Subtype Of Epidermolysis Bullosa Research Articles

Ophthalmologic Approach in Epidermolysis Bullosa: A Cross-Sectional Study With Phenotype-Genotype Correlations.

This study describes ophthalmologic and systemic clinical findings in different subtypes of epidermolysis bullosa (EB) establishing genotype-phenotype correlations. A cross-sectional study was conducted in 58 patients with EB together with the Dystrophic Epidermolysis Bullosa Research Association, Chile. Data were stratified by major subtypes such as "simplex epidermolysis bullosa" (EBS), "junctional epidermolysis bullosa" (JEB), "recessive and dominant dystrophic epidermolysis bullosa" and "dominant dystrophic epidermolysis bullosa" (DDEB), and "Kindler syndrome" (KS). The diagnosis was confirmed by skin immunofluorescence mapping and genetic testing. Best-corrected visual acuity, corneal erosions, corneal scarring, symblepharon, blepharitis, ectropion, limbal stem cell deficiency, and esophageal involvement were assessed. Clinical outcome was based on the presence of corneal involvement attributable to EB. The most common ocular manifestations were corneal erosion/scarring and recurrent erosions. Frequencies of the EB subtypes were as follows: 17% EBS, 12% JEB, 16% DDEB, 53% recessive and DDEB, and 2% KS. Patients with EBS and DDEB did not reveal ocular involvement. Patients with recessive dystrophic epidermolysis bullosa (RDEB) were most affected by the disease showing corneal involvement in 16 cases, whereas 2 patients with JEB and the single KS case also showed corneal disease. Before their visit, 24 patients had undergone esophageal dilation, 23 of them with RDEB and 1 with KS. Although ophthalmic complications are common in EB, the incidence varied with the EB subtype. We also establish the correlation between esophageal and corneal involvement in RDEB.

Developing Hand Therapy Interventions based on ICF Framework for Epidermolysis Bullosa, the “Worst Skin Disease You Have Never Heard Of*”: An Observational Case Series

Study Design-Case series. Epidermolysis Bullosa (EB) is a rare congenital condition, characterized by skin which erupts with blisters, creating deformities in the upper limb from shoulders to fingers, to a “mitten hand.” Care for this population requires a collaborative multidisciplinary team working with the person and their family. Participation in life is limited due to the skin fragility and loss of dexterity is impacted early in life, impairing childhood development, and growth into productive young adults. The University of Minnesota is the only center in the world performing Bone Marrow Transplant (BMT) for a small subset of those with the recessive form of Dystrophic EB (RDEB). While many who attend the EB Center may not be candidates for BMT treatment, all are provided comprehensive care of the EB multispecialty team, of which hand therapy is a part. Patients come from multiple countries as well as the USA, for extended stays. Since 2015 persons with hand deformities related to EB have been referred to hand therapy by multiple departments, toddlers to young adults. Intervention focuses on correction or prevention of finger/hand/wrist/elbow deformities including finger webbing, contracture, and hypermobility, depending on the EB disease type and the hand deformity. There are 4 major subtypes of EB, each with their own severity levels: EB Simplex, Junctional EB, Dystrophic EB (DEB) and Kindler’s Syndrome. The purpose of this case series is to increase the understanding of hand therapy intervention for EB, share lessons learned, and initiate a clinical pathway aligned with the International Classification of Functioning, Disability and Health (ICF).

Dystrophic Epidermolysis Bullosa

Epidermolysis bullosa is a rare inherited blistering disease with an incidence of 8-10 per million live births. Dystrophic epidermolysis bullosa is a type of epidermolysis bullosa caused by mutation in type VII collagen, COL7A1. There are 14 subtypes of dystrophic epidermolysis bullosa and 400 mutations of COL7A1. Electron microscopy is the gold standard diagnostic test but expensive. Immunofluorescence study is a suitable diagnostic alternative. Trauma prevention along with supportive care is the mainstay of therapy. Squamous cell carcinoma develops at an early age in epidermolysis bullosa than other patients, particularly in recessive dystrophic epidermolysis bullosa subtypes. Regular follow-up is imperative in detecting and preventing complications. Gene therapy, cell therapy and bone marrow transplantation are the emerging novel therapeutic innovations. Preventing possible skin and mucosal injury in patients requiring surgery should be worked on. Here, we present a case of dystrophic epidermolysis bullosa in a 26-year-old male. Keywords: blister; dystrophic epidermolysis bullosa; epidermolysis bullosa; knee disarticulation; surgery.

