Happle Rudolf
Department of Dermatology, Freiburg University Medical Center, Freiburg, Germany.
Eur J Med Genet. 2016 May;59(5):290-4. doi: 10.1016/j.ejmg.2016.04.001. Epub 2016 Apr 4.
Progressive osseous heteroplasia (POH) is a segmental disorder characterized by progressive heterotopic ossification that extends from dermal and subcutaneous tissues to deeper structures. So far, it has been taken as a rarely occurring bone disease with autosomal dominant inheritance. Here, arguments are presented in favor of the alternative concept that the disorder is merely a type 2 segmental manifestation of autosomal dominant GNAS inactivation disorders. Type 2 segmental mosaicism arises, in a heterozygous embryo, from a somatic mutational event that occurs at an early developmental stage, resulting in loss of the corresponding wild-type allele and giving rise to a homozygous or hemizygous cell clone. As a characteristic feature, such type 2 segmental involvement is far more pronounced than the type 1 segmental mosaicism as noted in otherwise healthy individuals. The concept of type 2 segmental mosaicism has been proven at the molecular level in six human traits including neurofibromatosis 1, Hailey-Hailey disease, and Gorlin syndrome. In POH, molecular proof of principle is so far lacking. The following lines of reasoning, however, support the hypothesis that POH can be explained by a similar mechanism. Firstly, POH has been found to be associated with different phenotypes caused by inactivating GNAS mutations, which is why it cannot be categorized as one distinct Mendelian trait. Secondly, POH occurs as a rather rare complication of these autosomal dominant traits, which is not compatible with the assumption of a separate Mendelian disorder. Thirdly, in a case of plate-like osteoma that represents a more superficial variant of POH, molecular proof of the concept of type 2 segmental manifestation has already been provided, and the available literature suggests that POH can be best explained by a similar mechanism. Moreover, findings obtained in animal experiments support the assumption that human POH represents such superimposed segmental manifestation of GNAS inactivation disorders.
进行性骨化性纤维发育不良（POH）是一种节段性疾病，其特征为进行性异位骨化，从皮肤和皮下组织延伸至更深层结构。到目前为止，它一直被视为一种罕见的常染色体显性遗传骨病。在此，我们提出论据支持另一种观点，即该疾病仅仅是常染色体显性GNAS失活疾病的2型节段性表现。2型节段性镶嵌现象在杂合子胚胎中源于早期发育阶段发生的体细胞突变事件，导致相应野生型等位基因丢失，从而产生纯合或半合子细胞克隆。作为一个特征，这种2型节段性受累远比在其他方面健康个体中所见到的1型节段性镶嵌现象更为明显。2型节段性镶嵌概念已在包括神经纤维瘤病1型、黑利-黑利病和戈林综合征在内的六种人类性状的分子水平上得到证实。在POH中，目前尚缺乏原理的分子证据。然而，以下推理思路支持POH可由类似机制解释这一假说。首先，已发现POH与由GNAS失活突变引起的不同表型相关，这就是为什么它不能被归类为一种独特的孟德尔性状。其次，POH作为这些常染色体显性性状相当罕见的并发症出现，这与单独的孟德尔疾病假设不相符。第三，在一例代表POH更浅表变体的板状骨瘤病例中，已经提供了2型节段性表现概念的分子证据，现有文献表明POH可以用类似机制得到最佳解释。此外，动物实验获得的结果支持人类POH代表GNAS失活疾病这种叠加性节段性表现这一假设。
