新发MBTPS2基因突变致毛囊性鱼鳞病、秃发、畏光综合征一例

【摘要】 本文首次报道1例MBTPS2基因c.1165C>T突变致毛囊性鱼鳞病、秃发、畏光综合征。先证者主要临床表现为皮肤干燥、先天性无头发、毛囊角化性丘疹、畏光,伴癫痫,智力、运动发育落后。应用二代测序及一代测序验证显示,先证者和其母亲在MBTPS2基因第9外显子区域存在c.1165C>T（p.pro389Ser）突变。根据患儿临床表现和MBTPS2基因突变遗传学特点,确诊为毛囊性鱼鳞病、秃发、畏光综合征。     

Ichthyosis follicularis with alopecia and photophobia in a girl with cataract: histological and electron microscopy findings

A rare congenital ectodermal disorder characterized by ichthyosis follicularis, alopecia and photophobia has been designated the acronym IFAP. An X-linked recessive mode of inheritance was initially proposed but a few recent reports in girls suggested genetic heterogeneity of this syndrome. We herein describe a 3-year-old girl with clinical and histological features typical of IFAP. In addition to the already known features of the syndrome the patient also developed bilateral cataract. Electron microscopy examination of the skin showed partial disruption of the intercellular bridges, spongiotic changes and decrease in the number and size of desmosomes supporting the notion that IFAP may be a cell-to-cell adhesion disorder.     

Ichthyosis follicularis,atrichia, and photophobia syndrome associated with a new mutation in MBTPS2

Ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome (OMIM 308205) is a rare X‐linked genetic disorder. Mutations in MBTPS2 underlie IFAP syndrome, with 19 different mutations reported to date. Keratosis follicularis spinulosa decalvans (KFSD) is an allelic disorder that results from a single recurrent mutation, p.Asn508Ser. We report a case from the UK of IFAP syndrome resulting from a new mutation, p.Asn508Thr, emphasizing the significant overlap between IFAP and KFSD at both the molecular and clinical levels. An area of alopecia on the scalp of the proband's mother was also noted, suggesting lyonization.     

Novel MBTPS2 Missense Mutation in the N‐Terminus Transmembrane Domain in a Patient with Ichthyosis Follicularis,Alopecia, and Photophobia Syndrome

Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome is an X‐linked dominant condition characterized by the triad of ichthyosis follicularis, alopecia, and photophobia caused by mutations in the MBTPS2 gene. Herein we describe a proband with IFAP syndrome with mild cutaneous manifestations and a novel MBTPS2 mutation in the N‐terminal transmembrane domain.     

Ichthyosis Follicularis, Alopecia, and Photophobia (IFAP) Syndrome Due to Mutation of the Gene MBTPS2 in a Large Australian Kindred

Abstract:   Ichthyosis follicularis, alopecia and photophobia (IFAP) is a rare genodermatosis. Most patients have been men without significant family history. We present the largest kindred of IFAP reported to date in the medical literature clearly demonstrating X-linked inheritance. The gene defect has recently been mapped to Xp22.11-p22.13. Missense mutations of the gene, MBTPS2, which codes for an intramembrane zinc metalloprotease essential for cholesterol homeostasis and endoplasmic reticulum stress response, are associated with the IFAP phenotype in this kindred. We describe the clinical features and discuss the differential diagnosis of IFAP. Our proband has benefited from treatment with acitretin.     

Ichthyosis follicularis, alopecia, and photophobia syndrome: a case report and a pathological insight into pilosebaceous anomaly

Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome (OMIM 308205) is an extremely rare X-linked oculocutaneous genetic disorder characterized by follicular keratotic papules, total to subtotal alopecia, and photophobia. Previous reports depicted the histopathological features of affected skin lesions, represented by marked follicular plugging and hypoplastic pilosebaceous structures. However, past studies provided limited pathological information of pilosebaceous unit anomaly. Here, we report a 3-year-old boy's case with this uncommon condition. In this case, scalp biopsy samples were processed by both vertical and transverse sectioning techniques, which enabled a more detailed and quantitative pathological analysis of pilosebaceous structures. In vertical slices, miniaturized anagen hair follicles with characteristic follicular plugs were observed. A transverse section identified abortive sebaceous glands in hair follicles, a finding rarely observed in vertical sections. In addition, a transverse slice demonstrated that the number of total hair follicles was not significantly decreased compared with the average hair follicle density in Asians, suggesting that the pilosebaceous hypoplasia might arise from impaired maturation, not from initiation defect, during hair follicle morphogenesis. This study provides a more comprehensive pathological insight into pilosebaceous anomaly in IFAP syndrome and substantiats the usefulness of the combination of vertical and transverse sectioning approaches in the pathological examination of congenital hypotrichosis, including IFAP syndrome.     

Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome treated with acitretin

We describe a 3-year-old male patient with the ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome, who developed cutaneous and ocular involvement in infancy. In addition, he had growth retardation and borderline intelligence; no other systemic involvement was found on detailed investigation. A moderate response to acitretin therapy (1 mg/kg) administered for 6 months was observed, with improvement in cutaneous features and corneal erosions and no change in alopecia or photophobia.     

Hereditary mucoepithelial dysplasia: clinical, ultrastructural and genetic study of eight patients and literature review

BACKGROUND: Hereditary mucoepithelial dysplasia is a dominantly inherited disease, mainly characterized by chronic mucosal lesions associated with keratitis, non-scarring alopecia, keratosis pilaris and perineal intertrigo. Since the original report by Witkop, this condition has been considered to be a disorder of desmosome/gap junction formation, but there has been no ex vivo investigation of these components using genetic and immunolabelling techniques. OBJECTIVES: To perform light and immunoelectron microscopic studies, and partial genetic analysis on five patients in a family and three sporadic cases and to point out similarities of this rare disorder with chronic mucocutaneous candidiasis and other follicular keratosis syndromes, i.e. ichthyosis follicularis-alopecia-photophobia (IFAP), keratitis-ichthyosis-deafness (KID) and Siemens syndromes. METHODS: Biopsies from the involved oral mucosa and armpit skin of patient 1 were prepared for standard histopathology, electron microscopy and immunocytochemistry. Microsatellite genotyping was performed in three affected family members. Direct sequencing after polymerase chain reaction amplification of the entire coding region was performed. RESULTS: A 14-year-old male had recurrent keratitis, widespread keratosis pilaris, perineal intertrigo, hypotrichosis and oral mucosal involvement. A similar phenotype was noted in four members of his family and in three sporadic cases. Histological examination of oral mucosa and skin samples showed a psoriasiform pattern, dyskeratotic features and cytoplasmic vacuoles. Expression of connexins (Cx), desmosomal, adherens junction and cytoskeleton proteins (Cx 26, 32 and 43, desmogleins 1 and 2, plakoglobin, desmoplakins I-II, plakophilin 1, beta-catenin, E-cadherin, keratins, beta-tubulin, vimentin and actin) was normal. Ultrastructural studies showed a reduced number of desmosomes. Dyskeratotic cells exhibited internalized gap junctions, long filamentous inclusions reactive with antikeratin antibodies, and bundles of perinuclear fibres resembling clear tonofilaments. Genetic analysis in the studied family excluded the desmosomal cadherins in chromosome 18q12 as candidate genes. CONCLUSIONS: A diagnosis of hereditary mucoepithelial dysplasia should be strongly suggested by the triad of non-scarring alopecia, well-demarcated erythema of oral mucosa and psoriasiform perineal rash, after exclusion of the clinically related follicular keratosis syndromes. Defective expression of cytoskeleton elements and/or a modification of mechanisms regulating junction-cytoskeleton assembly may be primarily responsible for impaired epithelial cohesion.     

A Novel Mutation in the MBTPS2 Gene Resulting in Ichthyosis Follicularis,Atrichia, and Photophobia Syndrome

Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare genetic disorder caused by mutations in the MBTPS2 gene. It is characterized by ichthyosis and alopecia from birth. Photophobia may be present in infancy or early childhood. Its mode of inheritance is X-linked recessive; thus, it mostly affects male. The disease severity varies, ranging from mild cases limited to the skin to the severe variant involving multiple extracutaneous features. A 7-year-old boy presented with scanty hair on scalp and eyebrows at birth. On physical examination, scaly patches were observed on the whole body and spiky follicular hyperkeratotic papules were observed on the face and trunk. He also suffered from severe photophobia. Histopathological examination of the scalp showed miniaturized hair follicles without perifollicular fibrosis. Genetic analysis revealed a novel mutation in the MBTPS2 gene which was a homozygous missense mutation of c.245T>C leading to an amino-acid substitution from phenylalanine to serine (p.Phe82Ser). We diagnosed this patient with IFAP syndrome. To date, 25 pathogenic MBTPS2 gene mutations have been identified. To our knowledge, c.245T>C is a novel homozygous missense mutation in the MBTPS2 gene, which has not been reported in Human Gene Mutation Database, ClinVar Database, and Leiden Open Variation Database. Previous reports suggested genotype-phenotype correlations in the MBTPS2 gene mutations. Supported by a previous notion that genotype correlates with phenotype, this novel mutation can be a predictive factor for the mild form of IFAP syndrome, restricted to the classic symptom triad.     

