Zollino M, Wright T J, Di Stefano C, Tosolini A, Battaglia A, Altherr M R, Neri G
Istituto di Genetica Medica, Facoltà di Medicina A. Gemelli, UCSC, Rome, Italy.
Am J Med Genet. 1999 Feb 19;82(5):371-5.
Chromosome imbalance affecting the short arm of chromosome 4 results in a variety of distinct clinical conditions. Most of them share a number of manifestations, such as mental retardation, microcephaly, pre- and post-natal growth retardation, anteverted and low-set ears, that can be considered as nonspecific signs, generally attributable to gene dosage impairment. On the other hand, more distinctive phenotypic traits correlate with the segmental aneuploidy. Duplications of the distal half of 4p give rise to the partial trisomy 4 syndrome, characterized by a "boxer" nose configuration and deep-set eyes. These signs are usually observed even in cases of small terminal duplications. Haploinsufficiency of 4p16.3 results in the so-called Wolf-Hirschhorn (WH) syndrome, a contiguous gene syndrome characterized by maxillary hypoplasia, large and protruding eyes, high nasal bridge, skeletal abnormalities, and midline defects. The smallest overlapping deletion described so far as a cause of this condition is only 165 kb long, suggesting that one or a few genes in this region act as "master" regulators of different developmental pathways. A "tandem" duplication of 4p16.1p16.3 was detected in association with a subtle deletion of 4p16.3pter on the same chromosome in a patient with the WH phenotype. The 3.2 Mb deletion, spanning the genomic region from the vicinity of D4S43 to the telomere, encompasses the recently delimited "WHS critical region" [Wright et al., 1997: Hum. Mol. Genet. 6:317-324]. This unusual chromosome rearrangement resulted in WH phenotype, clinical manifestations of partial 4p trisomy being mild or absent. This observation led us to speculate that the regulatory gene/genes in the critical WH region affect the expression of other genes in a dose-dependent manner. Haploinsufficiency of this region could be more deleterious than various partial trisomies.
影响4号染色体短臂的染色体失衡会导致多种不同的临床病症。其中大多数病症具有一些共同表现，如智力迟钝、小头畸形、产前和产后生长发育迟缓、耳前倾和低位耳，这些可被视为非特异性体征，通常归因于基因剂量受损。另一方面，更具特征性的表型特征与节段性非整倍体相关。4p远端一半的重复会导致部分4号染色体三体综合征，其特征为“拳击手”鼻型和深陷的眼睛。即使在小的末端重复病例中也通常会观察到这些体征。4p16.3单倍剂量不足会导致所谓的沃尔夫-赫希霍恩（WH）综合征，这是一种邻接基因综合征，其特征为上颌骨发育不全、眼睛大且突出、鼻梁高、骨骼异常和中线缺陷。迄今为止描述的导致这种病症的最小重叠缺失仅165 kb长，这表明该区域中的一个或几个基因充当不同发育途径的“主”调节因子。在一名具有WH表型的患者中，检测到4p16.1p16.3的“串联”重复与同一条染色体上4p16.3pter的微小缺失相关。这个3.2 Mb的缺失，跨越从D4S43附近到端粒的基因组区域，涵盖了最近划定的“WHS关键区域”[赖特等人，1997年：《人类分子遗传学》6:317 - 324]。这种不寻常的染色体重排导致了WH表型，部分4号染色体三体的临床表现轻微或不存在。这一观察结果使我们推测，关键的WH区域中的调节基因以剂量依赖方式影响其他基因的表达。该区域的单倍剂量不足可能比各种部分三体更具危害性。