The Conundrum of Allogeneic Bone Marrow Transplantation for Epidermolysis Bullosa

Epidermolysis bullosa is a heterogeneous group of heritable blistering disorders with considerable morbidity and mortality. Currently, there is no effective treatment or cure for epidermolysis bullosa, but bone marrow transplantation has been suggested to improve the clinical presentation and quality of life of some patients with the recessive dystrophic subtype of epidermolysis bullosa. In this issue, two studies (Hünefeld et al., and Egawa and Kabashima) address the issue whether bone marrow transplantation could be applied to patients with epidermolysis bullosa simplex with intraepidermal blistering. Utilizing a desmoglein-3 mouse model (Dsg3-/-) or keratin 5-specific reporter mice, the investigators show that transplanted bone marrow-derived cells migrate to the skin of bone marrow transplantation recipient mice, but these cells fail to transdifferentiate into epidermal keratinocytes, and there was no improvement in the clinical manifestations of the Dsg3-/- mice. Thus, further preclinical experimentation, possibly using mouse models that more faithfully recapitulate the epidermolysis bullosa simplex phenotype, is advisable before commencing clinical trials of bone marrow transplantation for epidermolysis bullosa simplex.

Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy

Epidermolysis bullosa (EB) is caused by mutations in as many as 19 distinct genes. We have developed a next-generation sequencing (NGS) panel targeting genes known to be mutated in skin fragility disorders, including tetraspanin CD151 expressed in keratinocytes at the dermal-epidermal junction. The NGS panel was applied to a cohort of 92 consanguineous families of unknown subtype of EB. In one family, a homozygous donor splice site mutation in CD151 (NM_139029; c.351+2T>C) at the exon 5/intron 5 border was identified, and RT-PCR and whole transcriptome analysis by RNA-seq confirmed deletion of the entire exon 5 encoding 25 amino acids. Immunofluorescence of proband's skin and Western blot of skin proteins with a monoclonal antibody revealed complete absence of CD151. Transmission electron microscopy showed intracellular disruption and cell-cell dysadhesion of keratinocytes in the lower epidermis. Clinical examination of the 33-year old proband, initially diagnosed as Kindler syndrome, revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures. The patient also had history of nephropathy with proteinuria. Collectively, the results suggest that biallelic loss-of-function mutations in CD151 underlie an autosomal recessive mechano-bullous disease with systemic features. Thus, CD151 should be considered as the 20th causative, EB-associated gene.

Diagnosis of Inherited Epidermolysis Bullosa in Resource-Limited Settings: Immunohistochemistry Revisited

Background: Immunofluorescence (IFM) antigen mapping is the most commonly used technique to diagnose and differentiate epidermolysis bullosa (EB). In India, IFM is limited to few research laboratories and is not readily available, making the diagnosis largely clinical and often inaccurate. Ob jective of the Study: To examine the diagnostic usefulness of immunohistochemistry (IHC) as compared to IFM in resource-limited settings. Methods: Forty-four consecutive EB patients were included in this study. IHC and IFM were performed on 7-µm frozen tissue sections using standard laboratory protocols with a limited panel of antibodies. The kappa coefficient of agreement was calculated with genetic analysis as the gold standard. Results: IFM and IHC accurately identified the subtype of EB in 80.9% (p < 0.001) of the cases, when a clear blister cavity was evident on biopsy. The sensitivities and specificities of IHC and IFM for diagnosing EB simplex, junctional EB, and dystrophic EB were 100, 100, and 60% and 82.4, 100, and 100%, respectively. IHC was equally effective (p < 0.001) in establishing the type of EB as IFM. Conclusions: IHC staining and its interpretation were simple and comparable to IFM. IHC had an advantage of showing subtle changes in the epidermal architecture that could not be appreciated on IFM and hence can be considered useful in resource-limited settings.

