Cardiofaciocutaneous (CFC) syndrome is one of the developmental disorders caused by a dysregulation of the Ras/mitogen-activated protein kinase (MAPK) pathway. RASopathies share overlapping clinical features, making the diagnosis challenging, especially in the newborn period. The majority of CFC syndrome cases arise by a mutation in the BRAF, MAP2K1, MAP2K2, or (rarely) KRAS genes. Germline KRAS mutations are identified in a minority of CFC and Noonan syndrome cases. Here, we describe a patient with a KRAS mutation presenting with a CFC syndrome phenotype. The female patient was referred for genetic testing because of congenital exophthalmos. Her facial appearance is distinctive with a coarse face, exophthalmos, ptosis, downslanting palpebral fissures, hypertelorism, deep philtrum, downturned corners of the mouth, and a short neck. She suffered from feeding difficulties, poor weight gain, and developmental delay. The sequencing of the genes involved in the MAPK pathway (PTPN11, SOS1, RAF1, KRAS, NRAS, MAP2K1, SHOC2, CBL, and SPRED1) identified a heterozygous de novo NM_004985.4:c.173C>T (p.Thr58Ile) in the KRAS gene. Germline KRAS mutations have been identified in approximately 2% of the reported NS cases and less than 5% of the reported CFC syndrome cases. Because CFC and Noonan syndrome share clinical overlapping features, the phenotype caused by KRAS mutations is often difficult to assign to one of the 2 entities. The mutation that we detected in our patient was previously reported in a patient with an Noonan syndrome phenotype. However, our patient predominantly exhibits CFC clinical features. In our case, coarse facial appearance and severe developmental delay help discriminate CFC from Noonan syndrome. Thus, patient follow-up, especially for delayed motor milestones suspected from RASopathies, is important for the discrimination of overlapping conditions as in the abovementioned syndromes.

中文翻译：

---

从头KRAS病原体变异病例中的心面部皮肤综合征表型。

心血管（CFC）综合征是Ras /促分裂原活化蛋白激酶（MAPK）通路失调引起的发育障碍之一。RASopathies具有重叠的临床特征，这使诊断具有挑战性，尤其是在新生儿期。大多数CFC综合征病例是由BRAF，MAP2K1，MAP2K2或（很少）KRAS基因突变引起的。在少数CFC和Noonan综合征病例中鉴定出种系KRAS突变。在这里，我们描述了一个具有CFC综合征表型的KRAS突变患者。该女性患者因先天性眼球突出而被转诊接受基因检测。她的脸部特征鲜明，面部粗糙，眼球突出，眼睑下垂，睑裂下垂，肢端亢进，发深，嘴角下垂和脖子短。她患有喂养困难，体重增加不良和发育迟缓。对MAPK途径中涉及的基因（PTPN11，SOS1，RAF1，KRAS，NRAS，MAP2K1，SHOC2，CBL和SPRED1）的测序确定了NM_004985.4：c.173C> T（p.Thr58Ile）杂合KRAS基因。在大约2％的报告NS病例和少于5％的报告的CFC综合征病例中鉴定出种系KRAS突变。因为CFC和Noonan综合征具有临床重叠特征，所以由KRAS突变引起的表型通常很难分配给这两个实体之一。我们先前在具有Noonan综合征表型的患者中报告了我们在患者中检测到的突变。但是，我们的患者主要表现出CFC的临床特征。就我们而言 面部粗糙和严重的发育迟缓有助于将CFC与Noonan综合征区分开。因此，患者的随访，特别是对于RASopathies怀疑的迟发性运动里程碑的随访，对于区分上述综合征中的重叠疾病很重要。