Atrichia, ichthyosis, follicular hyperkeratosis, chronic candidiasis, keratitis, seizures, mental retardation and inguinal hernia: a severe manifestation of IFAP syndrome?

A boy with congenital atrichia, ichthyosis follicular, keratitis, cutaneous infections and a huge inguinal hernia, but without deafness is reported. We believe it represents a new case of a rare X-linked recessive syndrome known as ichthyosis follicularis, alopecia, photophobia syndrome (IFAP). The differential diagnosis from keratitis ichthyosis deafness is discussed. The cutaneous infections seen in our case suggest the possibility of considering a genetic link between these syndromes.     

Adalimumab‐induced scalp psoriasis with severe alopecia

In recent years, with the increase usage of tumor necrosis factor (TNF) inhibitors, more side effects have revealed. The incidence of paradoxical psoriasis (psoriasis vulgaris, palmoplantar pustulosis, scalp psoriasis, or their combinations) ranges from 1 to 5%; however alopecia due to anti‐TNF‐α‐induced scalp psoriasis, rarely reported in the literature. We report a 37‐year‐old woman who developed palmoplantar pustulosis and scalp psoriasis with severe alopecia after 2 months of treatment with adalimumab for chronic plaque psoriasis. Biopsies from the palmar and scalp lesions showed psoriasiform changes. Adalimumab treatment was discontinued, and methotrexate was started (15 mg/weekly, subcutaneously) with topical adjuvant agents. A dramatic improvement was seen in both the skin and scalp with complete hair regrowth in 1 month. We conclude that, in anti‐TNF‐α‐induced scalp psoriasis, suspension of anti‐TNF‐α agent and systemic and topical treatments should be considered to avoid scarring alopecia.     

国内首报毛囊鱼鳞病、秃发、畏光综合征一例

患儿男，11岁。出生时发现全身无毛发，皮肤干燥、粗糙。出生后3个月出现畏光，反复发生上呼吸道感染，每月约2次，且经常腹泻。患儿身材矮小，视力差，眼结膜稍充血；角膜新生血管多、混浊，表面毛糙。听力无异常。牙齿形态无明显异常。全身毛发缺如，出汗正常，皮肤干燥，弥漫性菱形或多角形鳞屑斑，上肢鳞屑较厚，呈深褐色。腹部、腋部泛发钉突状毛囊突起。掌跖斑块状角化过度。指、趾甲均增厚，凹凸不平。双手展开时第3、4、5手指近端指间关节过伸。心、肺、肝、脾无异常。智力低下（语言智商52，操作智商 ＜ 40，总智商 ＜ 40）。腹部皮肤组织病理学检查提示鱼鳞病改变。染色体核型分析：46，XY。诊断：毛囊鱼鳞病、秃发、畏光综合征。     

MBTPS2基因新发突变致毛囊性鱼鳞病-脱发-畏光综合征一例

患者,男,4岁。脱发、全身丘疹伴畏光4年。基因检测示患儿MBTPS2基因有1个半合子突变,即c.3G>C(p.M1I)。母亲该位点杂合变异,父亲该位点无变异,诊断为毛囊性鱼鳞病-脱发-畏光综合征。     

Ichthyosis follicularis with congenital atrichia, nail dystrophy and palmoplantar keratoderma. Variant of IFAP syndrome or a new entity?

A 23-year-old man was seen for dry, rough skin and alopecia present since birth. There was no history of impaired sweating, photophobia, or lacrimation. Examination revealed generalized cutaneous thorn-like projections with nonscarring alopecia, twenty-nail dystrophy, and palmoplantar keratoderma.     