Successful Treatment of Epidermolysis Bullosa Pruriginosa with Oral Cyclosporine

Introduction: Epidermolysis bullosa (EB) pruriginosa is a rare distinct clinical subtype of dystrophic EB, in which skin fragility, blistering, and scar formation are associated with intense pruritus, nodular prurigo like lichenified lesions, nail dystrophy, and variable presence of papuloid lesions. Case Presentation: Herein, we report a case with a history of blistering since infancy followed by intensely pruritic papulonodules, predominantly on the shins, nail dystrophy, and milia formation. Conclusions: Our patient had an excellent response to systemic cyclosporine treatment.

Multigene Next-Generation Sequencing Panel Identifies Pathogenic Variants in Patients with Unknown Subtype of Epidermolysis Bullosa: Subclassification with Prognostic Implications

Multigene Next-Generation Sequencing Panel Identifies Pathogenic Variants in Patients with Unknown Subtype of Epidermolysis Bullosa: Subclassification with Prognostic Implications

Cardiomyopathy in Patients With Hereditary Bullous Epidermolysis

Background and objectiveIn recent decades, an association has been reported between epidermolysis bullosa (EB) and dilated cardiomyopathy (DC). DC is typically in an advanced phase when detected, leading to a poorer prognosis. Our objective was to determine the prevalence of DC in patients with EB seen in Hospital San Joan de Déu in Barcelona, Spain, between May 1986 and April 2015. MethodsThis was a descriptive, cross-sectional chart-review study in which we recorded the type and main subtypes of EB and the presence or absence of DC. ResultsFifty-seven patients with EB were found, 19 with EB simplex, 10 with junctional EB, 27 with dystrophic EB (14 dominant dystrophic and 13 recessive dystrophic), and just 1 with Kindler syndrome. DC was detected in only 2 patients with recessive dystrophic EB. Twenty-three patients had presented factors that could have had a causal relationship with the potential onset of DC. ConclusionsDC is a possible complication of EB, particularly in recessive dystrophic EB. Periodic follow-up should be performed to make an early diagnosis and start treatment.

Miocardiopatía en pacientes con epidermólisis ampollosa hereditaria

Introduction and objectiveIn recent decades, an association has been reported between epidermolysis bullosa (EB) and dilated cardiomyopathy (DC). DC is typically in an advanced phase when detected, leading to a poorer prognosis. Our objective was to determine the prevalence of DC in patients with EB seen in Hospital San Joan de Déu in Barcelona, Spain, between May 1986 and April 2015. MethodsThis was a descriptive, cross-sectional chart-review study in which we recorded the type and main subtypes of EB and the presence or absence of DC. ResultsFifty-seven patients with EB were found, 19 with EB simplex, 10 with junctional EB, 27 with dystrophic EB (14 dominant dystrophic and 13 recessive dystrophic), and just 1 with Kindler syndrome. DC was detected in only 2 patients with recessive dystrophic EB. Twenty-three patients had presented factors that could have had a causal relationship with the potential onset of DC. ConclusionDC is a possible complication of EB, particularly in recessive dystrophic EB. Periodic follow-up should be performed to make an early diagnosis and start treatment.

Inherited epidermolysis bullosa: A multisystem disease of skin and mucosae fragility

Epidermolysis bullosa (EB) is a blistering disorder that can be autosomic or dominantly inherited and has a wide spectrum of clinical presentations. The most recent classification divides EB into four basic subtypes: (1) EB simplex, (2) junctional EB, (3) dystrophic EB and (4) Kindler syndrome; depending on the level of the epidermal-dermal junction where the formation of blisters is present. With the use of immunohistochemistry and molecular biology, new mutation genes and proteins have been identified and more than thirty subtypes of EB have been described according to text phenotype, each affecting different key proteins for the structural integrity of the skin. The phenotype can be a mild one where blisters occur after minor trauma, but quality of life is preserved or a severe one with multisystemic manifestations affecting skin, mucous membranes, bones, joints, nutritional status, and cancer development leading to early death. We describe the clinical manifestations, diagnostic approach, and multidisciplinary management of EB subtypes.

Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases.

