Mohamed LAHKIM, PHC MD PhD std

1.
ECR – VIENNE 2016
Radiological phenotype - genotype correlations of
constitutional bone diseases (CBD) involving the
parathyroid hormone (PTH) and its signaling pathways
M. Lahkim*, A. Durand*, V. Merzoug*, A Linglart**, C. Adamsbaum*
•Pediatric Radiology ** Pediatric Endocrinology departments
•Bicêtre University Hospital, Paris Sud university
France

2. Introduction
• Genetic mutation of PTH / PTHrP receptor
different constitutional bone diseases:
acrodysostosis hypoparathyroidism
• Many descriptions of each disease but no study of
genotype/phenotype
• Objectives: To specify radiological semiology of
these diseases in order to refine their diagnosis and
to target the genetic research

3. Patients and methods
Retrospective study (1994 -2015) conducted in pediatric
radiology and endocrinology departments - Bicetre Hospital
(Reference Center of phospho-calcic bone diseases)
Inclusion criteria
▪ Short stature by genetic defect of PTH/PTH rp
receptor
▪ Age ≤ 18 years old at diagnosis
Control population
▪ 60 children (x males, x females ≤ 16 years old)
▪ Trauma or fever
▪ 180 normal radiographs of hands, long bones,
pelvis and vertebral column
Methods: Qualitative and semi-quantitative criteria’s grid

4. 36 patients / 7 CBD
• PHP1A (15 cases): loss of Gs-α function (mother).
• PHP1B (5 cases): default of Gs-α expression due to
methylation default
• Acrodysostosis (6 cases): inactivating mutation of PKAR1
• Hypoparathyroidism (4 cases): AIRE mutation
• Pseudo-PHP (4 cases): loss of Gs-α function (father)
• Brachydactyly type E(1 case): PTHLH mutation
• Metaphyseal acroskyphodysplasia (1 case): PDE4D
mutation

5. • Brachymetacarpia, brachyphalangia and brachymetatarsia
= Shortening of the metacarpals, metatarsals and phalanges
- Length of long axes ratio (M4/ M2 - M4/ M3…..)
• Coned epiphysis
• Subperiosteal resorption & mineralization
• Exostosis and ectopic ossifications
• Morphology of spine, pelvic bone and femoral necks
• Diaphyso-metaphyseal modelling abnormalities
Studied Items

6. • Brachymetacarpia, brachyphalangia and brachymetatarsia
= Shortening of the metacarpals, metatarsals and phalanges
- Length of long axes ratio (M4/ M2 - M4/ M3…..)
• Coned epiphysis
• Subperiosteal resorption & mineralization
• Exostosis and ectopic ossifications
• Morphology of spine, pelvic bone and femoral necks
• Diaphyso-metaphyseal modelling abnormalities
Studied Items
Subjective analysis
=
Gold standard

7. - Brachymetacarpia, brachymetatarsia, brachyphalangia
Constant in acrodysostosis, PHP1A, and pseudo-PHP
- Narrow lumbar canal: constant but in hypoparathyroidism
- Shortening of long bones: PHP1A and MASD
- Short femoral neck: PHP1A and brachydactyly type E
- Ectopic ossification and exostoses: PHP1A and pseudo-PHP
Results
Radiological phenotype by item

8. - Brachymetacarpia, brachymetatarsia, brachyphalangia
Constant in acrodysostosis, PHP1A, and pseudo-PHP
- Narrow lumbar canal: constant but in hypoparathyroidism
- Shortening of long bones: PHP1A and MASD
- Short femoral neck: PHP1A and brachydactyly type E
- Ectopic ossification and exostoses: PHP1A and pseudo-PHP
Results
Radiological phenotype by item

9. - Acrodysostosis: severe, bilateral & diffuse lesions
- Metaphyseal acroskyphodysplasia
* Severe and disseminated lesions
* Short femoral necks & Knee deformity
- PHP1A and PPHP: same signs but less severe
- PHP1B: Subtle anomalies
- Isolated hypoparathyroidism: bone hyperdensity
Results
Radiological phenotype by decreasing severity

10. Strengths and limits
Strengths
•Radiological phenotype - genotype correlations
synopsis
• Rather large series knowing the rarity of CBD, 36 vs
20 PHP (St. Vincent de Paul Hospital Series)
•First proposal of simple semi-quantitative methods
Limits
Young age of the patients

11. - Poznanski AK et al , The pattern of shortening of the bones
of the hand in PHP and PPHP: a comparison with
brachydactyly E, and acrodysostosis. Radiology 1977
Temtamy SA, Aglan M S. Brachydactyly. Orphanet J Rare
Dis 2008
Linglart A et al. Recurrent PRKAR1A mutation in
arcodysostosis with hormone resistance. N Engl J Med 2011
Comparison of results with a poor literature
Confirms radiological phenotype

12. - A fine radiological analysis can guide the diagnosis and
target the genetic research
- Standard radiographs of the hands = key point +++
- Results limited by the number of patients (rarity of these
CBD), but we continue this work on a larger cohort with a
higher percentage of patients in first infancy
Conclusion

13. mohamedlahkim@ymail.com
ECR 2016