Entry - #616229 - OSTEOGENESIS IMPERFECTA, TYPE XVI; OI16 - OMIM
# 616229

OSTEOGENESIS IMPERFECTA, TYPE XVI; OI16


Alternative titles; symbols

OI, TYPE XVI


Other entities represented in this entry:

CHROMOSOME 11p11.2 DELETION SYNDROME, 91.3-KB, INCLUDED

Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
11p11.2 Osteogenesis imperfecta, type XVI 616229 AR 3 CREB3L1 616215
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
GROWTH
Height
- Short stature
Other
- Small for gestational age
HEAD & NECK
Ears
- Conductive hearing loss (in 1 heterozygote)
Eyes
- Blue sclerae
Teeth
- Tooth agenesis
CHEST
Ribs Sternum Clavicles & Scapulae
- Beaded ribs
- Callus formation
- Rib fractures
SKELETAL
- Osteopenia
Skull
- Soft calvarial bones
- Widely open fontanels
Spine
- Vertebral compression fractures
Limbs
- Multiple fractures of extremities (may occur in utero)
- Accordion-like broadened appearance of tubular bones
- Bowing of upper extremities
- Bowing of lower extremities
- Micromelic limb shortening
- Rhizomelic limb shortening
- Mesomelic limb shortening
- Fractures with minimal trauma
- Small joint hypermobility
SKIN, NAILS, & HAIR
Skin
- Soft velvety skin (in some heterozygotes)
MISCELLANEOUS
- Onset in utero
- Heterozygotes may exhibit a mild form of the disorder
- Contiguous gene syndrome caused by deletion of 91.3kb on chromosome 11p11.2 involving the CREB3L1 (616215) and DGKZ (601441) genes
MOLECULAR BASIS
- Caused by mutation in the cAMP response element-binding protein 3-like 1 gene (CREB3L1, 616215.0001)
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 IV AD 3 166220 COL1A2 120160
7q21.3 Osteogenesis imperfecta, type II AD 3 166210 COL1A2 120160
7q21.3 Osteogenesis imperfecta, type III AD 3 259420 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 I AD 3 166200 COL1A1 120150
17q21.33 Osteogenesis imperfecta, type III AD 3 259420 COL1A1 120150
17q21.33 Osteogenesis imperfecta, type II AD 3 166210 COL1A1 120150
17q21.33 Osteogenesis imperfecta, type IV AD 3 166220 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 autosomal recessive osteogenesis imperfecta type XVI (OI16) is caused by homozygous mutation in the CREB3L1 gene (616215) on chromosome 11p11. Mildly affected heterozygous family members have been reported.

OI16 has also been reported in 1 family with a contiguous gene deletion including the CREB3L1 gene on chromosome 11p11.2.


Description

Osteogenesis imperfecta type XVI (OI16) is characterized by prenatal onset of multiple fractures of ribs and long bones, blue sclerae, decreased ossification of the skull, and severe demineralization. Heterozygous family members may exhibit recurrent fractures with minimal trauma, osteopenia, and blue sclerae (Keller et al., 2018; Lindahl et al., 2018).


Clinical Features

Symoens et al. (2013) reported a Turkish family in which 2 sibs had osteogenesis imperfecta. The first affected child had fractures in utero and was small for gestational age. He continued to have fractures after birth, and x-rays showed beaded ribs, callus formation, and multiple fractured tubular bones with an accordion-like broadened appearance. He was hospitalized several times due to recurrent constipation and bronchopneumonia, and developed cardiac insufficiency and hepatomegaly. He died at 9 months of age. A subsequent affected pregnancy was terminated at 19 weeks' gestation; postmortem showed thin ribs and fractures at the bowed humeri and femora. The parents, who were not known to be consanguineous but came from neighboring villages, had blue sclerae, soft velvety skin, and normal teeth; the mother also had small joint hypermobility, and the father had conductive hearing loss. There was a healthy daughter with blue sclerae who had not experienced any fractures, and the mother also had had 1 miscarriage of unknown cause.

