Entry - #619131 - OSTEOGENESIS IMPERFECTA, TYPE XXI; OI21 - OMIM
# 619131

OSTEOGENESIS IMPERFECTA, TYPE XXI; OI21


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
7p22.1 Osteogenesis imperfecta, type XXI 619131 AR 3 KDELR2 609024
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
GROWTH
Height
- Disproportionate short stature
Weight
- Low weight
Other
- Failure to thrive
HEAD & NECK
Eyes
- Blue sclerae (in some patients)
Teeth
- Overcrowded small teeth
- Dental caries
- Crumbling teeth
- Dentinogenesis imperfecta
CHEST
External Features
- Barrel-shaped chest
Ribs Sternum Clavicles & Scapulae
- Pectus excavatum
- Thin ribs
SKELETAL
- Multiple fractures, often after minor trauma
- Reduced bone mineral density
- Joint hypermobility
Skull
- Delayed mineralization
- Delayed closure of sutures
- Wormian bones
Spine
- Vertebral fractures
- Platyspondyly
- Scoliosis
Pelvis
- Coxa vara
- Coxa valga
Limbs
- Bowing of long bones (upper and lower extremities)
- Shortening of long bones (upper and lower extremities)
- Genua valga
Feet
- Pes planovalgus
MUSCLE, SOFT TISSUES
- Muscular hypotonia
NEUROLOGIC
Central Nervous System
- Neurodevelopmental delay (in some patients)
- Motor delay (in some patients)
MISCELLANEOUS
- Prenatal fractures in some patients
- Wheelchair-dependence in most patients
MOLECULAR BASIS
- Caused by mutation in the KDEL endoplasmic reticulum protein retention receptor 2 gene (KDELR2, 609024.0001)
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 II AD 3 166210 COL1A2 120160
7q21.3 Osteogenesis imperfecta, type III AD 3 259420 COL1A2 120160
7q21.3 Osteogenesis imperfecta, type IV AD 3 166220 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 XXI (OI21) is caused by homozygous or compound heterozygous mutation in the KDELR2 gene (609024) on chromosome 7p22.


Description

Osteogenesis imperfecta type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients exhibit disproportionate short stature and scoliosis, and are often wheelchair-bound by adulthood (van Dijk et al., 2020).


Clinical Features

Van Dijk et al. (2020) reported 6 patients from 4 families with osteogenesis imperfecta (OI), all of whom had been given a clinical diagnosis of progressively deforming OI type 2B/3. Four patients (P1, P2-1, P2-2, and P3) showed disproportionate short stature and had experienced multiple fractures from early childhood, leading to progressive skeletal deformation and requiring recurrent surgical interventions. In P2-1, P2-2, and P3, progression led to wheelchair dependence, in childhood for P2-1 and P2-2 and at 18 years for P3. No bisphosphonate therapy was available in childhood. In P1, low bone density was seen to improve with bisphosphonate therapy, and mobility was maintained at 12 years. Prenatal ultrasound showed a suspicion of a severe skeletal dysplasia in patients P4-1 and P4-2 and both pregnancies were terminated, at 24 and 22 weeks' gestational age, respectively. X-rays of both fetuses showed slender ribs and malformed bowed tibiae and femora due to multiple fractures, compatible with OI type 2B/3. None of the patients exhibited blue sclerae or dentinogenesis imperfecta.

Efthymiou et al. (2021) reported a Pakistani brother and sister and a Turkish boy with progressively deforming OI and neurodevelopmental delay, who had mutations in the KDELR2 gene. All 3 exhibited motor delay, and 2 had speech delay. Common features among the affected children included short stature, failure to thrive, wormian bones, bowed limbs, chest deformity, hypotonia, joint hypermobility, and dysmorphic facies. In addition, the Pakistani girl and the Turkish boy had blue sclerae, dentinogenesis imperfecta, and scoliosis; the Turkish boy had a femoral fracture, and the Pakistani boy had vertebral compression fractures and platyspondyly. The Pakistani sibs could not walk at ages 6 years and 2.75 years, respectively. The sister had not yet experienced a fracture, and spoke her first word at age 2 years. The Turkish boy developed independent ambulation and speech at 2 years of age, and at age 4 was comparable to his neurotypical peers. The authors stated that it was unclear whether speech delay was associated with mutation in the KDELR2 gene.


Inheritance

The transmission pattern of OI21 in the families reported by Van Dijk et al. (2020) was consistent with autosomal recessive inheritance.


Molecular Genetics

In 6 patients from 4 families with osteogenesis imperfecta, who were negative for mutation in known OI-associated genes, van Dijk et al. (2020) identified homozygosity or compound heterozygosity for mutations in the KDELR2 gene (609024.0001-609024.0004).

By family-based exome sequencing, Efthymiou et al. (2021) identified homozygous missense variants in the KDELR2 gene in 3 children with progressively deforming OI and neurodevelopmental delay: an R5W substitution (609024.0005) in 2 Pakistani sibs, and a Y162C change (609024.0006) in a Turkish boy. The mutations segregated with disease in each family, and were not found in the gnomAD database.


