Feingold Syndrome type 1 (FS1) is an autosomal dominant disorder due to a loss of function mutations in the MYCN gene. FS1 is generally clinically characterized by mild learning disability, microcephaly, short palpebral fissures, short stature, brachymesophalangy, hypoplastic thumbs, as well as syndactyly of toes, variably associated with organ abnormalities, the most common being gastrointestinal atresia. In current literature, more than 120 FS1 patients have been described, but diagnostic criteria are not well agreed upon, likewise the genotype–phenotype correlations are not well understood. Here, we describe 11 FS1 patients, belonging to six distinct families, where we have identified three novel MYCN mutations along with three pathogenetic variants, the latter which have already been reported. Several patients presented a mild phenotype of the condition and they have been diagnosed as being affected only after segregation analyses of the MYCN mutation identified in the propositus. We also describe here the first ever FS1 patient with severe intellectual disability having a maternally inherited MYCN variant together with an additional GNAO1 mutation inherited paternally. Mutations in the GNAO1 gene are associated with a specific form of intellectual disability and epilepsy, thus the finding of two different rare diseases in the same patient could explain his severe phenotype. Therein, a thorough investigation is merited into the possibility that additional variants in patients with a MYCN mutation and severe phenotype do exist. Finally, in order to guarantee a more reliable diagnosis of FS1, we suggest using both major and minor clinical‐molecular diagnostic criteria.

中文翻译：

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11 例新发 1 型 Feingold 综合征患者的临床和分子特征：对重度表型患者选择诊断标准和进一步基因检测的建议

Feingold 综合征 1 型 (FS1) 是一种常染色体显性遗传病，由于MYCN基因功能缺失突变所致。FS1 的临床特征通常是轻度学习障碍、小头畸形、短睑裂、身材矮小、短中指、拇指发育不良以及脚趾并指畸形，这些都与器官异常有关，最常见的是胃肠道闭锁。在目前的文献中，已经描述了 120 多名 FS1 患者，但诊断标准尚未达成一致，同样，基因型 - 表型相关性也不太清楚。在这里，我们描述了 11 名 FS1 患者，属于六个不同的家庭，我们在其中确定了三个新的MYCN突变以及三种致病变异，后者已被报道。几名患者表现出轻度表型，并且仅在对提案中确定的MYCN突变进行分离分析后才被诊断为受到影响。我们还在此描述了首位患有严重智力障碍的 FS1 患者，该患者具有母系遗传的MYCN变异以及父系遗传的额外GNAO1突变。GNAO1 中的突变基因与特定形式的智力障碍和癫痫有关，因此在同一患者身上发现两种不同的罕见疾病可以解释他的严重表型。其中，有必要对具有MYCN突变和严重表型的患者中的其他变异确实存在的可能性进行彻底调查。最后，为了保证更可靠的 FS1 诊断，我们建议同时使用主要和次要临床分子诊断标准。