Keller et al. (2018) studied a large Lebanese family in which the proband had shortened and angulated humeri, multiple fractures of the long bones of both legs, and apparently reduced skull mineralization at 12 weeks' gestation by ultrasound. Imaging at 14 weeks confirmed micromelia and angulated long bones, as well as ribs of normal length that were angulated, consistent with fractures. The pregnancy was terminated at 16 weeks due to suspected OI. Two prior pregnancies had been terminated due to in utero findings consistent with severe skeletal dysplasia, including severe long bone deformity with crumpling, angulation, and marked rhizomelic and mesomelic shortening. Calvarial bones were paper-thin and soft, with almost no ossification of the cranial vault, and severe demineralization was noted. In addition, there were 3 mildly affected family members, including the proband's brother, who was born with a fractured right femur but otherwise had normal long bones, ribs, thorax, and skull. At age 6 years, x-ray of his pelvis showed osteopenia. At age 15 years, he was osteopenic with blue sclerae but had no additional fractures. An affected sister also had blue sclerae and mild osteopenia, but no history of fractures. Their mother had blue sclerae and a history of recurrent fractures in childhood, including a fractured pelvis with minimal trauma at age 1 year, and a spiral fracture of 1 femur at age 16 years. Their maternal grandfather and great-grandfather, as well as a maternal granduncle, had recurrent fractures and were suspected to be mildly affected but were not available for clinical assessment. Their reportedly unaffected father declined clinical assessment.

Lindahl et al. (2018) reported a Somali family in which an 11-year-old boy with severe OI had experienced 27 major fractures despite bisphosphonate treatment. He was born with a femur fracture, and neonatal x-rays showed curved femora and humeri with suspected healed intrauterine fractures, multiple vertebral compression fractures, and rib fractures, as well as wormian bones. He had bluish-gray sclerae. In infancy he had an increased bleeding time, and during early childhood showed a tendency to bruise easily. At age 11, he exhibited marked short stature and hyperextensibility of small and large joints, with ambulation primarily by manual wheelchair. Skin turgor, elasticity, and healing were normal. Audiometry was normal. There were no signs of dentinogenesis imperfecta, but he had tooth agenesis, with 6 missing teeth. His parents and 4 sibs were healthy, with normal sclerae, no hyperextensibility, and no history of fractures.

Guillemyn et al. (2019) reported a female fetus with prenatal ultrasound findings of short tubular bones, multiple rib fractures, and a narrow thorax. Postnatal findings after pregnancy termination at 19 weeks' gestation included soft calvaria, microretrognathia, and short, bowed extremities. Radiographs revealed absence of calvarial mineralization and globally decreased bone density. The ribs were thin and wavy due to fractures. The tubular bones of the extremities were short and irregular and were flared at the metaphyses. The carrier parents had no overt clinical signs of OI or history of fractures, but both had decreased L1-L4 vertebral density and the father had decreased bone density in the left femur.


Cytogenetics

Using DNA from an affected fetus from a Turkish family with OI, Symoens et al. (2013) screened 14 known OI-associated genes but found no mutations. PCR amplification of the candidate gene CREB3L1 failed, and array CGH revealed a homozygous deletion (chr11:46,268,141-46,359,490) encompassing the CREB3L1 gene and the first exon of neighboring gene DGKZ (601441). Both parents and a healthy sib were heterozygous for the deletion. Expression analysis of dermal fibroblasts from the affected fetus showed complete absence of the CREB3L1 transcript; in addition, using primer pairs specific for DGKZ isoforms 1 and 2, in which exon 1 is present or absent, respectively, Symoens et al. (2013) found evidence for lack of expression of isoform 1 and normal expression of isoform 2 in cultured patient fibroblasts. The authors noted that no known function in bone formation had been associated with the DGKZ gene, and it was unclear what role it might play in the bone phenotype of the affected individuals. They also found that type I procollagen (see COL1A1, 120150) production was normal in patient fibroblasts, indicative of a tissue-specific effect of CREB3L1 on type I procollagen production.


