# 271665

SPONDYLOMETAEPIPHYSEAL DYSPLASIA, SHORT LIMB-HAND TYPE


Alternative titles; symbols

SMED-SL
SMED, SHORT LIMB-HAND TYPE
SMED, TYPE II
SPONDYLOMETAEPIPHYSEAL DYSPLASIA, SHORT LIMB-ABNORMAL CALCIFICATION TYPE
SMED, SHORT LIMB-ABNORMAL CALCIFICATION TYPE
SMED-SL/AC


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
1q23.3 Spondylometaepiphyseal dysplasia, short limb-hand type 271665 AR 3 DDR2 191311
Clinical Synopsis
 

INHERITANCE
- Autosomal recessive
GROWTH
Height
- Dwarfism, short-limbed
HEAD & NECK
Face
- Frontal bossing
- Flat midface
- Micrognathia
Eyes
- Prominent eyes
- Hypertelorism
Nose
- Flat nasal bridge
- Short nose
- Broad nares
Mouth
- High-arched palate
Neck
- Calcified styloid process
- Calcified stylomandibular ligaments
- Calcified thyroid cartilage
- Calcified cricoid cartilage
- Calcified body and greater cornua of hyoid
RESPIRATORY
Airways
- Trachea calcifications
- Bronchi calcifications
Lung
- Pneumonia, recurrent episodes
- Restrictive lung disease
CHEST
External Features
- Small chest
- Bell-shaped chest
Ribs Sternum Clavicles & Scapulae
- Pectus excavatum
- Progressive calcification of costochondral cartilage
- Short ribs
- Anterior rib cupping
- Posterior rib cupping
- Calcified coracoclavicular ligament
- Calcified coracoacromial ligament
SKELETAL
- Spondyloepimetaphyseal dysplasia
- Epiphyseal stippling (hips, distal and proximal humeri, proximal and distal femora, distal fibulae, proximal and distal tibiae, distal radii and ulnae)
Skull
- Calcification of falx cerebri
Spine
- Scoliosis
- Platyspondyly
- C1-C2 subluxation
- Hypoplastic odontoid process
Pelvis
- Hip subluxation
- Flared iliac wings
- Short sciatic notch
- Short ischia
Limbs
- Short limbs
- Elbow flexion contracture
- Knee flexion contracture
- Short, broad tubular bones
- Metaphyseal flaring (distal femora, proximal tibiae)
- Disproportionately long fibulae
- Calcified patellae
- Bowing of lower limbs
Hands
- Short fingers
- Short, wide phalanges
- Triangular shaped distal phalanges
- Short, wide metacarpals (wider distally than proximally)
- Carpal calcifications
Feet
- Metatarsus varus
NEUROLOGIC
Central Nervous System
- Atlantoaxial instability
- Developmental delay
- Syringomyelia
- Hypotonia
- Spinal cord compression
MOLECULAR BASIS
- Caused by mutation in the discoidin domain receptor family, member 2 gene (DDR2, 191311.0001)

TEXT

A number sign (#) is used with this entry because of evidence that spondylometaepiphyseal dysplasia, short limb-hand type, is caused by homozygous mutation in the DDR2 gene (191311) on chromosome 1q23.


Clinical Features

Borochowitz et al. (1993) described 3 cases of a 'new' severe short-limb bone dysplasia, which they termed spondylometaepiphyseal dysplasia, short limb-hand type. The 3 unrelated patients were born into 2 separate Sephardic Jewish families and a Puerto Rican family. Abnormalities included small stature with short limbs and short hands, a short nose with broad nasal bridge and wide nostrils, a long philtrum, ocular hypertelorism, retro/micrognathia, and a narrow chest. Radiologic abnormalities included platyspondyly, short tubular bones with very abnormal metaphyses and epiphyses beyond early infancy, short ribs, and a typical evolution of bony changes. Histologic findings were described in 1 patient. The parents were related in 1 of the Sephardic Jewish families in which, in addition to the patient described, 2 other sibs, who did not survive infancy, were affected.

Langer et al. (1993) reported 8 additional cases of this short-limb dysplasia with a rather typical clinical appearance including similar facies and seemingly characteristic deformity of the anterior thorax and sternum. Because of abnormal premature calcification in cartilaginous structures, Langer et al. (1993) referred to the condition as the short limb-abnormal calcification type of SMED. Atlantoaxial instability resulting in cord damage and death occurred in 4 of the 8 patients of Langer et al. (1993). Seven of the 8 patients were Puerto Rican; of these, there was 1 pair of affected sibs and another family with 3 affected sibs. The stippled calcification might suggest chondrodysplasia calcificans punctata but the other features serve to differentiate the condition. Calcification of the falx cerebri was noted in 1 patient at age 20 months. Calcification of costochondral cartilages is presumably responsible for the unusual and perhaps characteristic deformity of the anterior chest and sternum. Parental consanguinity was established in 1 of the Puerto Rican families reported by Langer et al. (1993).

