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Progressive osseous heteroplasia is not a Mendelian trait but a type 2 segmental manifestation of GNAS inactivation disorders: A hypothesis.
Eur J Med Genet 2016; 59(5):290-4EJ

Abstract

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.

Authors+Show Affiliations

Department of Dermatology, Freiburg University Medical Center, Freiburg, Germany. Electronic address: rudolf.happle@uniklinik-freiburg.de.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

27058263

Citation

Happle, Rudolf. "Progressive Osseous Heteroplasia Is Not a Mendelian Trait but a Type 2 Segmental Manifestation of GNAS Inactivation Disorders: a Hypothesis." European Journal of Medical Genetics, vol. 59, no. 5, 2016, pp. 290-4.
Happle R. Progressive osseous heteroplasia is not a Mendelian trait but a type 2 segmental manifestation of GNAS inactivation disorders: A hypothesis. Eur J Med Genet. 2016;59(5):290-4.
Happle, R. (2016). Progressive osseous heteroplasia is not a Mendelian trait but a type 2 segmental manifestation of GNAS inactivation disorders: A hypothesis. European Journal of Medical Genetics, 59(5), pp. 290-4. doi:10.1016/j.ejmg.2016.04.001.
Happle R. Progressive Osseous Heteroplasia Is Not a Mendelian Trait but a Type 2 Segmental Manifestation of GNAS Inactivation Disorders: a Hypothesis. Eur J Med Genet. 2016;59(5):290-4. PubMed PMID: 27058263.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Progressive osseous heteroplasia is not a Mendelian trait but a type 2 segmental manifestation of GNAS inactivation disorders: A hypothesis. A1 - Happle,Rudolf, Y1 - 2016/04/04/ PY - 2015/10/19/received PY - 2016/03/31/revised PY - 2016/04/01/accepted PY - 2016/4/9/entrez PY - 2016/4/9/pubmed PY - 2017/2/14/medline KW - Albright hereditary osteodystrophy KW - Osteoma cutis KW - Progressive osseous heteroplasia KW - Pseudohypoparathyroidism KW - Type 2 segmental manifestation of autosomal dominant disorders SP - 290 EP - 4 JF - European journal of medical genetics JO - Eur J Med Genet VL - 59 IS - 5 N2 - 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. SN - 1878-0849 UR - https://www.unboundmedicine.com/medline/citation/27058263/Progressive_osseous_heteroplasia_is_not_a_Mendelian_trait_but_a_type_2_segmental_manifestation_of_GNAS_inactivation_disorders:_A_hypothesis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1769-7212(16)30048-9 DB - PRIME DP - Unbound Medicine ER -