Catel-Manzke syndrome is characterized by the combination of Pierre Robin sequence and radial deviation, shortening as well as clinodactyly of the index fingers, due to an accessory ossification center. Mutations in TGDS have been identified as one cause of Catel-Manzke syndrome, but cannot be found as causative in every patient with the clinical diagnosis. We performed a chromosome microarray and/or exome sequencing in three patients with hand hyperphalangism, heart defect, short stature, and mild to severe developmental delay, all of whom were initially given a clinical diagnosis of Catel-Manzke syndrome. In one patient, we detected a large deletion of exons 1-8 and the missense variant c.1282C > T (p.Arg428Trp) in KYNU (NM_003937.2), whereas homozygous missense variants in KYNU were found in the other two patients (c.989G > A (p.Arg330Gln) and c.326G > C (p.Trp109Ser)). Plasma and urine metabolomic analysis of two patients indicated a block along the tryptophan catabolic pathway and urine organic acid analysis showed excretion of xanthurenic acid. Biallelic loss-of-function mutations in KYNU were recently described as a cause of NAD deficiency with vertebral, cardiac, renal and limb defects; however, no hand hyperphalangism was described in those patients, and Catel-Manzke syndrome was not discussed as a differential diagnosis. In conclusion, we present unrelated patients identified with biallelic variants in KYNU leading to kynureninase deficiency and xanthurenic aciduria as a very likely cause of their hyperphalangism, heart defect, short stature, and developmental delay. We suggest performance of urine organic acid analysis in patients with suspected Catel-Manzke syndrome, particularly in those with cardiac or vertebral defects or without mutations in TGDS.

中文翻译：

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KYNU 的双等位基因变异导致手部指骨过多的多系统综合征

Catel-Manzke 综合征的特征是 Pierre Robin 序列和由于副骨化中心导致的食指径向偏差、缩短以及指尖弯曲的组合。TGDS 突变已被确定为 Catel-Manzke 综合征的病因之一，但并非每位临床诊断患者都具有致病原因。我们对三名患有手部指趾过多、心脏缺陷、身材矮小和轻度至重度发育迟缓的患者进行了染色体微阵列和/或外显子组测序，所有这些患者最初都被临床诊断为 Catel-Manzke 综合征。在一名患者中，我们在 KYNU (NM_003937.2) 中检测到外显子 1-8 的大量缺失和错义变异 c.1282C > T (p.Arg428Trp)，而在另外两名患者中发现了 KYNU 中的纯合错义变异（ c.989G > A (p.Arg330Gln) 和 c.326G > C (p.Trp109Ser))。两名患者的血浆和尿液代谢组分析表明色氨酸分解代谢途径受阻，尿液有机酸分析显示黄嘌呤酸排泄。KYNU 的双等位基因功能丧失突变最近被描述为 NAD 缺乏并导致椎骨、心脏、肾脏和四肢缺陷的原因；然而，这些患者中没有描述手部指趾过多症，并且 Catel-Manzke 综合征也没有作为鉴别诊断进行讨论。总之，我们提出了在 KYNU 中鉴定出双等位基因变异的无关患者，导致犬尿氨酸酶缺乏和黄尿酸尿症，这很可能是其指骨增多、心脏缺陷、身材矮小和发育迟缓的原因。我们建议对疑似 Catel-Manzke 综合征的患者进行尿液有机酸分析，特别是那些患有心脏或脊椎缺陷或没有 TGDS 突变的患者。