PITX1 is a homeobox transcription factor essential for hindlimb morphogenesis. Two PITX1‐related human disorders have been reported to date: PITX1 ectopic expression causes Liebenberg syndrome, characterized by malformation of upper limbs showing a “lower limb” appearance; PITX1 deletions or missense variation cause a syndromic picture including clubfoot, tibial hemimelia, and preaxial polydactyly. We report two novel PITX1 missense variants, altering PITX1 transactivation ability, in three individuals from two unrelated families showing a distinct recognizable autosomal dominant syndrome, including first branchial arch, pelvic, patellar, and male genital abnormalities. This syndrome shows striking similarities with the Pitx1−/− mouse model. A partial phenotypic overlap is also observed with Ischiocoxopodopatellar syndrome caused by TBX4 haploinsufficiency, and with the phenotypic spectrum caused by SOX9 anomalies, both genes being PITX1 downstream targets. Our study findings expand the spectrum of PITX1‐related disorders and suggest a common pattern of developmental abnormalities in disorders of the PITX1–TBX4–SOX9 signaling pathway.

中文翻译：

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下颌骨盆髌骨综合征是一种新型的 PITX1 相关疾病，由于 PITX1 反式激活能力的改变。

PITX1 是后肢形态发生必不可少的同源盒转录因子。迄今为止已报道了两种PITX1相关的人类疾病：PITX1异位表达导致Liebenberg综合征，其特征是上肢畸形，呈现“下肢”外观；PITX1缺失或错义变异会导致综合征图片，包括畸形足、胫骨半侧畸形和轴前多指畸形。我们报告了两个新的PITX1错义变异，改变了 PITX1 反式激活能力，来自两个不相关家族的三个个体显示出明显可识别的常染色体显性遗传综合征，包括第一鳃弓、骨盆、髌骨和男性生殖器异常。这种综合征与Pitx1 -/- 小鼠模型。在由TBX4单倍体不足引起的 Ischiocoxopodopatellar 综合征和由SOX9异常引起的表型谱中也观察到了部分表型重叠，这两个基因都是 PITX1 下游靶标。我们的研究结果扩展了PITX1相关疾病的范围，并提出了PITX1-TBX4-SOX9信号通路疾病中发育异常的常见模式。