X-linked hypohidrotic ectodermal dysplasia (HED) is a rare congenital hereditary disorder primarily affecting ectodermal-derived organs, including hair, sweat glands, and teeth. This case report presents a prenatal diagnosis of HED in a fetus without a familial history or parental phenotypic manifestations. The critical prenatal ultrasound finding was an abnormality in the alveolar bone. Genetic testing confirmed the fetus as a hemizygote for a mutation in the ectodysplasin A gene. This comprehensive study delineates the prenatal ultrasound observations, genetic testing outcomes, and post-mortem pathological findings associated with this syndrome. We also highlight essential considerations for early diagnosis through prenatal ultrasound examinations.

Ectodermal dysplasias are clinically and genetically heterogeneous congenital disorders characterized by abnormal development of at least two of the four ectodermal tissues: teeth, hair, nails, and sweat glands. In this study, we summarized the clinical and molecular characteristics of the patients and contributed to the genotype-phenotype correlation. For genetic diagnosis, single-gene testing, clinical exome sequencing, whole-exome sequencing, and variant confirmation analyses were performed. In this study, 30 ectodermal dysplasia patients from 18 families and six patients with isolated ectodermal anomalies from three families were analyzed. A total of 21 unique variants were identified, five of which were novel. Of these, seven were classified as pathogenic, 11 as likely pathogenic, and three as variants of uncertain significance (LIPH, TSPEAR, HR). Hypohidrotic ectodermal dysplasia was the most frequently identified subtype, with variants in the EDAR gene found in 10 patients and in the EDA gene in seven patients. Two patients harbored WNT10A variants. Variants in the CDH3 gene were identified in six patients with macular degeneration. Additionally, variants in the LIPH and LPAR6 genes were detected in three patients presenting with woolly hair. In the remaining eight patients, variants were identified in the HR, TSPEAR, TP63, DSG1, and CST6 genes. Microcephaly was observed in 47% (8/17) of patients in the hypohidrotic ectodermal dysplasia group (EDA, EDAR) and in 66% (4/6) of patients carrying CDH3 variants. The patient with a TSPEAR variant also had Beckwith-Wiedemann syndrome. Our clinical findings, together with the identification of novel variants in EDAR, LIPH, LPAR6, HR, and TP63, expand the clinical and molecular spectrum of ectodermal dysplasias. A potential association between microcephaly and ectodermal dysplasia is discussed. This study highlights the genetic heterogeneity of ectodermal dysplasias and emphasizes the importance of combining detailed clinical evaluation with molecular diagnostics. • Ectodermal dysplasias (EDs) are congenital disorders characterized by abnormal development of at least two of four ectodermal structures, such as hair, nails, teeth, and sweat glands. EDs represent a clinically and genetically heterogeneous group of disorders with over 200 distinct types described. • In the current study, we report the clinical and molecular genetic analysis of 36 patients and contribute to the genotype-phenotype correlation. Five novel variants were identified. Microcephaly was observed in 47% of patients in the hypohidrotic ectodermal dysplasia group and in 66% of patients carrying CDH3 variants. The patient with a TSPEAR variant also had Beckwith-Wiedemann syndrome.

The hair follicle is an appendage of the skin that undergoes hair cycles throughout life. Recently, numerous genes expressed in the hair follicles have been identified, and variants in some of these genes are now known to underlie hereditary hair diseases in humans. Hereditary hair diseases are classified into non-syndromic and syndromic forms. In the Japanese population, the non-syndromic form of autosomal recessive woolly hair, which is caused by founder pathogenic variants in the lipase H (LIPH) gene, is the most prevalent hereditary hair disease. In addition, other types of hereditary hair diseases are known in Japan, such as Marie-Unna hereditary hypotrichosis, hypohidrotic ectodermal dysplasia, and tricho-rhino-phalangeal syndrome. To ensure correct diagnoses and appropriate patient care, dermatologists must understand the characteristics of each hair disorder. Elucidation of the molecular basis of hereditary hair diseases can directly tell us which genes are crucial for morphogenesis and development of hair follicles in humans. Therefore, continuation of "wet laboratory" research for these diseases remains important. To date, several syndromic forms of hereditary hair diseases have been approved as designated intractable diseases in Japan. As part of our efforts in the Project for Research on Intractable Diseases through the Ministry of Health, Labour, and Welfare of Japan, we anticipate that more hereditary hair diseases be recognized as designated intractable diseases in the future, which will be to the benefit of the affected individuals.

