Exploratory classification of clinical phenotypes in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis using cluster analysis.

A novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n = 8) and proteinase 3-ANCA-positive (n = 41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n = 47); cutaneous (n = 36); renal (n = 256), non-renal (n = 33); and both ENT and cutaneous symptoms (n = 6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n = 42), without s-Cr elevation (< 1.3 mg/dL) (n = 157), s-Cr elevation (≥ 1.3 mg/dL) with high CRP (> 10 mg/dL) (n = 71), or s-Cr elevation (≥ 1.3 mg/dL) without high CRP (≤ 10 mg/dL) (n = 157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis.

Segmental overgrowth and aneurysms due to mosaic PDGFRB p.(Tyr562Cys).

Activating variants in the platelet-derived growth factor receptor ß gene (PDGFRB) have been associated with Kosaki overgrowth syndrome, infantile myofibromatosis, and Penttinen premature aging syndrome. A recently described phenotype with fusiform aneurysm has been associated with mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant. Few reports however have examined the vascular phenotypes and mosaic effects of PDGFRB variants. We describe clinical characteristics of two patients with a recurrent mosaic PDGFRB p.(Tyr562Cys) variant identified via next-generation sequencing-based genetic testing. We observed intracranial fusiform aneurysm in one patient and found an additional eight patients with aneurysms and phenotypes associated with PDGFRB-activating variants through literature search. The conditions caused by PDGFRB-activating variants share overlapping features including overgrowth, premature aged skin, and vascular malformations including aneurysms. Aneurysms are progressive and can result in morbidities and mortalities in the absence of successful intervention. Germline and/or somatic testing for PDGFRB gene should be obtained when PDGFRB activating variant-related phenotypes are present. Whole-body imaging of the arterial tree and echocardiography are recommended after diagnosis. Repeating the imaging study within a 6- to 12-month period after detection is reasonable. Finally, further evaluation for the effectiveness and safety profile of kinase inhibitors in this patient population is warranted.

A novel homozygous RIPK4 variant in a family with severe Bartsocas-Papas syndrome.

Bartsocas-Papas syndrome (BPS) is a rare autosomal recessive disorder characterized by popliteal pterygia, syndactyly, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and genital malformations. Most of the BPS cases reported to date are fatal either in the prenatal or neonatal period. Causative genetic defects of BPS were mapped on the RIPK4 gene encoding receptor-interacting serine/threonine kinase 4, which is critical for epidermal differentiation and development. RIPK4 variants are associated with a wide range of clinical features ranging from milder ectodermal dysplasia to severe BPS. Here, we evaluated a consanguineous Turkish family, who had two pregnancies with severe multiple malformations compatible with BPS phenotype. In order to identify the underlying genetic defect, direct sequencing of the coding region and exon-intron boundaries of RIPK4 was carried out. A homozygous transversion (c.481G>C) that leads to the substitution of a conserved aspartic acid to histidine (p.Asp161His) in the kinase domain of the protein was detected. Pathogenicity predictions, molecular modeling, and cell-based functional assays showed that Asp161 residue is required for the kinase activity of the protein, which indicates that the identified variant is responsible for the severe BPS phenotype in the family.

More than meets the eye: Expanding and reviewing the clinical and mutational spectrum of brittle cornea syndrome.

Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non-ocular symptoms include not only hearing loss but also signs of connective tissue fragility, placing it in the Ehlers-Danlos syndrome (EDS) spectrum. It is caused by biallelic pathogenic variants in ZNF469 or PRDM5, which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5. We also performed a genotype- and phenotype-oriented literature overview of all (n = 85) reported patients with ZNF469 (n = 53) and PRDM5 (n = 32) variants. Musculoskeletal findings may be the main reason for referral and often raise suspicion of another heritable connective tissue disorder, such as kyphoscoliotic EDS, osteogenesis imperfecta, or Marfan syndrome, especially when a corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition.

How to Evaluate Acne in Reproductive-Age Women: An Epidemiological Study in Chinese Communities.