Molecular Genetics

In a large Lebanese family segregating an apparently recessive form of severe OI, Keller et al. (2018) performed exome sequencing and identified a 3-bp deletion in the CREB3L1 gene (616215.0001) for which the severely affected proband was homozygous. His mildly affected sibs and mother were heterozygous for the deletion, as was his reportedly unaffected father, who had declined clinical assessment.

In an 11-year-old Somali boy with severe OI, who was negative for mutation in the COL1A1 and COL1A2 (120160) genes, Lindahl et al. (2018) screened known OI-associated genes and identified homozygosity for a nonsense mutation in the CREB3L1 gene (Y428X; 616215.0002). His unaffected parents and 2 unaffected sibs were heterozygous for the mutation. The authors noted that the proband was the first child with recessive OASIS deficiency-associated OI to survive infancy.

Guillemyn et al. (2019) identified a homozygous missense mutation (A304V; 616215.0003) in the CREB3L1 gene in a female fetus from a consanguineous Turkish family with OI16. The mutation, which was identified by next-generation sequencing of an OI-associated gene panel and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Molecular modeling predicted that the mutation would result in impaired protein conformation.


REFERENCES

  1. Guillemyn, B., Kayserili, H., Demuynck, L., Sips, P., De Paepe, A., Syz, D., Coucke, P. J., Malfait, F., Symoens, S. A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta. Hum. Molec. Genet. 28: 1801-1809, 2019. [PubMed: 30657919, related citations] [Full Text]

  2. Keller, R. B., Tran, T. T., Pyott, S. M., Pepin, M. G., Savarirayan, R., McGillivray, G., UW Center for Mendelian Genomics, Nickerson, D. A., Bamshad, M. J., Byers, P. H. Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively. Genet. Med. 20: 411-419, 2018. [PubMed: 28817112, related citations] [Full Text]

  3. Lindahl, K., Astrom, E., Dragomir, A., Symoens, S., Coucke, P., Larsson, S., Paschalis, E., Roschger, P., Gamsjaeger, S., Klaushofer, K., Fratzl-Zelman, N., Kindmark, A. Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy. Bone 114: 268-277, 2018. [PubMed: 29936144, related citations] [Full Text]

  4. Symoens, S., Malfait, F., D'hondt, S., Callewaert, B., Dheedene, A., Steyaert, W., Bachinger, H. P., De Paepe, A., Kayserili, H., Coucke, P. J. Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J. Rare Dis. 8: 154, 2013. Note: Electronic Article. [PubMed: 24079343, images, related citations] [Full Text]


Hilary J. Vernon - updated : 10/27/2020
Marla J. F. O'Neill - updated : 08/07/2018
Creation Date:
Marla J. F. O'Neill : 2/16/2015
carol : 10/27/2020
carol : 08/08/2018
carol : 08/07/2018
carol : 02/18/2015
mcolton : 2/18/2015

# 616229

OSTEOGENESIS IMPERFECTA, TYPE XVI; OI16


Alternative titles; symbols

OI, TYPE XVI


Other entities represented in this entry:

CHROMOSOME 11p11.2 DELETION SYNDROME, 91.3-KB, INCLUDED

ORPHA: 216812, 666;   DO: 0110345;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
11p11.2 Osteogenesis imperfecta, type XVI 616229 Autosomal recessive 3 CREB3L1 616215

TEXT

A number sign (#) is used with this entry because of evidence that autosomal recessive osteogenesis imperfecta type XVI (OI16) is caused by homozygous mutation in the CREB3L1 gene (616215) on chromosome 11p11. Mildly affected heterozygous family members have been reported.

OI16 has also been reported in 1 family with a contiguous gene deletion including the CREB3L1 gene on chromosome 11p11.2.


Description

Osteogenesis imperfecta type XVI (OI16) is characterized by prenatal onset of multiple fractures of ribs and long bones, blue sclerae, decreased ossification of the skull, and severe demineralization. Heterozygous family members may exhibit recurrent fractures with minimal trauma, osteopenia, and blue sclerae (Keller et al., 2018; Lindahl et al., 2018).


