. We aim to describe the phenotype in the first Spanish family identified, highlight the skin anomalies as an important clue, and expand the genotypic spectrum. Two adult brothers from consanguineous parents with suspected ectodermal dysplasia (ED) since early childhood were re-evaluated. A comprehensive phenotypic exam and an aCGH + SNP4 × 180 K microarray followed by Sanger sequencing of the CLDN10 gene were performed. They presented hypohidrosis, xerosis, mild ichthyosis, plantar keratosis, palm hyperlinearity, alacrima, and xerostomia. In adulthood, they also developed a salt-losing nephropathy with hypokalemia and hypermagnesemia. The molecular study in both patients revealed a novel pathogenic homozygous deletion of 8 nucleotides in exon 2 of the CLDN10 gene [CLDN10 (NM_0006984.4): c.322_329delGGCTCCGA, p.Gly108fs*] leading to a premature truncation of the protein. Both parents were heterozygous carriers. Hypohidrosis, ichthyosis, and plantar keratosis associated with alacrima and xerostomia should raise suspicion for HELIX syndrome, which also includes nephropathy and electrolyte disturbances in adults. Given the potential for ED misdiagnosis in infancy, it is important to include the CLDN10 gene in a specific genodermatosis next-generation sequencing (NGS) panel to provide early diagnosis, accurate management, and genetic counseling.

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Congenital nail disorders are an uncommon presenting symptom which can be difficult to diagnose and manage. Nail diseases in the pediatric population differ from those in adults in terms of diagnosis, approach and management. In most cases, they do not require treatment and resolve with growth. Physicians need to be able to recognize them, to reassure the parents. The most frequently encountered pathologies associated with nail disorder are syndactyly, acrosyndactyly, symbrachydactyly, macrodactyly, Wassel I thumb duplication, Kirner\'s deformity and congenital onychodysplasia of the index finger. Treatment usually consists in surgical correction of the deformity. Nail malformation can also be an aspect of a systemic disease. It may provide a clue for screening, and should not be overlooked. Nail conditions can be the first sign of nail-patella syndrome, ectodermal dysplasia, dyskeratosis congenita, epidermolysis bullosa, pachyonychia congenita or lung disease. Medical treatment is therefore discussed on a case-by-case basis.

Ectodermal dysplasias are a heterogeneous group of disorders that are characterized by abnormal development of ectodermal structures like hair, teeth, nails, and sweat glands. Alhough they were earlier classified according to the structures affected and hence the clinical manifestations, recent developments inch towards a genetic basis for classification. They are currently divided into four groups of disorders based on the pathway involved, which includes the ectodysplasin/nuclear factor-kappa B (NFKB) pathway, wingless-type MMTV integration site family, member 10 ([wingless related integration site] WNT10), tumor protein p63 (TP63), and the structural group. In spite of attempts at the segregation of the various disorders, there is a great degree of overlap in clinical features among the conditions, which makes a thorough history-taking and clinical examination important in helping us arrive at a diagnosis and judge the various systems involved. A multidisciplinary approach forms the crux of the management of patients with ectodermal dysplasias and their families, with a focus on education, counseling, prosthesis, and an overall rehabilitative outlook. Special attention must also be paid to screening family members for varying severities of the disorders, and an attempt must be made at a genetic diagnosis with genetic counseling.

Adams-Oliver syndrome is a rare inherited condition characterized by scalp defects and limb abnormalities. It is caused by variants in different genes such as ARHGAP31. Here, we used an interdisciplinary approach to study a family with lower limb anomalies. We identified a novel variant in the ARHGAP31 gene that is predicted to result in a truncated protein with a constitutively activated catalytic site due to the loss of 688 amino acids involved in the C-terminal domain, essential for protein auto-inhibition. Pathogenic variants in ARHGAP31 exon 12, leading to a premature protein termination, are associated with Adams-Oliver syndrome. Bioinformatic analysis was useful to elucidate the impact of the identified genetic variant on protein structure. To better understand the impact of the identified variant, 3D protein models were predicted for the ARHGAP31 wild type, the newly discovered variant, and other pathogenetic alterations already reported. Our study identified a novel variant probably involved in Adams-Oliver syndrome and increased the evidence on the phenotypic variability in patients affected by this syndrome, underlining the importance of translational research, including experimental and bioinformatics analyses. This strategy represents a successful model to investigate molecular mechanisms involved in syndrome occurrence.

