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Spondylometaphyseal dysplasia, Kozlowski type(SMDK)

MedGen UID:
82698
Concept ID:
C0265280
Congenital Abnormality; Disease or Syndrome
Synonyms: Dysmorphism arthrogryposis skeletal maturation advanced; Jequier-Kozlowski syndrome; Skeletal dysplasia Jequier-Kozlowski type; SMD Kozlowski type; SMDK
SNOMED CT: Kozlowski spondylometaphyseal dysplasia (111304003); Spondylometaphyseal dysplasia Kozlowski type (111304003)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): TRPV4 (12q24.11)
 
Monarch Initiative: MONDO:0008477
OMIM®: 184252
Orphanet: ORPHA93314

Definition

The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias. [from GeneReviews]

Additional description

From OMIM
SMD Kozlowski (SMDK) is an autosomal dominant disorder characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles (Krakow et al., 2009).  http://www.omim.org/entry/184252

Clinical features

From HPO
Irregular acetabular roof
MedGen UID:
331872
Concept ID:
C1834975
Finding
Flat acetabular roof
MedGen UID:
373340
Concept ID:
C1837485
Finding
Flattening of the superior part of the acetabulum, which is a cup-shaped cavity at the base of the hipbone into which the ball-shaped head of the femur fits. The acetabular roof thereby appears horizontal rather than arched, as it normally does.
Delayed ossification of carpal bones
MedGen UID:
374771
Concept ID:
C1841684
Finding
Ossification of carpal bones occurs later than age-adjusted norms.
Carpal bone hypoplasia
MedGen UID:
355049
Concept ID:
C1863749
Finding
Underdevelopment of one or more carpal bones.
Dumbbell-shaped femur
MedGen UID:
870603
Concept ID:
C4025052
Anatomical Abnormality
The femur is shortened and displays flaring (widening) of the metaphyses.
Abnormal foot morphology
MedGen UID:
1762829
Concept ID:
C5399834
Anatomical Abnormality
An abnormality of the skeleton of foot.
Coxa vara
MedGen UID:
1790477
Concept ID:
C5551440
Anatomical Abnormality
Coxa vara includes all forms of decrease of the femoral neck shaft angle (the angle between the neck and the shaft of the femur) to less than 120 degrees.
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Pectus carinatum
MedGen UID:
57643
Concept ID:
C0158731
Finding
A deformity of the chest caused by overgrowth of the ribs and characterized by protrusion of the sternum.
Elbow flexion contracture
MedGen UID:
98367
Concept ID:
C0409338
Acquired Abnormality
An elbow contracture that limits the ability of the elbow joint to be extended (straightened), meaning that the elbow is fixed in an flexed (bent) position.
Delayed skeletal maturation
MedGen UID:
108148
Concept ID:
C0541764
Finding
A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Narrow greater sciatic notch
MedGen UID:
154353
Concept ID:
C0566888
Finding
A narrowing of the sacrosciatic notch, i.e., the deep indentation in the posterior border of the hip bone at the point of union of the ilium and ischium.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Platyspondyly
MedGen UID:
335010
Concept ID:
C1844704
Finding
A flattened vertebral body shape with reduced distance between the vertebral endplates.
Disproportionate short-trunk short stature
MedGen UID:
337580
Concept ID:
C1846435
Finding
A type of disproportionate short stature characterized by a short trunk but a average-sized limbs.
Odontoid hypoplasia
MedGen UID:
339524
Concept ID:
C1846439
Finding
The odontoid process, or dens, is a bony projection from the axis (C2) upward into the ring of the atlas (C1) at the top of the spine. During embryogenesis, the body of the odontoid derives from the centrum of the atlas and separates from the atlas, fusing with the superior portion of the axis. If the odontoid is hypoplastic or absent, the attachments for the apical and alar ligaments are missing, allowing for excessive rotation of the atlas, craniocervical instability, and possibly cord compression (summary by Stevens et al., 2009).
Flared metaphysis
MedGen UID:
337976
Concept ID:
C1850135
Finding
The presence of a splayed (i.e.,flared) metaphyseal segment of one or more long bones.
Enlarged joints
MedGen UID:
347068
Concept ID:
C1859111
Finding
Increase in size of one or more joints.
Cone-shaped epiphyses of the phalanges of the hand
MedGen UID:
347156
Concept ID:
C1859480
Finding
A cone-shaped appearance of the epiphyses of the fingers of the hand, producing a 'ball-in-a-socket' appearance. The related entity 'angel-shaped' epiphysis refers to a pronounced cone-shaped epiphysis in combination with a pseudoepiphysis at the distal end of a phalanx.
Flared iliac wing
MedGen UID:
356097
Concept ID:
C1865841
Finding
Widening of the ilium ala, that is of the wing of the ilium, combined with external rotation, leading to a flared appearance of the iliac wing.
Irregular, rachitic-like metaphyses
MedGen UID:
401062
Concept ID:
C1866700
Finding
Halberd-shaped pelvis
MedGen UID:
478749
Concept ID:
C3277119
Finding
An anomalous radiographic appearance of the developing pelvis, in which the greater ischiadic noth (incisura ischiadica major) is shallow and the pelvis takes on the appearance said to resemble a halberd (a weapon especially of the 15th and 16th centuries consisting typically of a battle-ax and pike mounted on a handle).
Irregular capital femoral epiphysis
MedGen UID:
866530
Concept ID:
C4020825
Anatomical Abnormality
Irregular surface of the normally relatively smooth capital femoral epiphysis.
Abnormal rib cage morphology
MedGen UID:
871275
Concept ID:
C4025763
Anatomical Abnormality
A morphological anomaly of the rib cage.
Spondylometaphyseal dysplasia
MedGen UID:
1674850
Concept ID:
C4759767
Disease or Syndrome
A heterogeneous group of disorders associated with walking and growth disturbances that become evident during the second year of life. Characteristics are platyspondyly (flattened vertebrae) and marked hip and knee metaphyseal lesions. The different forms of spondylometaphyseal dysplasia are distinguished by the localisation and severity of involvement of the affected metaphyses.
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.

