Urogenital presentation of a male patient with focal dermal hypoplasia.

Focal dermal hypoplasia (FDH) is a rare X-linked dominant syndrome characterized by streaky cutaneous atrophy in a blaschkoid distribution, skeletal dysplasias, and ocular abnormalities. Here, we report hypospadias and chordee identified in a male patient with molecularly confirmed FDH. This report highlights a new clinical manifestation of male patients with FDH.

Novel uses of laser therapy in Goltz syndrome.

Goltz syndrome is an X-linked dominant, multisystem birth defect due to PORCN mutation. The skin findings follow Blaschko's lines and often show epidermal atrophy and herniation of subcutaneous fatty tissue. Regarding treatment, light sources can offer a good therapeutic option for some manifestations of this rare disease and improve the aesthetic appearance of the skin lesions. We report two new cases of Goltz syndrome in which the cutaneous findings remarkably improved with pulsed dye laser and carbon dioxide laser.

Implementation of high-resolution melting analysis of the porcupine (PORCN) gene for molecular diagnosis of focal dermal hypoplasia: Identification of a novel mutation.

BACKGROUND: Focal dermal hypoplasia (FDH) is rare X-linked dominant disease characterized by atrophy and linear pigmentation of the skin, split hand/foot deformities and ocular anomalies. FDH is caused by mutations of the Porcupine (PORCN) gene, which encodes an enzyme that catalyzes the palmitoylation of Wnt ligands required for their secretion. High resolution melting analysis (HRM) is a technique that allows rapid, labor-efficient, low-cost detection of genomic variants. In the present study, we report the successful implementation of HRM in the molecular diagnosis of FDH. METHODS: Polymerase chain reaction and HRM assays were designed and optimized for each of the coding exons of the PORCN gene, processing genomic DNA samples form a non-affected control and a patient complying with the FDH diagnostic criteria. The causal mutation was characterized by Sanger sequencing from an amplicon showing a HRM trace suggesting heterozygous variation and was validated using an amplification-refractory mutation system (ARMS) assay. RESULTS: The melting profiles suggested the presence of a variant in the patient within exon 1. Sanger sequencing revealed a previously unknown C to T transition replacing a glutamine codon for a premature stop codon at position 28, which was validated using ARMS. CONCLUSIONS: Next-generation sequencing facilitates the molecular diagnosis of monogenic disorders; however, its cost-benefit ratio is not optimal when a single, small or medium size causal gene is already identified and the clinical diagnostic presumption is strong. Under those conditions, as it is the case for FDH, HRM represents a cost- and labor-effective approach.

Microphthalmia and linear skin defects syndrome: Precise diagnosis guides prognosis.

Microphthalmia and linear skin defects syndrome (MLS) is a rare X-linked dominant disorder characterized by microphthalmia and linear atrophic plaques of the face and neck. The diagnosis of MLS can be challenging secondary to both its rarity and to clinical overlap with Goltz syndrome. Whereas the skin lesions of MLS are more likely to improve in appearance with age, the lesions of Goltz are typically persistent.

Prenatal diagnosis of focal dermal hypoplasia: Report of three fetuses and review of the literature.

Focal dermal hypoplasia (FDH) is a rare syndrome characterized by pleiotropic features knowing to involve mostly skin and limbs. Although FDH has been described in children and adults, the cardinal signs of the fetal phenotype are not straightforward impacting the quality of the prenatal diagnosis. We describe in depth the ultrasound, radiological, macroscopical, and histological phenotype of three female fetuses with a severe form of FDH, propose a review of the literature and an attempt to delineate minimal and cardinal signs for FDH diagnosis. This report confirms the variability of FDH phenotype, highlights unreported FDH features, and allows delineating evocative clinical associations for prenatal diagnosis, namely intrauterine growth retardation, limbs malformations, anterior wall/diaphragm defects, and eye anomalies. © 2016 Wiley Periodicals, Inc.

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.

Ophthalmologic manifestations of focal dermal hypoplasia (Goltz syndrome): A case series of 18 patients.

Focal Dermal Hypoplasia (FDH) or Goltz syndrome is a rare multi-system disorder with cutaneous, ocular, dental, and skeletal anomalies due to dysplasia of mesoectodermal derived tissues. It is an X-linked inheritance syndrome caused by mutations in the PORCN gene. This study is aimed to investigate the ocular findings in patients with Goltz syndrome. To date, there have been a limited number of case reports on the ocular manifestations of FDH. This is a prospective, non-consecutive, observational case series. Prospective ophthalmologic evaluation was performed on 18 patients with confirmed genetic testing for FDH, Goltz Syndrome, as a component of a larger multi-subspecialty study to better characterize the findings of this condition. Special attention was placed on evaluating the incidence of anophthalmia, microphthalmia, colobomas (iris, optic nerve, and/or retinal), cataracts, nystagmus, and strabismus. A complete ophthalmologic exam was done on all the patients. The mean patient age was 12.8 years (1-55 years). Eighty-nine percent were female and 77% (14/18) of patients had some form of an ophthalmologic manifestation of the condition. Ophthalmological findings included chorioretinal colobomas (61%), iris colobomas (50%), microphthalmia (44%), anophthalmia (11%), cataracts (11%), and conjunctival and eyelid papillomas (5%). Nystagmus was present in 33% and strabismus in 22% of the patients. Visual acuity ranged from 20/20 to no light perception. This study demonstrates a higher incidence of ophthalmologic manifestations as previously reported (77% vs. 40%). To our knowledge, this is the largest case series reported in the literature with 18 patients.

