Osteogénesis imperfecta: mosaicismo germinal o evidencia de heterogeneidad genética. Presentación de una familia y revisión bibliográfica  <span class="so-article-trans-title" dir="auto"> Translated title: Osteogenesis imperfecta: germinal mosaicism or genetic heterogeneity evidence. Presentation of a family and a literature review </span>

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Abstract

La osteogénesis imperfecta clasifica entre las displasias óseas por alteraciones en la densidad y los defectos del modelaje óseo. El tipo I es la forma más frecuente de la enfermedad y se caracteriza por un patrón de herencia autosómico dominante. No es infrecuente que la enfermedad aparezca producto de una nueva mutación. También se ha demostrado que puede ser producida por mosaicismos germinales. Este trabajo documenta, por primera vez en Cuba, el caso de una familia con 3 individuos de diferente sexo afectados por osteogénesis imperfecta de tipo I mientras ninguno de los progenitores lo está. Se discute la posibilidad etiológica de un mosaicismo germinal y se valora asimismo la posibilidad de un patrón de herencia distinto del dominante, lo cual aportaría nueva evidencia de heterogeneidad genética.

Translated abstract

Osteogenesis imperfecta is one of the bone dysplasias caused by altered density and bone model defects. Type I is the most common form of disease and is characterized by an autosomal dominant inheritance pattern. Sometimes, this disease occurs as a result of a new mutation. It has been also demonstrated that it can be caused by germ mosaicisms. This paper documented for the first time in Cuba the case of a family with three (3) individuals of both sexes affected by type-1 osteogenesis imperfecta but their parents were not. The etiological possibilities of germ mosaicism and the possibilities of an inheritance pattern different from the dominant one were discussed, which would give new genetic heterogeneity evidence.

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Most cited references 18

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Genetic heterogeneity in osteogenesis imperfecta.

D Sillence, A Senn, D M Danks (1979)

An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.

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Type V osteogenesis imperfecta: a new form of brittle bone disease.

F Glorieux, Paul Bishop, H Plotkin … (2000)

Osteogenesis imperfecta (OI) is commonly subdivided into four clinical types. Among these, OI type IV clearly represents a heterogeneous group of disorders. Here we describe 7 OI patients (3 girls), who would typically be classified as having OI type IV but who can be distinguished from other type IV patients. We propose to call this disease entity OI type V. These children had a history of moderate to severe increased fragility of long bones and vertebral bodies. Four patients had experienced at least one episode of hyperplastic callus formation. The family history was positive for OI in 3 patients, with an autosomal dominant pattern of inheritance. All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. A radiodense metaphyseal band immediately adjacent to the growth plate was a constant feature in growing patients. Lumbar spine bone mineral density was low and similar to age-matched patients with OI type IV. None of the type V patients presented blue sclerae or dentinogenesis imperfecta, but ligamentous laxity was similar to that in patients with OI type IV. Levels of biochemical markers of bone metabolism generally were within the reference range, but serum alkaline phosphatase and urinary collagen type I N-telopeptide excretion increased markedly during periods of active hyperplastic callus formation. Qualitative histology of iliac biopsy specimens showed that lamellae were arranged in an irregular fashion or had a meshlike appearance. Quantitative histomorphometry revealed decreased amounts of cortical and cancellous bone, like in OI type IV. However, in contrast to OI type IV, parameters that reflect remodeling activation on cancellous bone were mostly normal in OI type V, while parameters reflecting bone formation processes in individual remodeling sites were clearly decreased. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations affecting glycine codons or splice sites. In conclusion, OI type V is a new form of autosomal dominant OI, which does not appear to be associated with collagen type I mutations. The genetic defect underlying this disease remains to be elucidated.

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High proportion of mutant osteoblasts is compatible with normal skeletal function in mosaic carriers of osteogenesis imperfecta.

Wayne Cabral, Joan C. Marini (2004)

Individuals with mosaicism for the autosomal dominant bone dysplasia osteogenesis imperfecta (OI) are generally identified by having more than one affected child. The mosaic carriers have both normal and mutant cell populations in somatic and germline tissues but are unaffected or minimally affected by the type I collagen mutation that manifests clinically in their heterozygous offspring. We determined the proportion of mutant osteoblasts in skeletal tissue of two mosaic carriers who each have a COL1A1 mutation in a high proportion of dermal fibroblasts. Both carriers had normal height and bone histology; the first carrier had normal lumbar spine measurements (L1-L4), as determined by dual-energy x-ray absorptiometry (Z = +1.17). In cultured cells from the first carrier, studied by labeled PCR and single-cell PCR over successive passages, the collagen mutation was present in 85% of fibroblasts and 50% and 75% of osteoblasts from her right iliac crest and left patella, respectively, with minimal selection. The second carrier was studied by PCR amplification of DNA from autopsy paraffin blocks. The proportion of heterozygous cells was 40% in calvarium, 65% in tracheal ring, and 70% in aorta. Thus, in OI, substantially normal skeletal growth, density, and histology are compatible with a 40%-75% burden of osteoblasts heterozygous for a COL1A1 mutation. These data are encouraging for mesenchymal stem-cell transplantation, since mosaic carriers are a naturally occurring model for cell therapy.

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Author and article information

Journal

Journal ID (publisher-id): ped

Title: Revista Cubana de Pediatría

Abbreviated Title: Rev Cubana Pediatr

Publisher: Centro Nacional de Información de Ciencias Médicas; Editorial Ciencias Médicas (La Habana, , Cuba )

ISSN (Print): 0034-7531

ISSN (Electronic): 1561-3119

Publication date (Print and electronic): September 2007

Volume: 79

Issue: 3

Affiliations

[01] La Habana orgnameHospital Pediátrico Docente William Soler Cuba ivan.hernandez@ 123456infomed.sld.cu

[02] orgnamePoliclínico Docente Felipe Poey

Article

Publisher ID: S0034-75312007000300012 Publisher ID: S0034-7531(07)07900312

SO-VID: c0dac222-ddca-40d6-b6d3-91d7ce09e47d

License:

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

History

Date received : 02 February 2007

Date accepted : 15 May 2007

Page count

Figures: 0, Tables: 0, Equations: 0, References: 14, Pages: 0

Product

SciELO Cuba

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Osteogénesis imperfecta: mosaicismo germinal o evidencia de heterogeneidad genética. Presentación de una familia y revisión bibliográfica Translated title: Osteogenesis imperfecta: germinal mosaicism or genetic heterogeneity evidence. Presentation of a family and a literature review

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