Entry - #301014 - OSTEOGENESIS IMPERFECTA, TYPE XIX; OI19 - OMIM
# 301014

OSTEOGENESIS IMPERFECTA, TYPE XIX; OI19


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
Xp22.12 Osteogenesis imperfecta, type XIX 301014 XLR 3 MBTPS2 300294
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- X-linked recessive
GROWTH
Height
- Short stature, severe
HEAD & NECK
Eyes
- Blue sclerae (uncommon)
CHEST
Ribs Sternum Clavicles & Scapulae
- Rib fractures, prenatal
- Discontinuously 'beaded' ribs
- Clavicular fractures, prenatal
- Pectus carinatum
- Pectus excavatum (uncommon)
SKELETAL
- Generalized osteopenia
- Multiple fractures
Spine
- Scoliosis
- Anterior vertebral wedging
- Flat biconcave vertebral bodies
Limbs
- Bowing of long bones of upper extremities
- Rhizomelia of upper extremities
- Bowing of long bones of lower extremities
- Rhizomelia of lower extremities
- Epiphyseal 'popcorn' calcification
LABORATORY ABNORMALITIES
- Elevated urinary pyridinoline crosslink profile
MISCELLANEOUS
- Prenatal fractures
- Variable presence of scoliosis and pectus deformities
- Fractures may decrease in frequency after puberty
MOLECULAR BASIS
- Caused by mutation in the membrane-bound transcription factor protease, site 2 gene (MBTPS2, 300294.0009)
Osteogenesis imperfecta - PS166200 - 26 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p34.2 Osteogenesis imperfecta, type VIII AR 3 610915 P3H1 610339
3p22.3 Osteogenesis imperfecta, type VII AR 3 610682 CRTAP 605497
5q33.1 Osteogenesis imperfecta, type XVII AR 3 616507 SPARC 182120
6q14.1 Osteogenesis imperfecta, type XVIII AR 3 617952 TENT5A 611357
7p22.1 Osteogenesis imperfecta, type XXI AR 3 619131 KDELR2 609024
7q21.3 Osteogenesis imperfecta, type III AD 3 259420 COL1A2 120160
7q21.3 Osteogenesis imperfecta, type IV AD 3 166220 COL1A2 120160
7q21.3 Osteogenesis imperfecta, type II AD 3 166210 COL1A2 120160
8p21.3 Osteogenesis imperfecta, type XIII AR 3 614856 BMP1 112264
9q31.2 Osteogenesis imperfecta, type XIV AR 3 615066 TMEM38B 611236
11p15.5 Osteogenesis imperfecta, type V AD 3 610967 IFITM5 614757
11p11.2 Osteogenesis imperfecta, type XVI AR 3 616229 CREB3L1 616215
11q13.5 Osteogenesis imperfecta, type X AR 3 613848 SERPINH1 600943
11q23.3 Osteogenesis imperfecta, type XXIII AR 3 620639 PHLDB1 612834
12q13.12 Osteogenesis imperfecta, type XV AR 3 615220 WNT1 164820
12q13.13 Osteogenesis imperfecta, type XII AR 3 613849 SP7 606633
15q22.31 Osteogenesis imperfecta, type IX AR 3 259440 PPIB 123841
15q25.1 Osteogenesis imperfecta, type XX AR 3 618644 MESD 607783
17p13.3 Osteogenesis imperfecta, type VI AR 3 613982 SERPINF1 172860
17q21.2 Osteogenesis imperfecta, type XI AR 3 610968 FKBP10 607063
17q21.33 Osteogenesis imperfecta, type II AD 3 166210 COL1A1 120150
17q21.33 Osteogenesis imperfecta, type IV AD 3 166220 COL1A1 120150
17q21.33 Osteogenesis imperfecta, type I AD 3 166200 COL1A1 120150
17q21.33 Osteogenesis imperfecta, type III AD 3 259420 COL1A1 120150
22q13.2 Osteogenesis imperfecta, type XXII AR 3 619795 CCDC134 618788
Xp22.12 Osteogenesis imperfecta, type XIX XLR 3 301014 MBTPS2 300294

TEXT

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XIX (OI19) is caused by mutation in the MBTPS2 gene (300294) on chromosome Xp22.


Description

Osteogenesis imperfecta type XIX (OI19) is characterized by prenatal fractures and generalized osteopenia, with severe short stature in adulthood, as well as variable scoliosis and pectal deformity, and marked anterior angulation of the tibia (Lindert et al., 2016).


Clinical Features

Lindert et al. (2016) studied 2 unrelated families segregating osteogenesis imperfecta in an X-linked inheritance pattern. The authors examined 6 of 12 affected males from a large Thai pedigree (family I). The proband had prenatal fractures of the ribs and long bones, and examination at age 2 years showed moderate short stature, blue sclerae, pectus carinatum, and bowing of lower extremity long bones. His L2-L4 bone mineral density z-score was -4.7. The proband's mother was healthy with normal weight, height, and bone mineral density. Affected adult males in the family had fractures beginning during gestation, severe short stature, white sclerae, variable scoliosis and pectal deformity, marked anterior angulation of the tibia, and generalized osteopenia. Family II was German and had 2 affected males, the 26-year-old proband and his 68-year-old maternal uncle. At birth, the proband had bowing of humeri, radii, and tibiae, with fractures of femora, ribs, and clavicles as well as generalized osteopenia. Both patients had numerous fractures of upper and lower extremity long bones in childhood, but the number of fractures declined after puberty. Both exhibited white sclerae, kyphoscoliosis with anterior vertebral wedging, and severe short stature, and the uncle had severe pectus excavatum. In both probands, osteoblasts showed broadly defective differentiation, and secretion of type I collagen was significantly reduced.


