Cleidocranial Dysplasia (Dysostosis)

Introduction

Skeletal dysplasia affecting bones formed by intramembranous ossification.
Epidemiology
- approximately 1 in 1,000,000 affected
Pathophysiology
- caused by defect in intramembranous ossification
  - leads to failure of formation of midline structures
    - characteristic feature is hypoplastic or absent clavicles
Genetics
- autosomal dominant
- RUNX2/CBFA1 mutation
  - transcription factor which regulates osteoblastic differentiation
Orthopaedic manifestations
- proportionate dwarfism
- clavicle dysplasia/aplasia
- wormian bones
- frontal bossing
- delayed fontanelle ossification
  - due to delay in closure of skull sutures
- coxa vara
- shortened middle phalanges of 3-5 fingers
- delayed ossification of pubis
- dental abnormalities
  - delayed eruption of permanent teeth

Presentation

Symptoms
- usually asymptomatic
Physical exam
- hypermobility of the shoulders
- frontal bossing
- hand deformities
  - examine middle phalanges for shortening
- delayed formation of permanent teeth
- abnormal range of motion at hips
  - if severe coxa vara may be present

Imaging

Radiographs
- recommended
  - AP chest
    - to identify clavicular dysmorphism
  - lateral skull
    - look for delayed closure of sutures
  - AP pelvis
    - look for coxa vara
    - look for failure of pubis to ossify

Treatment

Nonoperative
- observation
  - indications
    - clavicular hypoplasia
  - outcomes
    - most manifestations associated with this disease do not need intervention
Operative
- intertrochanteric osteotomy
  - indications
    - coxa vara with a neck shaft angle of less than 100 degrees

TAG

(OBQ07.241) A heterozygous loss of function mutation in which of the following genes would result in cleidocranial dysplasia? Topic

Review Topic

1. BMP-2
2. cAMP
3. c-fos
4. SOX-9
5. RUNX2

PREFERRED RESPONSE ▶

DISCUSSION: Cleidocranial dysplasia is a skeletal disorder with autosomal dominant inheritance. The clinical hallmarks of CCD are short stature, delayed closure of cranial fontanels and sutures, Wormian bones, frontal bossing, supernumerary and late erupting teeth, rudimentary or absent clavicles, wide pubic symphysis, and other skeletal anomalies. RUNX2, also known as Cbfa-1, is a transcription factor associated with osteoblast differentiation.

The reference by Khoshal et al reviews the orthopedic issues with campomelic dysplasia, which has improved life expectancy due to improvements in pulmonary treatment(s). There are several types of campomelic dysplasia; however, it is characterized by the presence of anteriorly bowed tibias with cutaneous dimpling, anterolaterally bowed femurs, thoracic kyphoscoliosis, hypoplastic scapulas, and absence or delayed ossification of thoracic pedicles.

The reference by Makitie et al reviews the Schmid type of metaphyseal chondrodysplasia, which is characterized by short stature, widened growth plates, and bowing of the long bones. It results from autosomal dominant mutations of COL10A1, the gene which encodes alpha1(X) chains of type X collagen.

Incorrect answers:
1: BMP-2 loss of function does not lead to cleidocranial dysplasia
2: overproduction of cAMP causes overexpression of c-fos, which regulates proliferation and differentiation of osteoblasts and osteoclasts, mutations in cAMP can lead to fibrous dysplasia
3: c-fos regulates proliferation and differentiation of osteoblasts and osteoclasts
4: campomelic dysplasia is caused by mutations in the SOX-9 gene

REFERENCES:

1. Khoshhal K, Letts RM. Orthopaedic manifestations of campomelic dysplasia. Clin Orthop Relat Res. 2002 Aug;(401):65-74. PMID:12151884. (Link to Abstract)

2. Mäkitie O, Susic M, Ward L, Barclay C, Glorieux FH, Cole WG. Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients. Am J Med Genet A. 2005 Sep 1;137A(3):241-8. PMID:16088909 (Link to Abstract)

Question Authors:

Ben Taylor MD, Jan Szatkowski MD, Michael Hughes MD,

Please Rate Educational Value!