BACKGROUND: Acne is not only a skin condition but also a cardinal component of many systemic diseases or syndromes. This study was aimed to investigate the prevalence of acne in reproductive-age women in Sichuan province, China, and to evaluate acne as a skin problem alone or a symptom of gynecological/endocrinological disease. METHODS: From October 2008 to September 2009, 1043 reproductive-age women from 19 to 45 years of age from seven communities of three districts in Sichuan province completed a standardized questionnaire and a physical examination. Acne was classified using the Pillsbury scale, and hirsutism was assessed using a modified Ferriman-Gallwey method. Diagnosis of polycystic ovary syndrome (PCOS) was based on the 2003 Rotterdam criteria. Some endocrine and metabolic markers were detected for the women diagnosed with PCOS related to acne and the control group. RESULTS: The prevalence of acne was 32.5%, and the highest prevalence (9.6%) was seen in the 19-24-year-old age group. Prevalence among women eating dessert frequently, exercising seldom, or among sedentary workers was significantly higher in the acne group (14.1%, 55.6%, and 51.3%, respectively) than in the nonacne group (10.8%, 45.7%, and 35.5%; all P<0.05). The prevalence of oligomenorrhea and hirsutism in the acne group (17.6%, 24.7%) was significantly higher than in the nonacne group (8.6%, 15.1%; both P<0.05). Among the participants with acne, 64.3% had acne alone, 18.3% were diagnosed with hyperandrogenism, and 17.4% were diagnosed with PCOS. The level of serum androstendione in the group of PCOS (10.98±3.12 nmol/L) was significantly higher than that in the control group (8.85±3.09nmol/L) (P<0.05). CONCLUSION: When reproductive-age women with acne are encountered in gynecology-endocrinology or dermatology clinics, physicians should consider evaluating them from PCOS, hyperandrogenism, or acne alone.

Prevalence of Congenital Cutaneous Anomalies in 1000 Newborns and a Review of the Literature.

OBJECTIVE: There are limited reports studying on congenital cutaneous anomalies in newborns, particularly in Turkey. Some of congenital cutaneous anomalies serve as an important clue for accompanying syndromes or other medical conditions. This study aimed to determine the prevalence of congenital cutaneous anomalies in newborns and to discuss their clinical significance with a brief review of literature. STUDY DESIGN: A total of 1,000 newborns were examined by a dermatologist in a hospital-based, cross-sectional, prospective study between October 2011 and April 2012. RESULTS: We observed 11 different congenital cutaneous anomalies in 48 newborns of 1,000 (4.8%). The most commonly seen anomalies were sacral dimple, accessory nipple, acrochordon, hypospadias, open spinal dysraphism, and accessory tragus. None of the newborns with cutaneous anomalies had any association. CONCLUSIONS: Although congenital cutaneous anomalies are rare in newborns, clinicians should be aware of them as they may be in association with syndromes and other medical conditions. It is also important to give appropriately provided information to avoid parents concerns.

[Cutaneous vascular anomalies in children]. / Les anomalies vasculaires cutanées chez l'enfant.

INTRODUCTION: Vascular anomalies, which are erroneously categorized under the term angiomas, are a highly heterogeneous group of lesions that are poorly understood and affect a mean of 5 to 10 % of children. The fortuitous discovery of propranolol's efficacy in one of these entities has made them a topical issue. OBJECTIVES: The paper's main objective is to inform family doctors of the various types of vascular anomalies, clarify their classification, and provide a common terminology. Its secondary objective is to provide a decision tree that enables primary care doctors to avoid diagnostic pitfalls, successfully detect cases, and optimize management. METHODS: Systematic review. CONCLUSIONS: According to a recent study, 71,3 % of publications use the term hemangioma erroneously, regardless of the authors' field. The key for family doctors is to use one international classification only, that of the International Society for the Study of Vascular Anomalies (ISSVA), in order to facilitate management and comprehension between the different healthcare levels. The diagnosis of vascular anomalies is clinical in 90 % of cases, so all family doctors can, whilst using a decision tree, diagnose a vascular anomaly and refer only those that are complex for specialist care. The most common vascular anomaly is infantile hemangioma in infants, which spontaneously regresses around the age of 5-7 years in 90 % of cases. Watchful waiting and regular follow-up suffice, therefore, in such settings.

Nevus comedonicus: a case series.

Twelve previously unreported cases of nevus comedonicus are presented. Characteristic closely grouped dilated follicular openings with horny plugs that mimic comedones led to the diagnosis. One patient had nevus comedonicus syndrome and there were cases with atypical locations and unusual complications of this condition. We also highlight clinical associations and therapeutic options.

Neural tube dysraphism: review of cutaneous markers and imaging.

Neural tube dysraphisms are congenital anomalies resulting from impaired formation of structures along the craniospinal axis during central nervous system development. When these malformations are large or lack a skin covering, they are easily recognized, whereas smaller or skin-covered malformations may not be readily apparent. Due to the intimate embryologic origin of the skin and nervous system, these occult malformations are often heralded by associated cutaneous abnormalities. In this article, the common clinical presentations and cutaneous markers of craniospinal dysraphism are reviewed, along with the recommended imaging modalities.