Gynecologic findings in Goltz syndrome: A case series.

There is limited information available related to the gynecologic findings in Goltz syndrome. We report exclusively on external genitalia findings in 17 girls with a known diagnosis of focal dermal hypoplasia. This is the largest series to date. Some of our findings have been reported previously; however, some novel features including short perineum body not previously mentioned are noted as well. We recommend referral to a pediatric gynecologist for early evaluation of the reproductive tract as this can have an impact on the future fertility of these girls.

Oral phenotype and variation in focal dermal hypoplasia.

Focal dermal hypoplasia (FDH) or Goltz Syndrome (OMIM# 305600) is an X-linked dominant ectodermal dysplasia caused by mutations in the PORCN gene. This gene encodes an endoplasmic reticulum transmembrane protein that is involved in processing the embryonically critical WNT signaling proteins. Individuals diagnosed with FDH were recruited to participate in the study through the National Foundation for Ectodermal Dysplasia. Individuals were evaluated to characterize the FDH phenotype. Each participant completed a brief dental survey and oral evaluation using artificial light. To identify the oral soft and hard tissue findings 19 individuals (16 female and 3 male) participated with a median age of 10 years (range 2-56 years). Soft and hard tissue defects were present in 68% (13) and 94% (18) of the patients, respectively. Dental anomalies were highly prevalent with 68% (13) demonstrating vertical enamel grooving, 52% (10) having peg shaped tooth deformities, and 78% (15) having enamel hypoplasia with or without discoloration. Cleft lip and cleft palate presented in 15% (3) of the participants. Other findings included 57% (11) having intra-oral lipoma or papilloma with no site predilection. Dental malocclusions were common with 63% (12) having some degree of malocclusion with 15% (3) of participants having class III malocclusion with an anterior dental cross bite. Participants frequently reported speech problems or difficulty with chewing (73%; N = 14). This study shows there is marked variation in the oral phenotype of individuals with FDH and underscores the important role of WNT signaling in oro-facial development.

The orthopedic characterization of Goltz syndrome.

Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is a rare condition in which congenital anomalies result in a multitude of defects that affect many systems of the body. These defects can involve the eyes, skin, teeth, and cardiovascular, skeletal, and gastrointestinal systems. There have been many associated abnormalities reported in the literature. An appreciation of the clinical presentation of Goltz syndrome is important because physicians rely heavily on recognition of key physical characteristics in order to help make a diagnosis. In this report, we summarize the clinical findings observed when we were afforded the unique opportunity to interview and physically examine 19 patients, the largest group of individuals with Goltz syndrome brought together in one place to date. The findings are intended to characterize the orthopedic phenotypic manifestations of Goltz syndrome. This collection of data revealed that the most common orthopedic findings were syndactyly (68%), ectrodactyly (68%), leg length discrepancy (57%), and reduction defects of long bones (52%). Nail irregularities were present in 89% of the patients seen.

Goltz syndrome and PORCN: A view from Europe.

Goltz syndrome (focal dermal hypoplasia) is an X-linked dominant, multisystem birth defect with lethality for male embryos. The hypoplastic skin lesions follow Blaschko's lines and often show herniation of subcutaneous fatty tissue. Extracutaneous defects mainly involve the brain, the bones, the teeth, and the eyes. All of these anomalies show a segmental arrangement reflecting functional X-chromosome mosaicism. The present contribution tells the story how the molecular cause of Goltz syndrome was investigated and found by the group of the geneticist Karl-Heinz Grzeschik from Marburg, Germany.

Phenotypic and molecular characterization of focal dermal hypoplasia in 18 individuals.

Focal dermal hypoplasia, or Goltz syndrome, is a highly variable X-linked dominant disorder with abnormalities in ectoderm and mesoderm derived tissues. Classic clinical features include patchy hypoplastic skin, split hand/foot deformities, and ocular malformations. We aimed to refine the understanding of the phenotypic spectrum and natural history of this disorder and now present multi-disciplinary clinical description and medical history review for 18 patients with focal dermal hypoplasia. All disease characteristics were analyzed and compiled in aggregate to aid in development of clinical diagnostic criteria. Medical history data unexpectedly revealed that the majority of patients (87%) had undergone tonsillectomy for obstructive sleep apnea, which exposed an important co-morbidity that is not well described in the literature, but managing physicians should be made aware of. Fifteen of the 18 patients underwent molecular sequencing of PORCN to detect heterozygous or mosaic mutations. Where no mutation was detected, we performed exon-targeted chromosomal microarray to evaluate for large deletions of the PORCN gene region. We detected a pathogenic genotype in 14 of 15 patients, including one novel chromosomal deletion and four novel PORCN sequence variants. Here, we provide phenotypic summary analysis of 18 patients with focal dermal hypoplasia and propose clinical diagnostic criteria.