Mapping

In a large Thai pedigree segregating OI in an X-linked inheritance pattern, Lindert et al. (2016) performed linkage analysis of the X chromosome and defined a 21.6-Mb critical region on Xp22 between markers DXS7108 and DXS1067, for which they obtained a lod score of 3.31. In a German family with OI, genomewide linkage analysis showed a positive lod score in a 30-Mb region of chromosome X, between SNPs rs11094708 and rs5906168.


Molecular Genetics

In a large Thai pedigree with OI mapping to chromosome Xp22 and negative for mutation in a set of 18 genes associated with OI and bone fragility, Lindert et al. (2016) sequenced the critical region on chromosome X and identified a missense mutation in the MBTPS2 gene (N459S; 300294.0009) that segregated with disease and was not found in 644 X chromosomes of unrelated Thai controls. In a German family with OI mapping to chromosome X, also negative for mutation in the 18-gene set, the authors performed X-exome sequencing and identified another missense variant in MBTPS2 (L505F; 300294.0010) that segregated with disease. Neither mutation was found in public variant databases. Proband osteoblasts showed broadly defective differentiation, and there was decreased proband secretion of type I collagen. The authors stated that this was the first reported form of OI due to X-linked recessive inheritance.


REFERENCES

  1. Lindert, U., Cabral, W. A., Ausavarat, S., Tongkobpetch, S., Ludin, K., Barnes, A. M., Yeetong, P., Weis, M., Krabichler, B., Srichomthong, C., Makareeva, E. N., Janecke, A. R., and 9 others. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nature Commun. 7: 11920, 2016. Note: Electronic Article. [PubMed: 27380894, related citations] [Full Text]


Contributors:
Marla J. F. O'Neill - updated : 07/31/2018
Creation Date:
Marla J. F. O'Neill : 07/31/2018
carol : 08/02/2018
carol : 07/31/2018

# 301014

OSTEOGENESIS IMPERFECTA, TYPE XIX; OI19


DO: 0111847;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
Xp22.12 Osteogenesis imperfecta, type XIX 301014 X-linked recessive 3 MBTPS2 300294

TEXT

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XIX (OI19) is caused by mutation in the MBTPS2 gene (300294) on chromosome Xp22.


Description

Osteogenesis imperfecta type XIX (OI19) is characterized by prenatal fractures and generalized osteopenia, with severe short stature in adulthood, as well as variable scoliosis and pectal deformity, and marked anterior angulation of the tibia (Lindert et al., 2016).


Clinical Features

Lindert et al. (2016) studied 2 unrelated families segregating osteogenesis imperfecta in an X-linked inheritance pattern. The authors examined 6 of 12 affected males from a large Thai pedigree (family I). The proband had prenatal fractures of the ribs and long bones, and examination at age 2 years showed moderate short stature, blue sclerae, pectus carinatum, and bowing of lower extremity long bones. His L2-L4 bone mineral density z-score was -4.7. The proband's mother was healthy with normal weight, height, and bone mineral density. Affected adult males in the family had fractures beginning during gestation, severe short stature, white sclerae, variable scoliosis and pectal deformity, marked anterior angulation of the tibia, and generalized osteopenia. Family II was German and had 2 affected males, the 26-year-old proband and his 68-year-old maternal uncle. At birth, the proband had bowing of humeri, radii, and tibiae, with fractures of femora, ribs, and clavicles as well as generalized osteopenia. Both patients had numerous fractures of upper and lower extremity long bones in childhood, but the number of fractures declined after puberty. Both exhibited white sclerae, kyphoscoliosis with anterior vertebral wedging, and severe short stature, and the uncle had severe pectus excavatum. In both probands, osteoblasts showed broadly defective differentiation, and secretion of type I collagen was significantly reduced.


Mapping

In a large Thai pedigree segregating OI in an X-linked inheritance pattern, Lindert et al. (2016) performed linkage analysis of the X chromosome and defined a 21.6-Mb critical region on Xp22 between markers DXS7108 and DXS1067, for which they obtained a lod score of 3.31. In a German family with OI, genomewide linkage analysis showed a positive lod score in a 30-Mb region of chromosome X, between SNPs rs11094708 and rs5906168.


Molecular Genetics

In a large Thai pedigree with OI mapping to chromosome Xp22 and negative for mutation in a set of 18 genes associated with OI and bone fragility, Lindert et al. (2016) sequenced the critical region on chromosome X and identified a missense mutation in the MBTPS2 gene (N459S; 300294.0009) that segregated with disease and was not found in 644 X chromosomes of unrelated Thai controls. In a German family with OI mapping to chromosome X, also negative for mutation in the 18-gene set, the authors performed X-exome sequencing and identified another missense variant in MBTPS2 (L505F; 300294.0010) that segregated with disease. Neither mutation was found in public variant databases. Proband osteoblasts showed broadly defective differentiation, and there was decreased proband secretion of type I collagen. The authors stated that this was the first reported form of OI due to X-linked recessive inheritance.


REFERENCES

  1. Lindert, U., Cabral, W. A., Ausavarat, S., Tongkobpetch, S., Ludin, K., Barnes, A. M., Yeetong, P., Weis, M., Krabichler, B., Srichomthong, C., Makareeva, E. N., Janecke, A. R., and 9 others. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nature Commun. 7: 11920, 2016. Note: Electronic Article. [PubMed: 27380894] [Full Text: https://doi.org/10.1038/ncomms11920]


Contributors:
Marla J. F. O'Neill - updated : 07/31/2018

Creation Date:
Marla J. F. O'Neill : 07/31/2018

Edit History:
carol : 08/02/2018
carol : 07/31/2018