BackgroundInherited epidermolysis bullosa (EB) comprises a highly heterogeneous group of rare diseases characterized by exacerbated skin and/or mucosal fragility and blister formation after minor mechanical trauma. Level of cleavage in the skin, clinical features with immunofluorescence antigen mapping and/or electron microscopy examination of a skin biopsy and/or gene involved, type(s) of mutation present and sometimes specific mutation(s), allow to define the EB type and subtype. This family of genodermatoses exposes patients to several complications, cutaneous squamous cell carcinoma (cSCC) being the most severe of them.ObjectiveThe aim of this systematic review was to document patients with EB who developed cSCC.MethodsA systematic literature search was performed, from inception to March 2014, using Medline, Embase, Cochrane and ClinicalTrials.gov databases. Only articles published in English and French were selected. The diagnosis of EB had to be confirmed by EM and/or IFM and/or mutation analysis, while cSCC had to be confirmed by histological analysis.ResultsOf 167 references in the original search, 69 relevant articles were identified, representing 117 cases. cSCCs were identified in all types of EB, though predominantly in recessive dystrophic EB (RDEB) forms (81 cases (69.2 %)). The median age at diagnosis was 36 years old (interquartile range (IQR), 27-48 years and range, 6-71 years) for all forms. Of those with measurements in the literature (88 cases (75.2 %)), tumor size was greater than 2 centimeters in 52 cases (59.1 %). The histopathological characteristics were specified in 88 cases (75.2 %) and well-differentiated forms predominated (73.9 %). No conclusion could be drawn on the choice of surgical treatment or the management in advanced forms.LimitationsThis study was retrospective and statistical analysis was not included due to various biases. This study design did not allow to infer prevalence, nor EB subtype risk for cSCC occurrence.ConclusionsOur study correlated with historical data shows that most of the cSCCs occurred in subjects with the RDEB subtype, however reports also show that cSCCs can present in any patients with EB. The first signs of cSCC developed at a younger age in EB patients than in non-EB patients. Interestingly, the cSCC duration, before its diagnosis, was shorter in individuals with RDEB than with junctional EB (JEB) and dominant dystrophic EB (DDEB).This study further emphasizes the importance of regular monitoring of EB patients, particularly with the RDEB subtype as they developed cSCC at a younger age.

Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry

Accurate estimation of the incidence and prevalence of each subtype of epidermolysis bullosa (EB) is essential before clinical trials can be designed and sufficient funding allocated by government agencies and third-party insurers for the care of these individuals. To determine the incidence and prevalence of inherited EB stratified by subtype in the United States during a 16-year period. Prospective cross-sectional and longitudinal study. Data were obtained from 3271 patients consecutively enrolled in the National Epidermolysis Bullosa Registry from January 1, 1986, through December 31, 2002, using a detailed instrument created with the assistance of the National Institutes of Health. Analyses were performed in January 1999 and April 2015. Participants were patients of all ages with EB. Extensive clinical and laboratory data were collected on patients who were subclassified and serially revalidated based on published diagnostic recommendations by an international panel of experts. Pertinent to this report, estimates were made of the incidence and prevalence during 2 time frames. During the first 5 years of funding of the registry, the overall incidence and prevalence of inherited EB were 19.60 and 8.22 per 1 million live births, respectively. When reassessed over the entire 16 years of the study, the prevalence rose to 11.07, whereas the overall incidence remained unchanged at 19.57 cases. Changes were also observed within some disease subsets as increased numbers of patients were identified, recruited, followed up longitudinally, and resubclassified as needed over time. For example, in 2002, the prevalence of EBS overall and localized EBS had increased considerably by 30.4% and 25.5%, respectively, whereas the prevalence of generalized intermediate EBS declined by 76.7% as a result of later subclassification of some of those patients into other subtypes. In contrast, no significant change was noted in the overall prevalence of JEB or generalized severe JEB, although there was a 73.0% decline in the prevalence of generalized intermediate JEB. Precise estimates of the incidence and prevalence of each major subtype of inherited EB in the United States are now available that should assist investigators in choosing which subtypes are amenable to properly designed, large-scale, clinical trials.

