Growth failure in focal dermal hypoplasia.

Focal dermal hypoplasia (FDH) is a rare genetic disorder caused by mutations in the PORCN gene located on the X chromosome. Short stature was previously noted to be a common finding in FDH, however the etiology of this is unclear. The present study sought to elucidate specific causes for short stature by assessing growth charts, determining bone ages and auxologic measurements, examining laboratory data for the common causes of growth failure, assessing dietary intake, and performing a growth hormone stimulation test. Sixteen patients with FDH between the ages of 3 and 18 years of age consented to the study. While 11 out of 16 patients had short stature based on height less than 2 standard deviations below mid-parental target height percentile and bone age not suggestive of likely catch-up growth, only four had a BMI less than the 5th percentile for age. Laboratory studies did not support a gastrointestinal, allergy or autoimmune cause of growth failure. Three patients had results suggestive of possible growth hormone deficiency. Although short stature is a common feature in FDH, our data suggests that severe undernutrition is not common in this group and that there may be underlying treatable causes for this short stature in some patients.

Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway.

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non-syndromic traits of the causative gene (e.g., non-syndromic hypodontia or missing teeth associated with pathogenic variants of EDA "ectodysplasin"). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT "wingless-type," TP63 "tumor protein p63") or the components of complex molecular structures (e.g., connexins, keratins, cadherins).

International research symposium on Goltz syndrome.

The International Research Symposium on Goltz Syndrome was held at Texas Children's Hospital on July 22 and 23, 2013. This unique research, educational, and family-oriented symposium was sponsored by the National Foundation for Ectodermal Dysplasias, Baylor College of Medicine and Texas Children's Hospital. Goltz syndrome, or Focal Dermal Hypoplasia (FDH), is a highly variable X-linked dominant disorder with abnormalities in tissues derived from the ectoderm and mesoderm. Classic clinical features include patchy hypoplastic skin, split hand/foot deformities, and ocular manifestations. FDH is caused by PORCN gene mutations. PORCN is involved in the secretion and signaling of Wnt proteins, which play a role in embryonic tissue development. The purpose of the International Research Symposium on Goltz Syndrome was to review the progress that has been made in recent years in research related to this rare disorder and to explore potential future research directions and treatments. This issue of American Journal of Medical Genetics contains the research findings from the evaluations from multiple subspecialties. There is a recommendation for a new diagnostic guideline to aid clinicians in identifying individuals with Focal Dermal Hypoplasia. A tissue repository has been instituted at Texas Children's Hospital, to aid future researchers in this area.

Growth, nutritional, and gastrointestinal aspects of focal dermal hypoplasia (Goltz-Gorlin syndrome).

Focal dermal hypoplasia (FDH) is a rare genetic disorder caused by mutations in the PORCN gene located on the X-chromosome. In the present study, we characterized the pattern of growth, body composition, and the nutritional and gastrointestinal aspects of children and adults (n = 19) affected with this disorder using clinical anthropometry and a survey questionnaire. The mean birth length (P < 0.06) and weight (P < 0.001) z-scores of the participants were lower than the reference population. The mean head circumference (P < 0.001), height (length) (P < 0.001), weight (P < 0.01), and BMI (P < 0.05) for age z-scores of the participants were lower than the reference population. The height-for-age and weight-for-age z-scores of the participants did not differ significantly between birth and current measurements. Three-fourths of the group reported having one or more nutritional or gastrointestinal problems including short stature (65%), underweight (77%), oral motor dysfunction (41%), gastroesophageal reflux (24%), gastroparesis (35%), and constipation (35%). These observations provide novel clinical information about growth, body composition, and nutritional and gastrointestinal aspects of children and adults with FDH and underscore the importance of careful observation and early clinical intervention in the care of individuals affected with this disorder.

Cognitive and psychological functioning in focal dermal hypoplasia.

Focal dermal hypoplasia (FDH) is a condition caused by heterozygous mutation of the PORCN gene on chromosome Xp22.3. It impacts the primitive ectoderm and mesoderm, affecting skin, teeth, nails, hair, musculoskeletal development, and vision and hearing. To date, there has been no systematic research examining the psychoeducational impact of the disorder. The current study examined emotional, behavioral, adaptive, and intellectual ability in 17 subjects with ages ranging from 3 to 55 with FDH attending the 2013 Annual Family Conference of the National Foundation for Ectodermal Dysplasias. Findings suggested overall average functioning in all areas. However, wide variability was noted in this sample, with 3 participants (18%) exhibiting overall cognitive ability in the borderline to impaired range. These findings are consistent with previous reports suggesting intellectual impairment in 15% of persons with FDH. Similarly, a subgroup of children was rated by parents as exhibiting difficulties with behavior (2 out of 11; 18%) and emotions (5 out of 11; 45%). Of particular concern was withdrawn behavior, reported by 65% of parents. These findings suggest that clinicians should routinely screen persons with FDH to rule out cognitive and emotional/behavioral difficulties and offer timely treatment. Future research should focus on identifying risk factors for psychoeducational problems in this population.