The spectrum of genodermatoses and congenital cutaneous conditions in northern Ethiopia.

Reports of congenital diseases in Africa are scanty, probably because of their rarity, the lack of knowledge among health workers, and the difficult political and social situation in different African countries. We describe here the spectrum of genetic and rare congenital cutaneous conditions encountered at the Italian Dermatological Center of Ayder referral hospital of Mekele, Ethiopia, over a 3-year period. All patients attending the Italian Dermatological Center were registered in a database, and medical records of genetic and congenital disorders diagnosed from January 2008 to December 2010 were retrospectively analyzed. Over the total, 24 different genetic and congenital disorders affecting 122 individuals (0.4% of the total case load) were observed. In our case series, we did not report any patient affected by albinism, in contrast with literature from other African countries. To our knowledge, this is the first report from northern Ethiopia. A brief update on the commonest disorders is included.

Clinical and magnetic resonance imaging findings in patients with Leigh syndrome and SURF1 mutations.

BACKGROUND: Mutation in the SURF1 is one of the most common nuclear mutations associated with Leigh syndrome and cytochrome c oxidase deficiency. This study aims to describe the phenotypic and imaging features in four patients with Leigh syndrome and novel SURF1 mutation. METHODS: The study included four patients with Leigh syndrome and SURF1 mutations identified from a cohort of 25 children with Leigh syndrome seen over a period of six years (2006-2012). All the patients underwent a detailed neurological assessment, muscle biopsy, and sequencing of the complete mitochondrial genome and SURF1. RESULTS: Three patients had classical presentation of Leigh syndrome. The fourth patient had a later age of onset with ataxia as the presenting manifestation and a stable course. Hypertrichosis, facial dysmorphism and hypopigmentation were the additional phenotypic features noted. On magnetic resonance imaging all patients had brainstem and cerebellar involvement and two had basal ganglia involvement in addition. The bilateral symmetrical hypertrophic olivary degeneration in these patients was striking. The SURF1 analysis identified previously unreported mutations in all the patients. On follow-up three patients expired and one had a stable course. CONCLUSIONS: Patients with Leigh syndrome and SURF1 mutation often have skin and hair abnormalities. Bilateral symmetrical hypertrophic olivary degeneration was a consistent finding on magnetic resonance imaging in these patients.

Craniofacial anomalies amongst births at two hospitals in Nairobi, Kenya.

The pattern of congenital oral and craniofacial anomalies (CFAs) in the Kenyan population remains unknown. The objective of this study was to describe the pattern of occurrence of CFAs at two hospitals in Nairobi. A descriptive cross-sectional study at the Kenyatta National Hospital and Pumwani Maternity Hospital was carried out from November 2006 to March 2007. Mothers who delivered at the hospitals consented to an interview and physical examination of their babies within 48 h of delivery. The anomalies were classified for type and magnitude. Data were analysed to determine the association of these anomalies with ages of the mothers, gender, weight, birth order, mode of delivery and birth status of the babies. During the study period, 7989 babies were born. The CFAs manifested in 1.8% of the total births and were more common in female (1.4%) than in male (1.0%) live births. 12.8% of stillbirths had CFAs, with lesions manifesting more in males (16.7%) than in females (6.9%). The commonest CFA was preauricular sinus (4.3/1000) followed by hydrocephalus (1.9/1000) then preauricular tags and cleft lip and palate (1.5/1000 and 1.3/1000 total births, respectively).

Epidemiología y clínica de las metástasis cutáneas en un hospital de Lima-Perú: Período 1996-2006 / Epidemiology and clinics of cutaneous metastases in a hospitalfrom LimaûPeru. Period 1996-2006