Research Techniques Made Simple: Immunofluorescence Antigen Mapping in Epidermolysis Bullosa

Inherited epidermolysis bullosa is a group of genetic blistering diseases with a broad spectrum of clinical severity and molecular defects. Epidermolysis bullosa results from mutations in genes encoding proteins involved in cell-cell and cell-matrix adhesion in the epidermis. Immunofluorescence antigen mapping makes use of monoclonal antibodies against proteins of the dermal-epidermal junction zone to determine the layer of skin where cleavage occurs and the relative protein abundance. It allows the diagnosis of the type and subtype of inherited epidermolysis bullosa and sheds light on molecular mechanisms underlying the disease. Immunofluorescence mapping steps include obtaining a skin biopsy sample, processing the biopsy material, antigen-antibody interaction on tissue, washing, incubation with fluorescently conjugated secondary antibodies, mounting, observation under a fluorescence microscope, and interpretation. A minimal antibody panel allows discrimination of the main epidermolysis bullosa subtypes. Extended panels can be used depending on the diagnostic or scientific question to be addressed. Immunofluorescence mapping contributed to significant progress in understanding epidermolysis bullosa, including identification of new underlying genetic mutations, mutation mechanisms, and the presence of revertant mosaicism. It is also an important tool in the assessment of the efficacy of experimental therapeutic approaches.

The distribution of epidermolysis bullosa in Australia with a focus on rural and remote areas.

Patients with epidermolysis bullosa (EB) require specialised medical care. In Australia this expertise is located in the major cities, with patients living in rural and remote areas having reduced access to these services. We aim to analyse the geographical distribution of patients with EB in Australia to determine the relevance of this potential geographical disadvantage for this population. Using postal codes obtained from the Australian National Diagnostic Laboratory Database for EB and the Australasian EB Registry, living patients with EB in Australia were categorised using the Australian standard geographical classification, remoteness areas. An analysis of EB subtype, including severity was also performed. A total of 318 patients were categorised, of whom 221 lived in major cities, 65 in inner regional areas, 26 in outer regional areas, four in remote and two in very remote areas. Half the patients living in remote and very remote areas had severe forms of EB. A significant proportion of patients with EB live outside the major cities in Australia. Half of the patients living in remote and very remote areas had severe forms of EB. Targeted strategies to improve access to EB-specific medical care may be needed for patients living in rural and remote areas.

Development and validation of an epidermolysis bullosa family/parental burden score.

The notion of the individual burden associated with a disease has been introduced to determine 'disability' in the broadest sense: psychological, social, economic and physical. Subtypes of epidermolysis bullosa (EB) are rare, life-threatening, untreatable chronic genodermatoses. To develop and validate a specific questionnaire assessing the burden on families of children with EB: Epidermolysis Bullosa Burden of Disease (EB-BoD). Items were generated by a verbatim report from parents of children with EB. Subsequently, a study was implemented for psychometric analysis. An epidermolysis bullosa burden-of-disease questionnaire was refined via item reduction according to inter-question correlations, consensus among experts and exploratory factor analysis. Internal consistency was determined by calculating Cronbach's α. Concurrent validity was determined by calculating the correlation between EB-BoD and the Short-Form 12 items (SF-12) questionnaire. From a primary list of 30 items, EB-BoD was reduced to a 20-item questionnaire, covering four disease aspects based on the exploratory factor analysis. Construct validity was demonstrated and the EB-BoD questionnaire showed good internal consistency (Cronbach's α = 0·9). The resulting EB-BoD score was significantly correlated to the mental dimension of SF-12 (r = -0·61), but it was not correlated to it's physical dimension (r = 0·04). EB-BoD scores were significantly discriminating between EB subtypes. The EB-BoD questionnaire appears to be a useful assessment tool regarding medical and socioeconomic issues in patients with EB and their families. EB-BoD scores correlate well with the family/parental burden experienced by the families of patients with EB.

Induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa (EB) is a group of genetically inherited skin disorders affecting nearly 1 to 3 of every 100,000 live births and almost 500,000 individuals worldwide (1). Autosomal recessive dystrophic EB (RDEB) is an aggressive EB subtype (approximately 25% of EB cases), caused by COL7A1 gene mutation encoding type VII collagen and resulting in binding defect of epidermis to dermal tissue, excessive skin and mucosal fragility, blistering and scarring. Lesions occur below the basement membrane zone in the upper part of the dermis. Until today no definite therapy is available and patients suffering from RDEB are managed conservatively avoiding skin damage and aiming in improve quality of life and reducing the risk of developing complications, such as infection and malnutrition, or undergo surgical or minimal invasive palliative procedures (2,3). Current research strategies include protein, gene and molecular therapies (4-6). In their article “Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa” Sebastiano et al. propose an innovating cell therapy for RDEB treatment, by developing a state of the art protocol of genetically repaired induced pluripotent stem cells (iPSCs) as to generate sheets of normal skin tissue to treat affected skin areas (7). Moreover, as numerous stem cells are needed in order to cover the affected surface area, authors outline the necessity for creating personalized iPSCs banks as to provide a constant long-term iPSCs source.

Generalized severe junctional epidermolysis bullosa with congenital absence of skin in churra lambs.

Up to 0.5% of churra lambs from two genetically related flocks showed congenital skin lesions of variable severity, jeopardizing the life of the lambs in the most severe cases. The primary objective of this study was to classify the type of congenital epithelial disease suffered by these animals, based on the description of the macroscopic skin defects, the histological and ultrastructural changes and the hereditary nature of the condition. Thirty affected newborn lambs from two genetically related flocks were studied. Three additional lambs acquired from two other flocks, which had no grossly apparent skin lesions and had died of infectious diseases, were studied as unaffected control animals. Histological and ultrastructural examinations of skin and oral mucosa samples were performed. Pedigree analyses were used to investigate genealogical relationships. Generalized severe junctional epidermolysis bullosa with congenital absence of skin was described in all lambs studied and an autosomal recessive mode of inheritance was identified. The pathological findings and mode of inheritance in these lambs are similar to an inherited epidermolysis bullosa subtype of humans, which has not been reported previously in veterinary medicine.

Epidermolysis bullosa and Kindler syndrome - where is the border in oral manifestaions

Epidermolysis bullosa (EB) represents a rare chronic autoimmune subepidermal vesiculobullous disorder that affects the skin and mucosa and is characterized by blistering and mechanical fragility of the skin. The most recent classification recognizes four major EB groups: intraepidermal EB (Simplex), junctional EB, dermolytic EB (Dystrophic), and mixed EB (Kindler syndrome). Kindler syndrome is a rare genodermatosis with clinical features of trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The clinical features of the syndrome have been annotated by different authors but definite criteria to confirm the diagnosis have not yet been generally accepted.

Immunofluorescence mapping in inherited epidermolysis bullosa: a study of 86 cases from India.

Epidermolysis bullosa (EB) poses diagnostic challenges in infancy. In India, the diagnosis is largely clinical. There were no facilities to perform immunofluorescence mapping (IFM) until recently, and electron microscopy, which requires expertise to interpret, is limited to a few research laboratories. To describe the patterns of IFM staining in the various forms of EB in Indian patients and to correlate these findings with clinical diagnosis. We conducted a cross-sectional study of IFM findings in EB. Antibodies against type IV collagen, cytokeratin 14, laminin 332 and type VII collagen were used. Clinical correlation was performed in all cases, and concordance-discordance rates were calculated. Eighty-six patients with a diagnosis of EB were included in the study. There were 29 with EB simplex (EBS), 18 with junctional EB (JEB) and 15 with dystrophic EB (DEB). The remaining 24 cases included rare variants, cases with overlapping clinical features and cases where the type of EB was not known. On IFM diagnosis, there were 32 cases of EBS, 15 JEB, 17 DEB and two Kindler syndrome. Two cases were not EB and 18 were inconclusive. IFM could establish the type in 12 of 15 cases (80%) that had overlapping clinical features. Most of these cases were under 1year of age. Overall the concordance was 57% and was seen best in cases of EBS. This is the first large study of IFM of the subtypes of EB in Indian patients. The study provides a framework for better understanding of EB in Indian patients and for better diagnosis and management, particularly in infancy.