Al-Gazali et al. (1996) described 2 affected sibs (a girl and a boy), born of a consanguineous Egyptian couple. Both children showed extensive calcification of epiphyses, ligaments, and chondral tissues. Intellectual development of both patients was normal. Ali et al. (2010) reported that both of the sibs had died, one at age 13 years from respiratory complications and the other suddenly at age 8 years from cord compression.

Bargal et al. (2009) reported 8 patients with SMED-SL, bringing the total number of reported patients to 20. They confirmed that this dysplasia is progressive with respect to the severity of the bowing of the lower limbs and to the appearance of the calcifications.

Smithson et al. (2009) described a 7-year-old boy from Pakistan with clinical and radiologic features of a relatively mild case of SMED-SL.

Dias et al. (2009) described 2 female sibs with clinical and radiographic features consistent with SMED-SL, who died suddenly in infancy from cord compression because of foramen magnum stenosis. Dias et al. (2009) suggested that the characteristic shape of the metacarpals and phalanges seen at a young age in SMED-SL provide an important diagnostic handle so that appropriate management may be instituted early.


Inheritance

Consanguinity in 13 of 17 reported families segregating SMED-SL and the occurrence of the disorder in sibs confirms autosomal recessive inheritance (Bargal et al., 2009).


Mapping

Using a homozygosity mapping strategy to study 3 unrelated Arab Muslim patients with SMED-SL, Bargal et al. (2009) identified an identical homozygous 2.4-Mb region on chromosome 1q23 between markers rs12059277 and rs10799915. The discoidin domain receptor-2 gene (DDR2; 191311) had been mapped within this region and was considered a strong candidate because of the similarity between the phenotype of the Ddr2 knockout mouse and that of SMED-SL patients.


Molecular Genetics

In 8 patients from 7 different consanguineous families with SMED-SL, Bargal et al. (2009) identified missense mutations in exon 17 of the DDR2 gene: 6 Arab Muslims from the Jerusalem area were homozygous for an R752C substitution (191311.0001), and 1 Algerian and 1 Pakistani patient were homozygous for an I726R (191311.0002) and a T713I (191311.0003) substitution, respectively. Bargal et al. (2009) also identified a splice site mutation (191311.0004) in the DDR2 gene, which resulted in the skipping of exon 17, in one of the consanguineous Jewish families originally reported by Borochowitz et al. (1993).

Ali et al. (2010) reported a novel DDR2 missense mutation (E113K; 191311.0005) that caused SMED-SL in 2 sibs of Pakistani origin. They also detected the R752C mutation (191311.0001), identified by Bargal et al. (2009), in the 2 Egyptian sibs described by Al-Gazali et al. (1996).


REFERENCES

  1. Al-Gazali, L. I., Bakalinova, D., Sztriha, L. Spondylo-meta-epiphyseal dysplasia, short limb, abnormal calcification type. Clin. Dysmorph. 5: 197-206, 1996. [PubMed: 8818447, related citations]

  2. Ali, B. R., Xu, H., Akawi, N. A., John, A., Karuvantevida, N. S., Langer, R., Al-Gazali, L., Leitinger, B. Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients. Hum. Molec. Genet. 19: 2239-2250, 2010. [PubMed: 20223752, images, related citations] [Full Text]

  3. Bargal, R., Cormier-Daire, V., Ben-Neriah, Z., Le Merrer, M., Sosna, J., Melki, J., Zangen, D. H., Smithson, S. F., Borochowitz, Z., Belostotsky, R., Raas-Rothschild, A. Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications. Am. J. Hum. Genet. 84: 80-84, 2009. [PubMed: 19110212, images, related citations] [Full Text]

  4. Borochowitz, Z., Langer, L. O., Jr., Gruber, H. E., Lachman, R., Katznelson, M. B.-M., Rimoin, D. L. Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand type: a congenital familial skeletal dysplasia with distinctive features and histopathology. Am. J. Med. Genet. 45: 320-326, 1993. [PubMed: 8434618, related citations] [Full Text]

  5. Dias, C., Cairns, R., Patel, M. S. Sudden death in spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type. Clin. Dysmorph. 18: 25-29, 2009. [PubMed: 19050401, related citations] [Full Text]

  6. Langer, L. O., Jr., Wolfson, B. J., Scott, C. I., Jr., Reid, C. S., Schidlow, D. V., Millar, E. A., Borns, P. F., Lubicky, J. P., Carpenter, B. L. M. Further delineation of spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type, with emphasis on diagnostic features. Am. J. Med. Genet. 45: 488-500, 1993. [PubMed: 8465857, related citations] [Full Text]