OBJETIVO: Determinar las características epidemiológicas y clínicas de las metástasis cutáneas en el Hospital Nacional EsSalud Edgardo Rebagliati Martins (HNERM) en el período 1996-2006. MATERIAL Y MÉTODOS: Estudio descriptivo de tipo serie de casos. La población de estudio estuvo constituida por los pacientes con diagnóstico de metástasis cutánea en el HNERM entre los años 1996 y 2006; no se realizó muestreo por ser la población pequeña y accesible. Los pacientes fueron seleccionados de acuerdo a criterios de inclusión y exclusión. Se revisó las historias clínicas de los pacientes obteniéndose las características epidemiológicas, clínicas, histopatológicas y supervivencia. RESULTADOS: Se diagnosticó 51 casos de metástasis cutáneas. La edad promedio fue de 65.0 ±15.4 años, el 58.8% correspondió al sexo femenino y el 41.2% al sexo masculino. El 29.4% se situó entre los 70-79 años, el 31.4% tenía diagnóstico previo de cáncer y el 23.5% tenía antecedentes familiares de cáncer. Se diagnosticó la metástasis cutánea antes que la neoplasia maligna primaria en el 67%. Las metástasis tuvieron origen en neoplasias dermatológicas en el 51.0% y en tumores de órganos sólidos en el 49.0% (cánceres de mama, riñón y vejiga). Los pacientes acudieron a consulta por presentar lesiones de tipo nódulo (31.4%) y tumor (9.8%). Las metástasis se localizaron en los varones predominantemente en el tórax posterior (19.0%) y en las piernas (14.3%); mientras que, en el tórax anterior (46.7%) y cuero cabelludo (23.3%) en las mujeres. La mediana de la supervivencia fue de 5.6 años. CONCLUSIONES: En el HNERM las metástasis cutáneas se presentan a edades avanzadas, predominan las de origen hematológico así como las originarias de mama y con frecuencia constituyen el primer signo para la identificación de una neoplasia oculta. Es relevante el antecedente familiar de neoplasia en los pacientes.

OBJECTIVES: To determine the clinical and epidemiology characteristics of cutaneous metastases at Hospital Nacional EsSalud Edgardo Rebagliati Martins during 1996-2006. MATERIALS AND METHODS: Descriptive study of cases series. The study population was constituted by patients with diagnoses of cutaneous metastases attended in the Hospital Edgardo Rebagliati Martins Essalud between 1996 and 2006; sampling was not performed because of population was small and accessible. Patients were selected in accordance with inclusion and exclusion criteria. Clinical past histories of patients were revised obtaining the next clinical, epidemiology and histopathology characteristics. Data obtained was registered in an instrument of data recollection and became part of a database. RESULTS: A total of 51 cutaneous metastases cases were diagnosed. The mean age of patientswas 65.0 ± 15.4 years, 58.8% corresponded female and the remaining 41.2% were male. The higher frequency was in patients between 70-79 years (29.4%), 31.4 % had previous diagnoses of cancer and 23.5% had family history of cancer (mainly father and brother). Cutaneous metastases were diagnosed before primary malignant neoplasea in 67% of patients. Metastases originated in hematological malignancies in 51.0% of cases and solid organ tumors in the remaining 49.0%. Solid organ tumors that most often gave rise to cutaneous metastases were breast, kidney and bladder. The patients attended mainly consulted for nodule like lesions (31.4%) and tumor (9.8%). Metastases were located predominantly in men in the posterior thorax (19.0%) and legs (14.3%), while in the anterior thorax (46.7%) and scalp (23.3%) in women. CONCLUSIONS: In the Hospital Nacional Edgardo Rebagliati, cutaneous metastases occur in later life, predominantly hematologic origin and those originating in breast and are often the first sign for the identification of occult neoplasy. It is relevant the family history of neoplasia in patients.

Abnormal skin barrier in the etiopathogenesis of atopic dermatitis.

PURPOSE OF REVIEW: Many recent studies have revealed the key roles played by Th1/Th2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the pathogenesis of atopic dermatitis. Accordingly, current therapy has been largely directed towards ameliorating Th2-mediated inflammation and/or pruritus. We will review here emerging evidence that the inflammation in atopic dermatitis results from inherited and acquired insults to the barrier and the therapeutic implications of this new paradigm. RECENT FINDINGS: Recent molecular genetic studies have shown a strong association between mutations in FILAGGRIN and atopic dermatitis, particularly in Northern Europeans. But additional acquired stressors to the barrier are required to initiate inflammation. Sustained hapten access through a defective barrier stimulates a Th1 --> Th2 shift in immunophenotype, which in turn further aggravates the barrier. Secondary Staphylococcus aureus colonization not only amplifies inflammation but also further stresses the barrier in atopic dermatitis. SUMMARY: These results suggest a new 'outside-to-inside, back to outside' paradigm for the pathogenesis of atopic dermatitis. This new concept is providing impetus for the development of new categories of 'barrier repair' therapy.