Recent clinical studies

Etiology

Ürel-Demir G, Şimşek-Kiper PÖ, Öncel İ, Utine GE, Haliloğlu G, Boduroğlu K
Eur J Paediatr Neurol 2021 May;32:46-55. Epub 2021 Mar 16 doi: 10.1016/j.ejpn.2021.03.011. PMID: 33774370
Nishimura G, Lausch E, Savarirayan R, Shiba M, Spranger J, Zabel B, Ikegawa S, Superti-Furga A, Unger S
Am J Med Genet C Semin Med Genet 2012 Aug 15;160C(3):190-204. Epub 2012 Jul 12 doi: 10.1002/ajmg.c.31335. PMID: 22791502
Unger S, Lausch E, Stanzial F, Gillessen-Kaesbach G, Stefanova I, Di Stefano CM, Bertini E, Dionisi-Vici C, Nilius B, Zabel B, Superti-Furga A
Am J Med Genet A 2011 Nov;155A(11):2860-4. Epub 2011 Sep 30 doi: 10.1002/ajmg.a.34268. PMID: 21964829
Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, Okenfuss EB, Janssens A, Voets T, Rimoin DL, Lachman RS, Nilius B, Cohn DH
Am J Hum Genet 2009 Mar;84(3):307-15. Epub 2009 Feb 19 doi: 10.1016/j.ajhg.2009.01.021. PMID: 19232556Free PMC Article
Borochowitz Z, Berant M, Kristal H
Skeletal Radiol 1988;17(3):181-6. doi: 10.1007/BF00351004. PMID: 3375844

Diagnosis

Ürel-Demir G, Şimşek-Kiper PÖ, Öncel İ, Utine GE, Haliloğlu G, Boduroğlu K
Eur J Paediatr Neurol 2021 May;32:46-55. Epub 2021 Mar 16 doi: 10.1016/j.ejpn.2021.03.011. PMID: 33774370
Tchio Tchoumba MA, Bai Y, Jin R, Yu X, Male M
Orthop Surg 2020 Feb;12(1):333-336. Epub 2019 Dec 6 doi: 10.1111/os.12546. PMID: 31808622Free PMC Article
Bieganski T, Beighton P, Lukaszewski M, Bik K, Kuszel L, Wasilewska E, Kozlowski K, Czarny-Ratajczak M
Eur J Med Genet 2017 Oct;60(10):509-516. Epub 2017 Jul 4 doi: 10.1016/j.ejmg.2017.07.004. PMID: 28687525Free PMC Article
Dai J, Kim OH, Cho TJ, Schmidt-Rimpler M, Tonoki H, Takikawa K, Haga N, Miyoshi K, Kitoh H, Yoo WJ, Choi IH, Song HR, Jin DK, Kim HT, Kamasaki H, Bianchi P, Grigelioniene G, Nampoothiri S, Minagawa M, Miyagawa SI, Fukao T, Marcelis C, Jansweijer MC, Hennekam RC, Bedeschi F, Mustonen A, Jiang Q, Ohashi H, Furuichi T, Unger S, Zabel B, Lausch E, Superti-Furga A, Nishimura G, Ikegawa S
J Med Genet 2010 Oct;47(10):704-9. Epub 2010 Jun 24 doi: 10.1136/jmg.2009.075358. PMID: 20577006
Guzman CM, Aaron GR
Pediatr Dent 1993 Jan-Feb;15(1):49-52. PMID: 8233993