Pathogenic variants in NOTCH1 are associated with non-syndromic congenital heart disease (CHD) and Adams-Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1 variants is characterized by variable expressivity and incomplete penetrance; however, data on systematic phenotypic characterization are limited. We report the genotype and phenotype of a cohort of 33 individuals (20 females, 13 males; median age 23.4 years, range 2.5-68.3 years) from 11 families with causative NOTCH1 variants (9 inherited, 2 de novo; 9 novel), ascertained from a proband with CHD. We describe the cardiac and extracardiac anomalies identified in these 33 individuals, only four of whom met criteria for AOS. The most common CHD identified was tetralogy of Fallot, though various left- and right-sided lesions and septal defects were also present. Extracardiac anomalies identified include cutis aplasia (5/33), cutaneous vascular anomalies (7/33), vascular anomalies of the central nervous system (2/10), Poland anomaly (1/33), pulmonary hypertension (2/33), and structural brain anomalies (3/14). Identification of these findings in a cardiac proband cohort supports NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1 molecular testing (any familial CHD, simplex tetralogy of Fallot or hypoplastic left heart); (2) Cascade testing in all at-risk relatives; and (3) A thorough physical exam, in addition to cardiac, brain (structural and vascular), abdominal, and ophthalmologic imaging, in all gene-positive individuals. This information is important for guiding the medical management of these individuals, particularly given the high prevalence of NOTCH1 variants in the CHD population.

Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is an exceedingly rare condition associated with mutations in the PVL4 gene. It is characterised by sparse, brittle hair, eyebrows and eyelashes, abnormal dentition and nails, along with bilateral cutaneous syndactyly involving the fingers and toes. We report a 2-year-old girl who presented to us with bilateral complete simple syndactyly of the third and fourth web spaces of the hands, along with bilateral syndactyly of both feet involving the second to fourth toes. Upon examination, sparse hair and eyebrows, along with abnormal dentition, were noted. Thorough clinical examination and genetic analysis were conducted on the affected child and her father, who exhibited similar clinical features. Genetic analysis revealed a homozygous nonsense mutation in the PVL4 gene in both individuals. According to the literature, EDSS1 has been reported in only 10 families worldwide, and there are no reported cases from India. Level of Evidence: Level V (Therapeutic).

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.

Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly (TEBC) syndrome is a rare autosomal dominant condition, recently linked to the protein kinase D1 (PRKD1) gene. The phenotype of TEBC remains incomplete at this point. Our aim is to improve the characterization of the clinical and molecular aspects of the TEBC syndrome. We report on the 8th patient carrying a heterozygous de novo variation of PRKD1 c.2134G > A, p. (Val712Met) identified by trio exome sequencing. The proband presents with partial atrioventricular septal defect, brachydactyly, ectodermal dysplasia, telangiectasia that developed in childhood, intellectual disability with microcephaly, multicystic renal dysplasia and moderate hormonal resistance. In view of this 8th description and review of the literature, it appears that neurodevelopmental disorders and microcephaly are frequently associated with PRKD1 missense variants, adding to the four main clinical signs described initially in the TEBC syndrome. Further descriptions are required to confirm the observed endocrine and kidney abnormalities. This should contribute to a more comprehensive understanding of the phenotypic spectrum and may help establish genotype-phenotype correlations. In the context of genotype-first strategy, accurate patient descriptions are fundamental. Characterization of specific syndromic associations is essential for variant interpretation support and patient follow-up, even in very rare diseases, such as the TEBC syndrome.

Background and Objectives: Ectodermal dysplasia (ED)-a genetic disorder-is characterized by severe tooth deficiency. We compared the mandibular volume and the sagittal and horizontal mandibular widths between patients with ED (ED group) and individuals without tooth deficiency (control group) using three-dimensional modeling. We hypothesized that the mandibular volume differs in ED cases owing to congenital tooth deficiency. Materials and Methods: We used previously obtained cone-beam computed tomography (CBCT) images of 13 patients with ED. The control group data comprised retrospective CBCT images of patients of similar age and sex with a skeletal relationship of class 1. Further, using the three-dimensional image analysis software, the tooth crowns were separated from the mandible, the mandible was reconstructed and the gonion-to-gonion distance in the mandible was marked, the distance to the menton point was measured, and the distance between the two condyles was measured and compared with the control group. Results: Overall, 46.2% and 53.8% of the participants were men and women, respectively. In the ED group, the mean age of the participants was 15.46 (range, 6-24) years, and the mean number of mandibular teeth was 4.62. Notably, the edentulous mandible volume of the ED group (27.020 mm3) was statistically significantly smaller than that of the control group (49.213 mm3) (p < 0.001). There was no difference between the two groups in terms of the marked points. For data analysis, the Shapiro-Wilk test, independent samples t-test, and Mann-Whitney U test were used. Conclusions: It has been considered that mandible volume does not develop in ED cases because of missing teeth. Modern practices, such as the CBCT technique and three-dimensional software, may be effective in identifying the true morphologic features, especially in patients with genetic syndromes affecting the maxillofacial structure.