REFERENCES

  1. Efthymiou, S., Herman, I., Rahman, F., Anwar, N., Maroofian, R., Yip, J., Mitani, T., Calame, D. G., Hunter, J. V., Sutton, V. R., Yilmaz Gulec, E., Duan, R., and 10 others. Two novel bi-allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features. (Letter) Am. J. Med. Genet. 185A: 2241-2249, 2021. [PubMed: 33964184, images, related citations] [Full Text]

  2. van Dijk, F. S., Semler, O., Etich, J., Kohler, A., Jimenez-Estrada, J. A., Bravenboer, N., Claeys, L., Riesebos, E., Gegic, S., Piersma, S. R., Jimenez, C. R., Waisfisz, Q., and 26 others. Interaction between KDELR2 and HSP47 as a key determinant in osteogenesis imperfecta caused by bi-allelic variants in KDELR2. Am. J. Hum. Genet. 107: 989-999, 2020. [PubMed: 33053334, images, related citations] [Full Text]


Contributors:
Marla J. F. O'Neill - updated : 05/24/2021
Creation Date:
Marla J. F. O'Neill : 12/18/2020
alopez : 06/21/2024
alopez : 08/17/2021
carol : 05/25/2021
alopez : 05/24/2021
alopez : 12/18/2020

# 619131

OSTEOGENESIS IMPERFECTA, TYPE XXI; OI21


ORPHA: 666;   DO: 0112201;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
7p22.1 Osteogenesis imperfecta, type XXI 619131 Autosomal recessive 3 KDELR2 609024

TEXT

A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XXI (OI21) is caused by homozygous or compound heterozygous mutation in the KDELR2 gene (609024) on chromosome 7p22.


Description

Osteogenesis imperfecta type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients exhibit disproportionate short stature and scoliosis, and are often wheelchair-bound by adulthood (van Dijk et al., 2020).


Clinical Features

Van Dijk et al. (2020) reported 6 patients from 4 families with osteogenesis imperfecta (OI), all of whom had been given a clinical diagnosis of progressively deforming OI type 2B/3. Four patients (P1, P2-1, P2-2, and P3) showed disproportionate short stature and had experienced multiple fractures from early childhood, leading to progressive skeletal deformation and requiring recurrent surgical interventions. In P2-1, P2-2, and P3, progression led to wheelchair dependence, in childhood for P2-1 and P2-2 and at 18 years for P3. No bisphosphonate therapy was available in childhood. In P1, low bone density was seen to improve with bisphosphonate therapy, and mobility was maintained at 12 years. Prenatal ultrasound showed a suspicion of a severe skeletal dysplasia in patients P4-1 and P4-2 and both pregnancies were terminated, at 24 and 22 weeks' gestational age, respectively. X-rays of both fetuses showed slender ribs and malformed bowed tibiae and femora due to multiple fractures, compatible with OI type 2B/3. None of the patients exhibited blue sclerae or dentinogenesis imperfecta.

Efthymiou et al. (2021) reported a Pakistani brother and sister and a Turkish boy with progressively deforming OI and neurodevelopmental delay, who had mutations in the KDELR2 gene. All 3 exhibited motor delay, and 2 had speech delay. Common features among the affected children included short stature, failure to thrive, wormian bones, bowed limbs, chest deformity, hypotonia, joint hypermobility, and dysmorphic facies. In addition, the Pakistani girl and the Turkish boy had blue sclerae, dentinogenesis imperfecta, and scoliosis; the Turkish boy had a femoral fracture, and the Pakistani boy had vertebral compression fractures and platyspondyly. The Pakistani sibs could not walk at ages 6 years and 2.75 years, respectively. The sister had not yet experienced a fracture, and spoke her first word at age 2 years. The Turkish boy developed independent ambulation and speech at 2 years of age, and at age 4 was comparable to his neurotypical peers. The authors stated that it was unclear whether speech delay was associated with mutation in the KDELR2 gene.


Inheritance

The transmission pattern of OI21 in the families reported by Van Dijk et al. (2020) was consistent with autosomal recessive inheritance.


Molecular Genetics

In 6 patients from 4 families with osteogenesis imperfecta, who were negative for mutation in known OI-associated genes, van Dijk et al. (2020) identified homozygosity or compound heterozygosity for mutations in the KDELR2 gene (609024.0001-609024.0004).

By family-based exome sequencing, Efthymiou et al. (2021) identified homozygous missense variants in the KDELR2 gene in 3 children with progressively deforming OI and neurodevelopmental delay: an R5W substitution (609024.0005) in 2 Pakistani sibs, and a Y162C change (609024.0006) in a Turkish boy. The mutations segregated with disease in each family, and were not found in the gnomAD database.


REFERENCES

  1. Efthymiou, S., Herman, I., Rahman, F., Anwar, N., Maroofian, R., Yip, J., Mitani, T., Calame, D. G., Hunter, J. V., Sutton, V. R., Yilmaz Gulec, E., Duan, R., and 10 others. Two novel bi-allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features. (Letter) Am. J. Med. Genet. 185A: 2241-2249, 2021. [PubMed: 33964184] [Full Text: https://doi.org/10.1002/ajmg.a.62221]

  2. van Dijk, F. S., Semler, O., Etich, J., Kohler, A., Jimenez-Estrada, J. A., Bravenboer, N., Claeys, L., Riesebos, E., Gegic, S., Piersma, S. R., Jimenez, C. R., Waisfisz, Q., and 26 others. Interaction between KDELR2 and HSP47 as a key determinant in osteogenesis imperfecta caused by bi-allelic variants in KDELR2. Am. J. Hum. Genet. 107: 989-999, 2020. [PubMed: 33053334] [Full Text: https://doi.org/10.1016/j.ajhg.2020.09.009]


Contributors:
Marla J. F. O'Neill - updated : 05/24/2021

Creation Date:
Marla J. F. O'Neill : 12/18/2020

Edit History:
alopez : 06/21/2024
alopez : 08/17/2021
carol : 05/25/2021
alopez : 05/24/2021
alopez : 12/18/2020