  7. Smithson, S. F., Grier, D., Hall, C. M. Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type. Clin. Dysmorph. 18: 31-35, 2009. [PubMed: 19050402, related citations] [Full Text]


George E. Tiller - updated : 08/22/2013
Nara Sobreira - updated : 9/21/2009
Nara Sobreira - updated : 7/6/2009
Iosif W. Lurie - updated : 8/13/1996
Creation Date:
Victor A. McKusick : 2/19/1993
carol : 08/06/2020
alopez : 09/19/2016
alopez : 08/22/2013
terry : 3/21/2012
carol : 9/23/2009
terry : 9/21/2009
carol : 7/6/2009
carol : 7/6/2009
carol : 8/13/1996
terry : 4/27/1994
mimadm : 3/12/1994
carol : 3/1/1993
carol : 2/25/1993
carol : 2/19/1993

# 271665

SPONDYLOMETAEPIPHYSEAL DYSPLASIA, SHORT LIMB-HAND TYPE


Alternative titles; symbols

SMED-SL
SMED, SHORT LIMB-HAND TYPE
SMED, TYPE II
SPONDYLOMETAEPIPHYSEAL DYSPLASIA, SHORT LIMB-ABNORMAL CALCIFICATION TYPE
SMED, SHORT LIMB-ABNORMAL CALCIFICATION TYPE
SMED-SL/AC


ORPHA: 93358;   DO: 0112196;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
1q23.3 Spondylometaepiphyseal dysplasia, short limb-hand type 271665 Autosomal recessive 3 DDR2 191311

TEXT

A number sign (#) is used with this entry because of evidence that spondylometaepiphyseal dysplasia, short limb-hand type, is caused by homozygous mutation in the DDR2 gene (191311) on chromosome 1q23.


Clinical Features

Borochowitz et al. (1993) described 3 cases of a 'new' severe short-limb bone dysplasia, which they termed spondylometaepiphyseal dysplasia, short limb-hand type. The 3 unrelated patients were born into 2 separate Sephardic Jewish families and a Puerto Rican family. Abnormalities included small stature with short limbs and short hands, a short nose with broad nasal bridge and wide nostrils, a long philtrum, ocular hypertelorism, retro/micrognathia, and a narrow chest. Radiologic abnormalities included platyspondyly, short tubular bones with very abnormal metaphyses and epiphyses beyond early infancy, short ribs, and a typical evolution of bony changes. Histologic findings were described in 1 patient. The parents were related in 1 of the Sephardic Jewish families in which, in addition to the patient described, 2 other sibs, who did not survive infancy, were affected.

Langer et al. (1993) reported 8 additional cases of this short-limb dysplasia with a rather typical clinical appearance including similar facies and seemingly characteristic deformity of the anterior thorax and sternum. Because of abnormal premature calcification in cartilaginous structures, Langer et al. (1993) referred to the condition as the short limb-abnormal calcification type of SMED. Atlantoaxial instability resulting in cord damage and death occurred in 4 of the 8 patients of Langer et al. (1993). Seven of the 8 patients were Puerto Rican; of these, there was 1 pair of affected sibs and another family with 3 affected sibs. The stippled calcification might suggest chondrodysplasia calcificans punctata but the other features serve to differentiate the condition. Calcification of the falx cerebri was noted in 1 patient at age 20 months. Calcification of costochondral cartilages is presumably responsible for the unusual and perhaps characteristic deformity of the anterior chest and sternum. Parental consanguinity was established in 1 of the Puerto Rican families reported by Langer et al. (1993).

Al-Gazali et al. (1996) described 2 affected sibs (a girl and a boy), born of a consanguineous Egyptian couple. Both children showed extensive calcification of epiphyses, ligaments, and chondral tissues. Intellectual development of both patients was normal. Ali et al. (2010) reported that both of the sibs had died, one at age 13 years from respiratory complications and the other suddenly at age 8 years from cord compression.

Bargal et al. (2009) reported 8 patients with SMED-SL, bringing the total number of reported patients to 20. They confirmed that this dysplasia is progressive with respect to the severity of the bowing of the lower limbs and to the appearance of the calcifications.

Smithson et al. (2009) described a 7-year-old boy from Pakistan with clinical and radiologic features of a relatively mild case of SMED-SL.

Dias et al. (2009) described 2 female sibs with clinical and radiographic features consistent with SMED-SL, who died suddenly in infancy from cord compression because of foramen magnum stenosis. Dias et al. (2009) suggested that the characteristic shape of the metacarpals and phalanges seen at a young age in SMED-SL provide an important diagnostic handle so that appropriate management may be instituted early.


