背景:心面皮肤综合征(CFCS)属于放射病,一组由编码大鼠肉瘤/丝裂原活化蛋白激酶(RAS/MAPK)途径蛋白质的基因突变引起的疾病。这是一种罕见的综合症,报告了约300名患者。主要临床表现包括面部畸形,生长失败,心脏缺陷,发育迟缓,外胚层异常.四个基因的突变(主要是错义)(BRAF,MAP2K1,MAP2K2和KRAS)已与CFCS相关。然而,全基因缺失/重复和染色体微缺失也有报道.具体来说,包括MAP2K2基因的19p13.3缺失是心面皮肤微缺失综合征的原因,其受影响的受试者比CFCS普通人群表现出更严重的表型。
方法:特此,我们报道了一名产前诊断为脐膨出的女性新生儿,通过羊膜穿刺术进行进一步的遗传研究。其中,阵列比较基因组杂交(a-CGH)鉴定出19p13.3微缺失,跨越1.27Mb,包括MAP2K2基因。出生时的临床特征(粗糙的面部有畸形特征,稀疏而脆弱的头发,皮肤血管畸形和过度角化病变,室间隔缺损,和脐膨出)与CFCS诊断兼容,和进一步的出生后遗传调查被认为是不必要的。出院后不久,在大约一个月的生命中,她因反复呕吐而重新进入我们的新生儿重症监护病房,对肥厚性幽门狭窄(HPS)进行及时识别和治疗。
结论:我们的报告支持19p13.3微缺失作为一种连续基因综合征,其中与MAP2K2相邻的基因的参与可能会改变患者的表型。它强调了CFCS如何影响受试者,包括那些19p13.3缺失的,可能有相关的胃肠道缺陷(例如,脐膨出和HPS),提供有关19p13.3微缺失综合征的进一步数据,并更好地表征其基因组和表型特征。这些患者的复杂临床表现可能会因其他原因而恶化,甚至早熟,HPS等危及生命的疾病。临床医生必须考虑,预测和/或及时治疗可能的内科和外科并发症,目的是减少不良后果。广泛的诊断工作,和早期,连续,和多学科后续行动,以及综合护理,是任何单个患者的纵向临床演变所必需的。
BACKGROUND: Cardio-facio-cutaneous syndrome (CFCS) belongs to RASopathies, a group of conditions caused by mutations in genes encoding proteins of the rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathway. It is a rare syndrome, with about 300 patients reported. Main clinical manifestations include facial dysmorphisms, growth failure, heart defects, developmental delay, and ectodermal abnormalities. Mutations (mainly missense) of four genes (BRAF, MAP 2 K1, MAP 2 K2, and KRAS) have been associated to CFCS. However, whole gene deletions/duplications and chromosomal microdeletions have been also reported. Specifically, 19p13.3 deletion including MAP 2 K2 gene are responsible for cardio-facio-cutaneous microdeletion syndrome, whose affected subjects show more severe phenotype than CFCS general population.
METHODS: Hereby, we report on a female newborn with prenatal diagnosis of omphalocele, leading to further genetic investigations through amniocentesis. Among these, array comparative genomic hybridization (a-CGH) identified a 19p13.3 microdeletion, spanning 1.27 Mb and including MAP 2 K2 gene. Clinical features at birth (coarse face with dysmorphic features, sparse and friable hair, cutaneous vascular malformations and hyperkeratotic lesions, interventricular septal defect, and omphalocele) were compatible with CFCS diagnosis, and further postnatal genetic investigations were not considered necessary. Soon after discharge, at around 1 month of life, she was readmitted to our Neonatal Intensive Care Unit due to repeated episodes of vomiting, subtending a hypertrophic pyloric stenosis (HPS) which was promptly identified and treated.
CONCLUSIONS: Our report supports the 19p13.3 microdeletion as a contiguous gene syndrome, in which the involvement of the genes contiguous to MAP 2 K2 may modify the patients\' phenotype. It highlights how CFCS affected subjects, including those with 19p13.3 deletions, may have associated gastrointestinal defects (e.g., omphalocele and HPS), providing further data on 19p13.3 microdeletion syndrome, and a better characterization of its genomic and phenotypic features. The complex clinical picture of such patients may be worsened by additional, and even precocious, life-threatening conditions like HPS. Clinicians must consider, anticipate and/or promptly treat possible medical and surgical complications, with the aim of reducing adverse outcomes. Extensive diagnostic work-up, and early, continuous, and multidisciplinary follow-up, as well as integrated care, are necessary for the longitudinal clinical evolution of any single patient.