Clinical Features

Symoens et al. (2013) reported a Turkish family in which 2 sibs had osteogenesis imperfecta. The first affected child had fractures in utero and was small for gestational age. He continued to have fractures after birth, and x-rays showed beaded ribs, callus formation, and multiple fractured tubular bones with an accordion-like broadened appearance. He was hospitalized several times due to recurrent constipation and bronchopneumonia, and developed cardiac insufficiency and hepatomegaly. He died at 9 months of age. A subsequent affected pregnancy was terminated at 19 weeks' gestation; postmortem showed thin ribs and fractures at the bowed humeri and femora. The parents, who were not known to be consanguineous but came from neighboring villages, had blue sclerae, soft velvety skin, and normal teeth; the mother also had small joint hypermobility, and the father had conductive hearing loss. There was a healthy daughter with blue sclerae who had not experienced any fractures, and the mother also had had 1 miscarriage of unknown cause.

Keller et al. (2018) studied a large Lebanese family in which the proband had shortened and angulated humeri, multiple fractures of the long bones of both legs, and apparently reduced skull mineralization at 12 weeks' gestation by ultrasound. Imaging at 14 weeks confirmed micromelia and angulated long bones, as well as ribs of normal length that were angulated, consistent with fractures. The pregnancy was terminated at 16 weeks due to suspected OI. Two prior pregnancies had been terminated due to in utero findings consistent with severe skeletal dysplasia, including severe long bone deformity with crumpling, angulation, and marked rhizomelic and mesomelic shortening. Calvarial bones were paper-thin and soft, with almost no ossification of the cranial vault, and severe demineralization was noted. In addition, there were 3 mildly affected family members, including the proband's brother, who was born with a fractured right femur but otherwise had normal long bones, ribs, thorax, and skull. At age 6 years, x-ray of his pelvis showed osteopenia. At age 15 years, he was osteopenic with blue sclerae but had no additional fractures. An affected sister also had blue sclerae and mild osteopenia, but no history of fractures. Their mother had blue sclerae and a history of recurrent fractures in childhood, including a fractured pelvis with minimal trauma at age 1 year, and a spiral fracture of 1 femur at age 16 years. Their maternal grandfather and great-grandfather, as well as a maternal granduncle, had recurrent fractures and were suspected to be mildly affected but were not available for clinical assessment. Their reportedly unaffected father declined clinical assessment.

Lindahl et al. (2018) reported a Somali family in which an 11-year-old boy with severe OI had experienced 27 major fractures despite bisphosphonate treatment. He was born with a femur fracture, and neonatal x-rays showed curved femora and humeri with suspected healed intrauterine fractures, multiple vertebral compression fractures, and rib fractures, as well as wormian bones. He had bluish-gray sclerae. In infancy he had an increased bleeding time, and during early childhood showed a tendency to bruise easily. At age 11, he exhibited marked short stature and hyperextensibility of small and large joints, with ambulation primarily by manual wheelchair. Skin turgor, elasticity, and healing were normal. Audiometry was normal. There were no signs of dentinogenesis imperfecta, but he had tooth agenesis, with 6 missing teeth. His parents and 4 sibs were healthy, with normal sclerae, no hyperextensibility, and no history of fractures.

Guillemyn et al. (2019) reported a female fetus with prenatal ultrasound findings of short tubular bones, multiple rib fractures, and a narrow thorax. Postnatal findings after pregnancy termination at 19 weeks' gestation included soft calvaria, microretrognathia, and short, bowed extremities. Radiographs revealed absence of calvarial mineralization and globally decreased bone density. The ribs were thin and wavy due to fractures. The tubular bones of the extremities were short and irregular and were flared at the metaphyses. The carrier parents had no overt clinical signs of OI or history of fractures, but both had decreased L1-L4 vertebral density and the father had decreased bone density in the left femur.