Respiratory problems in patients with ectodermal dysplasia syndromes.

The ectodermal dysplasias (EDs) are a heterogeneous group of disorders characterized by a deficiency of ectoderm- and mesoderm-derived tissues and appendages, particularly hair, skin, teeth, and nails. Many of these disorders are associated with a greater risk of respiratory disease than found in the general population. There are no published papers that comprehensively describe these findings and the possible etiologies. Patients have been reported with dramatic decrease in mucous glands in the respiratory tract. Anatomic defects, including cleft palate, that predispose to respiratory infection, are associated with several of the ED syndromes. Atopy and immune deficiencies have been shown to have a higher prevalence in ED syndromes. Clinicians who care for patients affected by ED syndromes should be aware of the potential respiratory complications, and consider evaluation for structural anomalies, atopy and immunodeficiency in individuals with recurrent or chronic respiratory symptoms.

Prevalence of atopic disorders and immunodeficiency in patients with ectodermal dysplasia syndromes.

BACKGROUND: Ectodermal dysplasia (ED) syndromes are a diverse group of disorders that affect multiple ectodermally derived tissues. Small studies and case reports suggest an increase in atopy and primary immunodeficiencies (PIDs) among patients with ED syndromes. OBJECTIVE: To determine the prevalence of clinical symptoms suggestive of atopy or immunodeficiency among a large cohort of children with ED syndromes. METHODS: A 9-page questionnaire was mailed to families who were members of the National Foundation for Ectodermal Dysplasias. The surveys were completed by parents of children younger than 18 years with a diagnosis of an ED syndrome or carrier state. Portions of the questionnaire were adapted from previously validated questionnaires developed by the International Study of Asthma and Allergies in Childhood (ISAAC). RESULTS: We received 347 completed questionnaires (41%). When compared with the 13- to 14-year-old children surveyed by ISAAC, we found both all-aged and age-matched children with ED syndromes, respectively, had significantly higher rates of asthma (32.2% and 37.2% vs 16.4%), rhinitis symptoms (76.1% and 78.3% vs 38.9%), and eczema (58.9% and 48.9% vs 8.2%). The prevalence of physician-diagnosed food allergies (20.7%) and PIDs (6.1%) in these ED patients also exceeded known rates in the general pediatric population. CONCLUSION: This large-scale, retrospective study demonstrates a greater reported prevalence of symptoms suggestive of atopic disorders and PIDs among children with ED syndromes than the general pediatric population. A combination of genetic and environmental factors in ED syndromes may contribute to breaches of skin and mucosal barriers, permitting enhanced transmission and sensitization to irritants, allergens, and pathogens.

Psychoeducational characteristics of children with hypohidrotic ectodermal dysplasia.

OBJECTIVE: Hypohidrotic ectodermal dysplasia (HED) is an X-linked hereditary disorder characterized by hypohidrosis, hypotrichosis, and anomalous dentition. Estimates of up to 50% of affected children having intellectual disability are controversial. METHOD: In a cross-sectional study, 45 youth with HED (77% males, mean age 9.75 years) and 59 matched unaffected controls (70% males, mean age 9.79 years) were administered the Kaufman Brief Intelligence Test and the Kaufman Test of Educational Achievement, and their parents completed standardized neurodevelopmental and behavioral measures, educational, and health-related information regarding their child, as well as standardized and nonstandardized data regarding socioeconomic information for their family. RESULTS: There were no statistically significant differences between the two groups in intelligence quotient composite and educational achievement scores, suggesting absence of learning disability in either group. No gender differences within or between groups were found on any performance measures. Among affected youth, parental education level correlated positively with (1) cognitive vocabulary scores and cognitive composite scores; (2) educational achievement for mathematics, reading, and composite scores. CONCLUSION: Youth affected with HED and unaffected matched peers have similar profiles on standardized measures of cognition, educational achievement, and adaptive functioning although children with HED may be at increased risk for ADHD.

Molecular Pathway-Based Classification of Ectodermal Dysplasias: First Five-Yearly Update.

To keep pace with the rapid advancements in molecular genetics and rare diseases research, we have updated the list of ectodermal dysplasias based on the latest classification approach that was adopted in 2017 by an international panel of experts. For this purpose, we searched the databases PubMed and OMIM for the term "ectodermal dysplasia", referring mainly to changes in the last 5 years. We also tried to obtain information about those diseases on which the last scientific report appeared more than 15 years ago by contacting the authors of the most recent publication. A group of experts, composed of researchers who attended the 8th International Conference on Ectodermal Dysplasias and additional members of the previous classification panel, reviewed the proposed amendments and agreed on a final table listing all 49 currently known ectodermal dysplasias for which the molecular genetic basis has been clarified, including 15 new entities. A newly reported ectodermal dysplasia, linked to the gene LRP6, is described here in more detail. These ectodermal dysplasias, in the strict sense, should be distinguished from syndromes with features of ectodermal dysplasia that are related to genes extraneous to the currently known pathways involved in ectodermal development. The latter group consists of 34 syndromes which had been placed on the previous list of ectodermal dysplasias, but most if not all of them could actually be classified elsewhere. This update should streamline the classification of ectodermal dysplasias, provide guidance to the correct diagnosis of rare disease entities, and facilitate the identification of individuals who could benefit from novel treatment options.

