印迹障碍是由基因组印记失调引起的先天性疾病，影响生长、神经认知发育、代谢和癌症易感性。这一类疾病通常具有多种临床特征的重叠。在罕见情况下，同一患者可能同时存在两种完全表达的印迹障碍。迄今已报道了十几例此类情况。其中大多数是Beckwith-Wiedemann光谱（BWSp）和暂时性新生儿糖尿病（TNDM）或BWSp和伪副甲状腺功能减退症1B型（PHP1B）患者。所有这些患者都表现出多位点印迹干扰（MLID）。在这里，我们报道了首例在缺乏MLID情况下共同出现BWS和PHP1B的病例。全基因组甲基化和SNP阵列分析表明，11p15.5染色体上KCNQ1OT1:TSS-DMR的甲基化缺失是BWSp的分子病因，upd（20）pat是PHP1B的病因。缺乏MLID和20号染色体杂合子型表明BWSp和PHP1B在我们的患者中通过不同的独立机制产生。然而，我们不能排除11号染色体上的表观遗传缺陷和20号染色体上的UPD可能来源于一个迄今不明的共同易感分子病变的罕见组合。更好地理解两种印迹障碍同时出现的分子机制将改进这些罕见病例的遗传咨询和家族复发风险的估计。此外，我们的研究还支持进行多位点分子检测以揭示MLID以及印迹障碍的复杂病例的重要性。 版权所有 © 2023 Pignata, Cecere, Acquaviva, D’Angelo, Cioffi, Pellino, Palumbo, Palumbo, Carella, Sparago, De Brasi, Cerrato and Riccio.

Imprinting disorders are congenital diseases caused by dysregulation of genomic imprinting, affecting growth, neurocognitive development, metabolism and cancer predisposition. Overlapping clinical features are often observed among this group of diseases. In rare cases, two fully expressed imprinting disorders may coexist in the same patient. A dozen cases of this type have been reported so far. Most of them are represented by individuals affected by Beckwith-Wiedemann spectrum (BWSp) and Transient Neonatal Diabetes Mellitus (TNDM) or BWSp and Pseudo-hypoparathyroidism type 1B (PHP1B). All these patients displayed Multilocus imprinting disturbances (MLID). Here, we report the first case of co-occurrence of BWS and PHP1B in the same individual in absence of MLID. Genome-wide methylation and SNP-array analyses demonstrated loss of methylation of the KCNQ1OT1:TSS-DMR on chromosome 11p15.5 as molecular cause of BWSp, and upd(20)pat as cause of PHP1B. The absence of MLID and the heterodisomy of chromosome 20 suggests that BWSp and PHP1B arose through distinct and independent mechanism in our patient. However, we cannot exclude that the rare combination of the epigenetic defect on chromosome 11 and the UPD on chromosome 20 may originate from a common so far undetermined predisposing molecular lesion. A better comprehension of the molecular mechanisms underlying the co-occurrence of two imprinting disorders will improve genetic counselling and estimate of familial recurrence risk of these rare cases. Furthermore, our study also supports the importance of multilocus molecular testing for revealing MLID as well as complex cases of imprinting disorders.Copyright © 2023 Pignata, Cecere, Acquaviva, D’Angelo, Cioffi, Pellino, Palumbo, Palumbo, Carella, Sparago, De Brasi, Cerrato and Riccio.