Cytogenetics

Using DNA from an affected fetus from a Turkish family with OI, Symoens et al. (2013) screened 14 known OI-associated genes but found no mutations. PCR amplification of the candidate gene CREB3L1 failed, and array CGH revealed a homozygous deletion (chr11:46,268,141-46,359,490) encompassing the CREB3L1 gene and the first exon of neighboring gene DGKZ (601441). Both parents and a healthy sib were heterozygous for the deletion. Expression analysis of dermal fibroblasts from the affected fetus showed complete absence of the CREB3L1 transcript; in addition, using primer pairs specific for DGKZ isoforms 1 and 2, in which exon 1 is present or absent, respectively, Symoens et al. (2013) found evidence for lack of expression of isoform 1 and normal expression of isoform 2 in cultured patient fibroblasts. The authors noted that no known function in bone formation had been associated with the DGKZ gene, and it was unclear what role it might play in the bone phenotype of the affected individuals. They also found that type I procollagen (see COL1A1, 120150) production was normal in patient fibroblasts, indicative of a tissue-specific effect of CREB3L1 on type I procollagen production.


Molecular Genetics

In a large Lebanese family segregating an apparently recessive form of severe OI, Keller et al. (2018) performed exome sequencing and identified a 3-bp deletion in the CREB3L1 gene (616215.0001) for which the severely affected proband was homozygous. His mildly affected sibs and mother were heterozygous for the deletion, as was his reportedly unaffected father, who had declined clinical assessment.

In an 11-year-old Somali boy with severe OI, who was negative for mutation in the COL1A1 and COL1A2 (120160) genes, Lindahl et al. (2018) screened known OI-associated genes and identified homozygosity for a nonsense mutation in the CREB3L1 gene (Y428X; 616215.0002). His unaffected parents and 2 unaffected sibs were heterozygous for the mutation. The authors noted that the proband was the first child with recessive OASIS deficiency-associated OI to survive infancy.

Guillemyn et al. (2019) identified a homozygous missense mutation (A304V; 616215.0003) in the CREB3L1 gene in a female fetus from a consanguineous Turkish family with OI16. The mutation, which was identified by next-generation sequencing of an OI-associated gene panel and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Molecular modeling predicted that the mutation would result in impaired protein conformation.


REFERENCES

  1. Guillemyn, B., Kayserili, H., Demuynck, L., Sips, P., De Paepe, A., Syz, D., Coucke, P. J., Malfait, F., Symoens, S. A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta. Hum. Molec. Genet. 28: 1801-1809, 2019. [PubMed: 30657919] [Full Text: https://doi.org/10.1093/hmg/ddz017]

  2. Keller, R. B., Tran, T. T., Pyott, S. M., Pepin, M. G., Savarirayan, R., McGillivray, G., UW Center for Mendelian Genomics, Nickerson, D. A., Bamshad, M. J., Byers, P. H. Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively. Genet. Med. 20: 411-419, 2018. [PubMed: 28817112] [Full Text: https://doi.org/10.1038/gim.2017.115]

  3. Lindahl, K., Astrom, E., Dragomir, A., Symoens, S., Coucke, P., Larsson, S., Paschalis, E., Roschger, P., Gamsjaeger, S., Klaushofer, K., Fratzl-Zelman, N., Kindmark, A. Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy. Bone 114: 268-277, 2018. [PubMed: 29936144] [Full Text: https://doi.org/10.1016/j.bone.2018.06.019]

  4. Symoens, S., Malfait, F., D'hondt, S., Callewaert, B., Dheedene, A., Steyaert, W., Bachinger, H. P., De Paepe, A., Kayserili, H., Coucke, P. J. Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J. Rare Dis. 8: 154, 2013. Note: Electronic Article. [PubMed: 24079343] [Full Text: https://doi.org/10.1186/1750-1172-8-154]


Contributors:
Hilary J. Vernon - updated : 10/27/2020
Marla J. F. O'Neill - updated : 08/07/2018

Creation Date:
Marla J. F. O'Neill : 2/16/2015

Edit History:
carol : 10/27/2020
carol : 08/08/2018
carol : 08/07/2018
carol : 02/18/2015
mcolton : 2/18/2015