Growth, nutritional, and gastrointestinal aspects of ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC) syndrome.

Ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC) is a rare genetic disorder due to mutations in the TP63 gene. In the present study, we characterized the pattern of growth and body composition and the nutritional and gastrointestinal aspects of children and adults (n = 18) affected with this disorder using clinical anthropometry and a survey questionnaire. The mean birth weight and height-for-age z-scores of the AEC patients were significantly lower than those of the reference population. The weight-for-age z-score of the AEC cohort increased significantly with advancing age because of increasing body fat. Cleft lip and palate were present in 47% and 94%, respectively, of the AEC cohort; 28% had dentures. One-fourth or more of the AEC cohort reported having nutritional and/or gastrointestinal problems including the need for supplemental formula feedings, gastrostomy placement, gastroesophageal reflux, and constipation. Our observations provide novel clinical information about growth, body composition, and nutritional and gastrointestinal aspects of children and adults with AEC.

Head and neck manifestations and quality of life of patients with ectodermal dysplasia.

OBJECTIVES: Ectodermal dysplasias (EDs) are a group of genetic disorders characterized by deficient ectodermal and mesodermal development. Studies examining resultant otolaryngologic issues are few. The objectives of this study were to delineate the head and neck manifestations and quality of life in EDs. STUDY DESIGN AND SETTING: For 75 individuals, comprehensive histories were taken and otolaryngologic examinations were performed, and subjects rated their otolaryngologic symptom severity. A validated quality of life instrument (SF-8) was administered. RESULTS: The majority of subjects had a diagnosis of hypohidrotic ED (72%). Otolaryngologic conditions included otitis media (28%), cerumen impaction (48%), nasal obstruction/crusting (51%), heat intolerance (76%), and eczema (39%). Physical findings included peg teeth/hypodontia (76%), alopecia (41%), nasal crusting (41%), and saddle nose deformity (44%). Quality of life scores were generally high. Overall, health was rated "good to excellent" by 87 percent. CONCLUSION: Patients with ED frequently experience significant otolaryngologic symptoms, although most patients report a good quality of life. SIGNIFICANCE: A greater understanding of the otolaryngologic issues in ED should help facilitate diagnosis and improve management.

Platelet function disorder in Gardner-Diamond syndrome: a case report and review of the literature.

The Gardner-Diamond syndrome is a disorder characterized by recurrent spontaneous painful bruising in patients with underlying psychosis and neurosis. Despite the presence of other symptoms suggestive of an underlying disorder of primary hemostasis in a large percentage of reported patients, results of testing for von Willebrand disease or platelet function disorders are lacking. The authors describe a case of Gardner-Diamond syndrome in an adolescent girl who had abnormal platelet responses during platelet aggregation studies. A review of the literature revealed only three additional patients with Gardner-Diamond syndrome who have had platelet aggregation studies reported. To date, all patients with Gardner-Diamond syndrome reported to have undergone platelet aggregation studies have had abnormal results.

Growth characteristics of children with ectodermal dysplasia syndromes.

OBJECTIVE: Clinical observations suggested that growth abnormalities may be present in children with ectodermal dysplasia (ED) syndromes. This study characterizes the longitudinal pattern of growth in a cohort of children with the ED syndromes. We hypothesized that (1) linear and ponderal growth abnormalities are present in children with ED from infancy through adolescence, and (2) linear and ponderal growth abnormalities differ among the clinical variants of these disorders. METHODS: We studied 138 children who had ED and were registered with the National Foundation for Ectodermal Dysplasias, 74% of whom had clinical features consistent with the hypohidrotic EDs (HEDs). Height (or length) and weight measurements were obtained by standardized techniques and from review of available medical records. We converted these measurements to weight-for-height (children younger than 5 years and <103 cm in length) or BMI (children > or =2 years old). Height, weight, weight-for-height, and BMI were converted to age- and gender-specific z scores. We applied linear regression, 1-sample t tests, and analysis of variance to detect linear and ponderal growth abnormalities in children with ED compared with a reference population. RESULTS: Mean weight-for-age, weight-for-height, and BMI-for-age z scores but not height-for-age z score, were significantly lower in children with the ED syndromes than in the reference population. Mean weight-for-age and weight-for-height z scores but not BMI-for-age or height-for-age z scores increased significantly with increasing age. The mean height-for-age z score of children with the ED syndromes other than the HEDs was significantly lower than that of children with the HEDs. CONCLUSIONS: Growth abnormalities, measured as weight deficits, were present at an early age in children with the ED syndromes and persisted through adolescence. Height deficits were seen only in children with ED syndromes other than HEDs. Clinicians should evaluate carefully children with ED syndromes for growth abnormalities.