DIAPHYSEAL DYSPLASIA
 

DEFINITION:

A congenital bone dysplasia characterized by progressive bone formation within the diaphyseal region of long bones and cranial hyperostosis.
EPIDEMIOLOGY:

* incidence: rare
* age of onset:
o midchildhood
* risk factors:
o familial - autosomal dominant with variable penetrance
+ many de novo mutations resulting in sporadic cases
+ chrom. #: 19q13.1-19q13.3
+ gene: beta 1-latency-associated peptide (beta 1-LAP)
o M = F

PATHOGENESIS:
1. Background

* disease orginially described by E.A. Cockayne then further characterized by M. Camurati and G. Engelman all in the 1920's
* also called by the following names:
o Progressive Diaphyseal Dysplasia
o Camurati-Engelmann Syndrome
o Engelmann Syndrome
o Ribbing Disease
o Osteopathia Hyperostotica Scleroticans Multiplex Infantilis

2. Genetic Defect

* hypothesized that a mutation in the beta 1-LAP gene -> enhanced activation of Transforming Growth Factor (TGF)-beta 1 -> suppression of fibroblast growth + proliferation of osteoblasts -> enhanced bone formation -> hyperostosis and sclerosis of the diaphysis of long bones (Saito, T. et al., J. Biol. Chem. 276(15): 11469 (2001).)
* 3 different missense mutations have been identified in the beta 1-LAP gene (Kinoshita et al., Nature Genetics 26: 19-20 (2000).)

CLINICAL FEATURES:
1. Musculoskeletal Manifestations

* a wide variance in phenotypic expression (i.e., asymptomatic to severely handicapped)
* muscular pain
* muscular weakness (especially around the pelvic girdle)
* muscular wasting
* wide-based waddling gait
* varus or valgus deformities of the knees
* flexion deformities of the elbows, knees, and/or hips
* scoliosis and/or increased lumbar lordosis
* thin body habitus
* flat feet

2. Complications

* fractures of long bones
* cranial nerve compression (i.e., optic nerve)
* raised intracranial pressure

3. Others

* delayed puberty
* feeding problems

INVESTIGATIONS:
1. Skeletal X-Rays
1. Long Bones

* most evident in the femur and tibia but the long bones of the upper limbs can also be affected
* progressive diaphyseal broadening with thickened cortices
* irregular cortical thickening and sclerosis
* irregular endosteal and periosteal opposition
* narrowing of the medullary canal
* the metaphyseal and epiphyseal regions tend to be spared
* Erlenmeyer flask defects

2. Skull

* cranial hyperostosis particularly at the base of the skull
* focal sclerosis at the base of the skull

3. Others

* wide, poorly modeled metacarpals and phalanges
* vertebral sclerosis confined to the posterior part of the vertebral bodies and arches (on CT)

2. Molecular Characterization

* identification of a mutation in the beta 1-LAP gene

MANAGEMENT:
1. Supportive

* multidisciplinary approach:
o Paediatrics, Rheumatology, Orthopedics, Physiotherapy

2. Medical

* steroid therapy (refer to a Rheumatologist for management)
* ? Pamidronate

3. Prognosis

* normal life span and intelligence
* tends to present in midchildhood, reaches an advanced stage in adolescence and remains static or advances slowly in adulthood

REFERENCES:
1. Buyse, Mary-Louise. Birth Defects Encyclopedia (2nd Edition). p. 531-532 (1994).
2. Jones, K.L., Smith's Recognizable Patterns of Human Malformation Syndromes (5th Edition). p. 480-481.
3. Ghadami, M. et al., Genetic Mapping of the Camurati-Engelmann Disease Locus to Chromosome 19q13.1-q13.3. Am. J. Hum. Genet. 66(1): 143 (2000).