Department of Pediatrics, Division of Medical Genetics, Helen DeVos Children's Hospital, Spectrum Health, Grand Rapids, Michigan, USA.
Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.
Am J Med Genet A. 2022 Sep;188(9):2834-2849. doi: 10.1002/ajmg.a.62764. Epub 2022 Apr 29.
Pleiotropy is defined as the phenomenon of a single gene locus influencing two or more distinct phenotypic traits. However, nicotinamide adenine dinucleotide (NAD+) deficiency through diet alone can cause multiple or single malformations in mice. Additionally, humans with decreased NAD+ production due to changes in pathway genes display similar malformations. Here, I hypothesize NAD+ deficiency as a pleiotropic mechanism for multiple malformation conditions, including limb-body wall complex (LBWC), pentalogy of Cantrell (POC), omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex, vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association (hereafter VACTERL), oculoauriculovertebral spectrum (OAVS), Mullerian duct aplasia-renal anomalies-cervicothoracic somite dysplasia (MURCS), sirenomelia, and urorectal septum malformation (URSM) sequence, along with miscarriages and other forms of congenital malformation. The term Congenital NAD Deficiency Disorder (CNDD) could be considered for patients with these malformations; however, it is important to emphasize there have been no confirmatory experimental studies in humans to prove this hypothesis. In addition, these multiple malformation conditions should not be considered individual entities for the following reasons: First, there is no uniform consensus of clinical diagnostic criteria and all of them fail to capture cases with partial expression of the phenotype. Second, reports of individuals consistently show overlapping features with other reported conditions in this group. Finally, what is currently defined as VACTERL is what I would refer to as a default label when more striking features such as body wall defects, caudal dysgenesis, or cloacal exstrophy are not present.
并指-肢体-腹壁复合畸形（LBWC）、Cantrell 五联征（POC）、脐膨出-内脏外翻-肛门闭锁-脊髓发育不良（OEIS）复合畸形、椎体-肛门-心脏-气管食管瘘-肾脏-肢体（VACTERL）联合畸形、眼-耳-脊椎发育不良（OAVS）、米勒管发育不全-肾畸形-颈胸体节发育不良（MURCS）、并腿畸形、泄殖腔畸形（URSM）序列、流产及其他先天性畸形，这些病症具有相同的遗传病因，即 NAD+缺乏。我推测 NAD+缺乏是多种畸形的发生机制之一。尽管目前尚无在人体中证实该假说的实验研究，但鉴于这些畸形存在相同的遗传病因，可将其命名为先天性 NAD 缺乏症（CNDD）。此外，这些多种畸形不应被视为独立的疾病实体，原因如下：首先，目前尚缺乏统一的临床诊断标准，且所有标准均无法涵盖部分表型的病例。其次，报道的病例始终表现出与该组中其他已报道疾病的重叠特征。最后，目前被定义为 VACTERL 的疾病，我认为是当存在腹壁缺陷、尾部发育不良或泄殖腔外翻等更明显特征时的默认标签。