Inheritance

Consanguinity in 13 of 17 reported families segregating SMED-SL and the occurrence of the disorder in sibs confirms autosomal recessive inheritance (Bargal et al., 2009).


Mapping

Using a homozygosity mapping strategy to study 3 unrelated Arab Muslim patients with SMED-SL, Bargal et al. (2009) identified an identical homozygous 2.4-Mb region on chromosome 1q23 between markers rs12059277 and rs10799915. The discoidin domain receptor-2 gene (DDR2; 191311) had been mapped within this region and was considered a strong candidate because of the similarity between the phenotype of the Ddr2 knockout mouse and that of SMED-SL patients.


Molecular Genetics

In 8 patients from 7 different consanguineous families with SMED-SL, Bargal et al. (2009) identified missense mutations in exon 17 of the DDR2 gene: 6 Arab Muslims from the Jerusalem area were homozygous for an R752C substitution (191311.0001), and 1 Algerian and 1 Pakistani patient were homozygous for an I726R (191311.0002) and a T713I (191311.0003) substitution, respectively. Bargal et al. (2009) also identified a splice site mutation (191311.0004) in the DDR2 gene, which resulted in the skipping of exon 17, in one of the consanguineous Jewish families originally reported by Borochowitz et al. (1993).

Ali et al. (2010) reported a novel DDR2 missense mutation (E113K; 191311.0005) that caused SMED-SL in 2 sibs of Pakistani origin. They also detected the R752C mutation (191311.0001), identified by Bargal et al. (2009), in the 2 Egyptian sibs described by Al-Gazali et al. (1996).


REFERENCES

  1. Al-Gazali, L. I., Bakalinova, D., Sztriha, L. Spondylo-meta-epiphyseal dysplasia, short limb, abnormal calcification type. Clin. Dysmorph. 5: 197-206, 1996. [PubMed: 8818447]

  2. Ali, B. R., Xu, H., Akawi, N. A., John, A., Karuvantevida, N. S., Langer, R., Al-Gazali, L., Leitinger, B. Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients. Hum. Molec. Genet. 19: 2239-2250, 2010. [PubMed: 20223752] [Full Text: https://doi.org/10.1093/hmg/ddq103]

  3. Bargal, R., Cormier-Daire, V., Ben-Neriah, Z., Le Merrer, M., Sosna, J., Melki, J., Zangen, D. H., Smithson, S. F., Borochowitz, Z., Belostotsky, R., Raas-Rothschild, A. Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications. Am. J. Hum. Genet. 84: 80-84, 2009. [PubMed: 19110212] [Full Text: https://doi.org/10.1016/j.ajhg.2008.12.004]

  4. Borochowitz, Z., Langer, L. O., Jr., Gruber, H. E., Lachman, R., Katznelson, M. B.-M., Rimoin, D. L. Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand type: a congenital familial skeletal dysplasia with distinctive features and histopathology. Am. J. Med. Genet. 45: 320-326, 1993. [PubMed: 8434618] [Full Text: https://doi.org/10.1002/ajmg.1320450308]

  5. Dias, C., Cairns, R., Patel, M. S. Sudden death in spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type. Clin. Dysmorph. 18: 25-29, 2009. [PubMed: 19050401] [Full Text: https://doi.org/10.1097/MCD.0b013e3283186907]

  6. Langer, L. O., Jr., Wolfson, B. J., Scott, C. I., Jr., Reid, C. S., Schidlow, D. V., Millar, E. A., Borns, P. F., Lubicky, J. P., Carpenter, B. L. M. Further delineation of spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type, with emphasis on diagnostic features. Am. J. Med. Genet. 45: 488-500, 1993. [PubMed: 8465857] [Full Text: https://doi.org/10.1002/ajmg.1320450419]

  7. Smithson, S. F., Grier, D., Hall, C. M. Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type. Clin. Dysmorph. 18: 31-35, 2009. [PubMed: 19050402] [Full Text: https://doi.org/10.1097/MCD.0b013e3283189762]


Contributors:
George E. Tiller - updated : 08/22/2013
Nara Sobreira - updated : 9/21/2009
Nara Sobreira - updated : 7/6/2009
Iosif W. Lurie - updated : 8/13/1996

Creation Date:
Victor A. McKusick : 2/19/1993

Edit History:
carol : 08/06/2020
alopez : 09/19/2016
alopez : 08/22/2013
terry : 3/21/2012
carol : 9/23/2009
terry : 9/21/2009
carol : 7/6/2009
carol : 7/6/2009
carol : 8/13/1996
terry : 4/27/1994
mimadm : 3/12/1994
carol : 3/1/1993
carol : 2/25/1993
carol : 2/19/1993