Ectodermal dysplasia is a rare disease that belongs to a diverse group of inherited monogenic disorders involving defects in one or more ectodermally or mesodermally derived tissues. Hypohidrotic ectodermal dysplasia, also known as Christ-Siemens-Touraine syndrome is a type of ectodermal dysplasia characterized by a triad of anhidrosis, dysodontia, and hypotrichiasis. The most prevalent method of transmission is X-linked recessive, manifesting fully in men and only partially in female carrier heterozygotes. Atrophic rhinitis and nasal myiasis are rare characteristics of this condition. We hereby report a case of a 52-year-old female with atrophic rhinitis and nasal myiasis who was managed conservatively. Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features. Classic HED can be diagnosed after infancy based on physical features in most affected individuals. Identification of a hemizygous EDA pathogenic variant in an affected male or biallelic EDAR, EDARADD, or WNT10A pathogenic variants in an affected male or female confirms the diagnosis. The diagnosis of mild HED is established in a female by identification of a heterozygous EDA, EDAR, EDARADD, or WNT10A pathogenic variant. The diagnosis of mild HED is established in a male by identification of a heterozygous EDAR, EDARADD, or WNT10A pathogenic variant. Treatment of manifestations: Wigs or special hair care formulas for sparse, dry hair may be useful. Access to an adequate water supply and a cool environment during hot weather. Skin care products for eczema and exposures that exacerbate dry skin. Early dental treatment; bonding of conical teeth; orthodontics as necessary; dental implants in the anterior portion of the mandibular arch in older children; replacement of dental prostheses as needed, often every 2.5 years; dental implants in adults; dietary counseling for individuals with chewing and swallowing difficulties; therapeutics to maintain oral lubrication and control caries; fluoride treatment to prevent caries. Nasal and aural concretions may be removed with suction devices or forceps as needed by an otolaryngologist. Prevention of nasal concretions through humidification of ambient air is helpful. Lubrication eye drops. Management of recurrent respiratory infections and asthma per primary care provider with referral to allergist and/or pulmonologist as needed. Surveillance: Dental evaluation by age one year with follow-up dental evaluations every six to 12 months. Assess for skin, hair, ophthalmologic, and respiratory manifestations annually and/or as needed. Assess for abnormal nasal and aural secretions annually and/or as needed. Agents/circumstances to avoid: Exposure to extreme heat. Evaluation of relatives at risk: If the family-specific pathogenic variant(s) are known, molecular genetic testing of at-risk relatives should be offered to permit early diagnosis and treatment, especially to avoid hyperthermia. Pregnancy management: Optimal prenatal nutrition for mothers who are unaffected heterozygotes or those who are affected with HED. Affected women at risk for hyperthermia should not become overheated during pregnancy. EDA-related HED is inherited in an X-linked manner. EDAR-, EDARADD-, and WNT10A-related HED are inherited in an autosomal recessive or an autosomal dominant manner. X-linked HED: If the mother of a proband is heterozygous for an EDA pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. If the father of the proband has an EDA pathogenic variant, he will transmit it to all his daughters and none of his sons. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may show manifestations of ectodermal dysplasia. Molecular genetic identification of female heterozygotes requires prior identification of the EDA pathogenic variant in the family. Autosomal recessive HED: The parents of a child with autosomal recessive HED are presumed to be heterozygous for a pathogenic variant in EDAR, EDARADD, or WNT10A. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygote detection for at-risk relatives requires prior identification of the EDAR, EDARADD, or WNT10A pathogenic variants in the family. Autosomal dominant HED: Some individuals diagnosed with autosomal dominant HED have an affected parent. Each child of an individual with autosomal dominant HED has a 50% chance of inheriting the EDAR, EDARADD, or WNT10A pathogenic variant. Once the EDA, EDAR, EDARADD, or WNT10A pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for HED are possible.