Therapy

Dai J, Kim OH, Cho TJ, Schmidt-Rimpler M, Tonoki H, Takikawa K, Haga N, Miyoshi K, Kitoh H, Yoo WJ, Choi IH, Song HR, Jin DK, Kim HT, Kamasaki H, Bianchi P, Grigelioniene G, Nampoothiri S, Minagawa M, Miyagawa SI, Fukao T, Marcelis C, Jansweijer MC, Hennekam RC, Bedeschi F, Mustonen A, Jiang Q, Ohashi H, Furuichi T, Unger S, Zabel B, Lausch E, Superti-Furga A, Nishimura G, Ikegawa S
J Med Genet 2010 Oct;47(10):704-9. Epub 2010 Jun 24 doi: 10.1136/jmg.2009.075358. PMID: 20577006

Prognosis

Cho TJ, Matsumoto K, Fano V, Dai J, Kim OH, Chae JH, Yoo WJ, Tanaka Y, Matsui Y, Takigami I, Monges S, Zabel B, Shimizu K, Nishimura G, Lausch E, Ikegawa S
Am J Med Genet A 2012 Apr;158A(4):795-802. Epub 2012 Mar 14 doi: 10.1002/ajmg.a.35268. PMID: 22419508
Unger S, Lausch E, Stanzial F, Gillessen-Kaesbach G, Stefanova I, Di Stefano CM, Bertini E, Dionisi-Vici C, Nilius B, Zabel B, Superti-Furga A
Am J Med Genet A 2011 Nov;155A(11):2860-4. Epub 2011 Sep 30 doi: 10.1002/ajmg.a.34268. PMID: 21964829
Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, Okenfuss EB, Janssens A, Voets T, Rimoin DL, Lachman RS, Nilius B, Cohn DH
Am J Hum Genet 2009 Mar;84(3):307-15. Epub 2009 Feb 19 doi: 10.1016/j.ajhg.2009.01.021. PMID: 19232556Free PMC Article

Clinical prediction guides

Cho TJ, Matsumoto K, Fano V, Dai J, Kim OH, Chae JH, Yoo WJ, Tanaka Y, Matsui Y, Takigami I, Monges S, Zabel B, Shimizu K, Nishimura G, Lausch E, Ikegawa S
Am J Med Genet A 2012 Apr;158A(4):795-802. Epub 2012 Mar 14 doi: 10.1002/ajmg.a.35268. PMID: 22419508
Unger S, Lausch E, Stanzial F, Gillessen-Kaesbach G, Stefanova I, Di Stefano CM, Bertini E, Dionisi-Vici C, Nilius B, Zabel B, Superti-Furga A
Am J Med Genet A 2011 Nov;155A(11):2860-4. Epub 2011 Sep 30 doi: 10.1002/ajmg.a.34268. PMID: 21964829
Dai J, Kim OH, Cho TJ, Schmidt-Rimpler M, Tonoki H, Takikawa K, Haga N, Miyoshi K, Kitoh H, Yoo WJ, Choi IH, Song HR, Jin DK, Kim HT, Kamasaki H, Bianchi P, Grigelioniene G, Nampoothiri S, Minagawa M, Miyagawa SI, Fukao T, Marcelis C, Jansweijer MC, Hennekam RC, Bedeschi F, Mustonen A, Jiang Q, Ohashi H, Furuichi T, Unger S, Zabel B, Lausch E, Superti-Furga A, Nishimura G, Ikegawa S
J Med Genet 2010 Oct;47(10):704-9. Epub 2010 Jun 24 doi: 10.1136/jmg.2009.075358. PMID: 20577006
Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, Okenfuss EB, Janssens A, Voets T, Rimoin DL, Lachman RS, Nilius B, Cohn DH
Am J Hum Genet 2009 Mar;84(3):307-15. Epub 2009 Feb 19 doi: 10.1016/j.ajhg.2009.01.021. PMID: 19232556Free PMC Article

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