Factores relacionados con la aparición de estrías atróficas en mujeres adolescentes de dos establecimientos educativos privados de la ciudad de Medellín, 1997-1998 / Related factors with atrophic stretch marks in adolescent female students from two private educational establishments from the city of Medellin, 1997-1999

Objetivos: determinar la prevalencia de estrías atróficas e identificar la frecuencia de lo factores de riesgo relacionados con su aparición en mujeres adolescentes. Métodos: se realizó un estudio descriptivo en 210 estudiantes entre 12 y 18 años de dos establecimientos educativos privados de la ciudad de Medellín, Colombia. A cada estudiante se le aplicó una encuesta autodirigida y se le realizó un examen físico para observar la presencia de estrías. Resultados: el 75,2% de las adolescentes presentaron estrías, el 59,5% tenían entre 15 a 18 años. La localización más frecuente fueron los glúteos (78,3%). Se encontró asociación entre las estrías y factores como: obesidad (p=0,011), antecedentes familiares positivos (p=0,006), uso de hormonas no esteroideas (anticonceptivos) (p=0,003), consumo de productos dietéticos (p=0,025) y grasas (p= 0,026). No se encontró correlación con el fototipo, enfermedades, uso de esteroides, hábito de fumar y práctica de ejercicio. Conclusiones: las estrías atróficas son una entidad clínica de alta prevalencia en mujeres jóvenes, afectando múltiples zonas corporales con deterioro de la autoimagen. Ciertas conductas de alimentación y consumo de medicamentos, además de los antecedentes familiares, pueden estar implicados en el aumento de la frecuencia de esta enfermedad.

Objective: This study was designed to determine the prevalence of stretch marks in adolescent young woman and to identify the associated risk factors. Methods: It was performed a descriptive study on 210 students between 12 and 18 years old from two private schools in Medellín, Colombia. Each student answered a questionnaire and was examined. Results: 75.2% of the adolescents had stretch marks and 59.5% of them were between 15 and 18 years old. Most frequent affected body site was the buttock (78.3%). It was found a greater prevalence between the presence of stretch marks and factors like: obesity (p=0.011), family members with stretch marks (p= 0.006), use of nonsteroidal hormones (p=0.003), diet products (p=0.025), and fats (p=0.0265). It was not found association with phototype, diseases, glucocorticoids, smoking or exercise. Conclusions: The stretch marks are very frequent in adolescent female, they are a source of esthetic discomfort and have great psychological impact on those who have them. Eating habits, medications intake, personal and family histories can influence the appearance of stretch marks.

Factores de riesgo asociados a estrías atróficas en mujeres adolescentes de un colegio privado, Medellín, 2003 / Risk factors associated with strechmarks in teenage girls of a private school, Medellin, 2003

Se realizó un estudio de casos y controles, en 289 estudiantes entre 12 y 18 años de un colegio privado de la ciudad de Medellín, para determinar la posible asociación entre la aparición de estrías atróficas con algunos factores de riesgo. A cada estudiante se le realizó una entrevista y se le practicó examen físico para determinar la presencia de estrías. Se encontró una asociación estadísticamente significativa con índice de masa corporal mayor de 25kg/m2 (p=0,0007) y con el consumo de productos dietéticos (p=0,0011). La práctica de ejercicio se encontró como factor protector con un OR de 0,55 (IC 95 %; 0,33-0,91). No se encontró asociación con el consumo de grasas, anticonceptivos orales, licor, cigarrillo, medicamentos, antecedentes familiares de estrías, antecedentes personales patológicos, talla, edad de aparición de las estrías y menarca. No se obtuvo información suficiente para evaluar asociación del consumo de esteroides por vía oral y aparición de estrías.

A case-control study, in 289 students between ages of 12 and 18 years who studied in a private school of the city of Medellín, was designed to determine the association between the appearance of atrophic striae and certain life styles, family and personal history and other variables. Each student was interviewed and a physical evaluation was done to determine the presence of striae. An association statistically significant was found between a body mass index greater than 25 kg/mt2 (p=0.0007) and the intake of diet products (p=0.0011) with the appearance of striae. The regular frequency of exercise was found to be a protective factor with an OR of 0.55 and a CI (0.33-0.91). There was no association between the intake of fat, birth control pills, alcohol, cigarettes and drugs, family history of striae, personal history of disease, age of appearance of striae, first menses and height for age. There was not enough information to determine the association between the intake of steroids and the appearance of striae.

Merosin-deficient congenital muscular dystrophy in Korea.

Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of muscle disorders, presenting at birth or early infancy with hypotonia, muscle weakness, joint contractures, and dystrophic changes in the muscles. Merosin-deficient CMD (MDCMD) is rare in Asian populations, but more common in Caucasians, comprising about 50% of CMDs. We report, for the first time in Korea, eight patients with merosin-deficient CMD, confirmed by immunohistochemical staining of muscle or skin samples. We also describe their wide spectrum of clinical features and neuroimaging findings. Among 35 patients diagnosed as CMD, almost 23% of them were proved to have MDCMD with typical phenotypic presentation. We infer that prevalence of MDCMD in Korea may not be as low as expected. One of the patients was diagnosed by skin biopsy, which is good alternative for diagnosis of MDCMD.