1.0

Average 1.0 of 8 Ratings

TAG

(OBQ05.105) An 8-year-old boy presents with extreme shoulder motion and frontal bossing. A chest radiograph and AP pelvis radiograph are shown. What is the most likely diagnosis? Topic

Review Topic

FIGURES: A

1. Cleidocranial dysplasia
2. Renal osteodystrophy
3. Spondyloepiphyseal dysplasia tarda
4. Hypothyroidism
5. Bilateral slipped capital femoral epiphyses

PREFERRED RESPONSE ▶

DISCUSSION: The clinical presentation and radiographs are consistent with cleidocranial dysplasia, which is an autosomal dominant form of proportionate dwarfism. The radiographs in Figure A show clavicle dysmorphism. The pelvic radiographs in Figure B shows failure of the pubic symphysis to ossify and distinctive lateral notching of the capital femoral epiphysis. Cleidocranial dysplasia primarily involves bones formed by intramembranous ossification such as facial bones, cranium, and clavicles. The result is failure of formation of midline structures, such as the clavicle and pubic symphysis. Additional clinical features include growth retardation, craniofacial abnormalities, scoliosis, and developmental coxa vara or coxa valga. The reference by Richie et al discusses management options for hip conditions associated with cleidocranial dysplasia. Spondyloepiphyseal dysplasia tarda presents with coxa vara but generally with non-ossified capital femoral epiphyses. Although the radiographs might be confused with SCFE, clavicle dysmorphism is not associated with SCFE. Hypothyroidism can lead to bilateral SCFE or a bilateral LCP type picture, but again is not characterized by clavicle dysmorphism. Renal osteodystrophy would present with bones suggestive of osteomalacia and abnormalities of the epiphysis.

REFERENCES:

1. Sponseller PD in Lovell and Winter’s Pediatric Orthopaedics, ed.5. 2001, pp243-285

2. Richie MF, Johnston CE 2nd. Management of developmental coxa vara in cleidocranial dysostosis. Orthopedics. 1989 Jul;12(7):1001-4. PMID:2771815 (Link to Abstract)

Question Authors:

Guillem Lomas MD, Derek Moore, Eric Shirley MD,

Please Rate Educational Value!

3.0

Average 3.0 of 15 Ratings

Level of Evidence 5 and Other Journal Articles (includes Case Reports, Expert Opinions, Personal Observations, and Biomechanic Studies)

Khoshhal K, Letts RM. Orthopaedic manifestations of campomelic dysplasia. Clin Orthop Relat Res. 2002 Aug;(401):65-74. PMID:12151884. (Link to Abstract)
Mäkitie O, Susic M, Ward L, Barclay C, Glorieux FH, Cole WG. Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients. Am J Med Genet A. 2005 Sep 1;137A(3):241-8. PMID:16088909 (Link to Abstract)

Textbooks

Review of Orthopaedics, 6th Edition, Mark D. Miller MD, Stephen R. Thompson MBBS MEd FRCSC, Jennifer Hart MPAS PA-C ATC, an imprint of Elsevier, Philadelphia, Copyright 2012
AAOS Comprehensive Orthopaedic Review, Jay R. Leiberman. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2009
Orthopaedic Knowledge Update 10, John M Flyn. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2011
Hoppenfeld SP. Surgical Exposures in Orthopaedics: The Anatomic Approach. Lipponcott, Williams, and Wilkins, Philadelphia, PA, Copyright 2009
Orthopaedic In-training Examination (OITE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Self-Assessment Examination (SAE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012

Undefined

Richie MF, Johnston CE 2nd. Management of developmental coxa vara in cleidocranial dysostosis. Orthopedics. 1989 Jul;12(7):1001-4. PMID:2771815 (Link to Abstract)
Sponseller PD in Lovell and Winter’s Pediatric Orthopaedics, ed.5. 2001, pp243-285

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