Ichthyosis follicularis with alopecia and photophobia (IFAP) syndrome

A 12-year-old boy born of a nonconsanguineous marriage presented with dry rough skin and photophobia since birth. His growth and developmental milestones were normal and there was no history of any neurological problem, hearing deficit or scarring around the hair follicles. Cutaneous examination revealed diffuse thinning of scalp hair with loss of eyebrows and eyelashes and a sandpapery texture of the skin all over the body, suggestive of ichthyosis follicularis with alopecia and photophobia syndrome.     

MBTPS2 mutation in a British pedigree with keratosis follicularis spinulosa decalvans

Keratosis follicularis spinulosa decalvans (KFSD; OMIM 308800) is an X-linked disorder characterized by widespread hyperkeratotic follicular papules (including keratosis pilaris-like lesions), facial erythema, hypotrichosis and scarring alopecia. KFSD results from mutations in the MBTPS2 gene. Mutations in this gene also underlie ichthyosis follicularis, alopecia and photophobia syndrome. We report a British pedigree with KFSD resulting from the mutation p.Asn508Ser. This particular mutation has been reported in three other pedigrees with KFSD (Dutch, American, British) and is the only pathogenic mutation reported in this disorder to date. However, the same mutation has also been reported in a Chinese pedigree with IFAP syndrome, highlighting the clinical heterogeneity and overlapping molecular pathology of these two disorders.     

Compound heterozygous mutations in desmoplakin associated with skin fragility,follicular hyperkeratosis,alopecia, and nail dystrophy

Desmoplakin mutations are associated with a wide variety of phenotypes affecting the skin, nails, hair, and heart. A 21‐month‐old boy was born with multiple erosions resembling epidermolysis bullosa, complete alopecia, nail dystrophy, palmoplantar keratoderma, and areas of follicular hyperkeratosis. He was found to have two heterozygous mutations in the desmoplakin gene: c.478 C>T in exon 4 (p.Arg160X) and c.3630T>A in exon 23 (Tyr1210X). This case expands the clinical spectrum associated with desmoplakin mutations and highlights a mutation in exon 23 that has not been previously reported in the literature.     

Keratosis follicularis spinulosa decalvans: report of a new pedigree

Summary Keratosis follicularis spinulosa decalvans is a rare, X-linked genodermatosis characterized by follicular hyperkeratosis, scarring alopecia of the scalp, eyebrows and eyelashes, corneal dystrophy and photophobia. We describe two cases from a large family, the first with keratosis follicularis spinulosa decalvans to be reported in the U.K.     

76例重型斑秃的临床分析

目的 :探讨重型斑秃的临床特征。方法 :回顾分析了近 4年诊治的 76例重型斑秃病例。结果 :重型斑秃中女性患者的病程比男性患者长 (P <0 0 5 ) ,与重型斑秃中的斑秃相比 ,甲异常改变更多见于全秃和普秃患者 (P <0 0 5 ) ,有家族斑秃史患者与无家族斑秃史患者比较 ,两者的初次发病年龄有显著性差异 (P <0 0 5 ) ,发病前伴有精神神经因素诱发者比无伴有精神神经因素诱发者病程要短 (P <0 0 5 )。结论 :女性重型斑秃患者可能病程更容易持续延绵、迁移反复 ,重型斑秃中有家族斑秃史者 ,它的发病年龄更早 ,甲异常改变不但多见于病程较长、病情顽固、反复的患者 ,而且也多见于病情较重的患者 ,全秃和普秃患者甲异常改变更多见 ,重型斑秃的治疗应注意精神因素的影响及强调综合治疗。     

Sarcoidosis presenting as non‐scarring non‐scalp alopecia

In this article we describe a 39‐year‐old man who presented with non‐scarring non‐scalp alopecia of his limbs as the initial presentation of sarcoidosis. Alopecia is a rare cutaneous manifestation of sarcoidosis. A literature review has found only one other example of sarcoidosis presenting as non‐scarring non‐scalp alopecia in an area other than the scalp in a patient who was otherwise asymptomatic. Several reported cases have described scarring alopecia of the scalp, which is the area of skin most commonly affected by sarcoidosis. There has been one documented case of sarcoidosis manifesting as total body non‐scarring alopecia in a patient who had systemic symptoms of sarcoidosis. Other cases have presented rare cutaneous manifestations of sarcoidosis but in all these cases several other organ systems have been involved, and the patient has had systemic symptoms on presentation or the cutaneous presentation did not include non‐scalp non‐scarring alopecia.