Dermatologic findings of focal dermal hypoplasia (Goltz syndrome).

Goltz syndrome, caused by mutations in PORCN, is an X-linked dominant ectodermal dysplasia which is also known as focal dermal hypoplasia. This name is derived from the predominant pathologic skin findings of the syndrome. Nineteen Goltz-affected participants attended a multidisciplinary scientific and clinical conference convened by the National Foundation for Ectodermal Dysplasia which allowed further characterization of the features of this very rare condition. At birth, the affected areas of skin are typically erythematous and fragile. The hallmark cutaneous features, which vary widely due to mosacism and X-inactivation, include the previously described skin changes of asymmetric Blaschko-linear and reticulated atrophy, pigmentary changes, and telangectasias. Lipomatous changes and papillomas as characteristically defined were reported in the majority of patients. A newly recognized skin finding was progressive hyperpigmented freckling that occurred within the hypopigmented areas which were noted to be photosensitive. Many patients also had a pebbly texture to the central face, dorsal hands and feet. Punctate erosions within the atrophic areas and hypohidrosis were also common. Most had patchy alopecia and many had diffusely thin hair. Scanning electron microscopy of the hair shafts revealed abnormalities in the majority of participants with several different features identified, including atrophic hairs with reduced diameters, markedly flattened hairs as noted in cross-sectional views, trichorrhexis nodosa, pili torti, and pili trianguli et canaliculi. Nail changes included V-nicking and longitudinal ridging of the nail plate, in addition to micronychia. Early recognition of the dermatologic features, in addition to the variable but universal limb anomalies, of Goltz syndrome will allow early and accurate diagnosis without the need for extensive diagnostic studies, while also allowing for accurate prognosis and appropriate genetic counseling.

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.

Setleis syndrome: clinical, molecular and structural studies of the first TWIST2 missense mutation.

Setleis syndrome is characterized by bitemporal scar-like lesions and other characteristic facial features. It results from recessive mutations that truncate critical functional domains in the basic helix-loop-helix (bHLH) transcription factor, TWIST2, which regulates expression of genes for facial development. To date, only four nonsense or small deletion mutations have been reported. In the current report, the clinical findings in a consanguineous Turkish family were characterized. Three affected siblings had the characteristic features of Setleis syndrome. Homozygosity for the first TWIST2 missense mutation, c.326T>C (p.Leu109Pro), was identified in the patients. In silico analyses predicted that the secondary structure of the mutant protein was sustained, but the empirical force field energy increased to an unfavorable level with the proline substitution (p.Leu109Pro). On a crystallographically generated dimer, p.Leu109 lies near the dimer interface, and the proline substitution is predicted to hinder dimer formation. Therefore, p.Leu109Pro-TWIST2 alters the three dimensional structure and is unable to dimerize, thereby hindering the binding of TWIST2 to its target genes involved in facial development.

Oesophageal duplication cysts, a rare cause of neck lump treated by ultrasound guided drainage: case report and review of the literature.

Oesophageal duplication cysts are a rare congenital anomaly of the foregut which usually present in infancy with respiratory symptoms, recurrent pneumonia and feeding difficulty. Other presenting symptoms depend on the location of the cyst and can include dysphagia, chest pain, arrhythmias and features of mediastinal compression. Treatment is usually surgical resection, recommended for complete resolution of symptoms, histological diagnosis and exclusion of malignancy. Here, we present a case of infected oesophageal duplication cyst which presents as a neck lump in a 43-year-old female with a background of Goltz syndrome, azygos fissure and congenital aortic stenosis. Surgical resection was decided against owing to the patient's high risk secondary to co-morbidities and instead ultrasound guided drainage was carried out successfully. The patient was symptom free and well at 1-year follow-up. Oesophageal duplication is an unusual presentation of a neck lump in an adult and whilst the usual treatment is surgical resection, we present here a case treated in an entirely different manner.

Focal dermal hypoplasia without focal dermal hypoplasia.

Focal dermal hypoplasia (FDH; Goltz-Gorlin syndrome) is an X-linked dominant disorder affecting mainly tissues of ectodermal and mesodermal origin. The phenotype is characterized by hypoplastic linear skin lesions, eye malformations, hair and teeth anomalies, and multiple limbs malformations. The disorder is caused by PORCN mutations. Here we describe a mother and daughter with FDH in whom a c.938T>G in PORCN was detected. Neither of the two had FDH, but otherwise the phenotype was classical. Focal skin hypoplasia is a hallmark of FDH but the present family indicates that FDH should also be considered in absence of this skin manifestation.