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Orthopaedic conditions in RAS/Mapk family disorders
Kent Reinker, MD
Clinical Professor
U. Texas, San Antonio
What’s to be covered?
• Diagnosis• Lower Extremity• Upper Extremity• Spine• Generalized
We will draw heavily from
• Orthopaedic Conditions in Ras/MAPK Related Disorders, Reinker, Stevenson, Tsung, J Pediatr Orthop. 2011:599-605.
• Costello syndrome: orthopaedic manifestations and functional health, Yassir, Grottkau, Goldberg. J Pediatr Orthop. 2003 Jan-Feb;23(1):94-8
Diagnosis
• RAS/MAPK disorders overlap– Phenotypic overlap
• Growth delay• Hypotonia• Cardiac Anomaly• Characteristic facies
Diagnosis• RAS/MAPK disorders overlap
– Genotype overlap• Noonan Genotype
– PTPN, SOS1, KRAS, NRAS, RAF1, BRAF, MEK1, SHOC2, CBL, Unknown
• CFC Genotype– BRAF, MEK1, MEK2, KRAS, Unknown
• Costello Genotype– HRAS, Unknown
• Leopard Genotype– PTPN, RAF1
Costello Syndrome – Goldberg, JPO 23:94-8,2003
• 18 Patients– 16 Short, broad hyperextensible digit
• Wrists & elbows flexed to 90 degrees• 10 Decreased elbow ROM
– 13 Tight heel cords– 5 Vertical talus– 7 Planovalgus– 6 Overriding 2nd toes– 4 Metatarsus adductus
Costello Syndrome-Goldberg
• 3 Plantar flexed great toe• 3 Hip subluxations• 3 Kyphosis• 3 Scoliosis• 1 Radial head subluxation• 1 Pectus excavatum
Methods
• We examined patients at the last combined meeting of the Costello, CFC, and Noonan Societies and combined these with a number of patients previously known by the authors
ResultsTotal Noonan CFC Costello Goldberg
Patient # 49 19 26 3 18
Pes planus 24 5 (26%) 18 (69%) 1 (33%) 7 (39%)
Hypotonia 21 6 (31.5% 14 (54%) 1 (33%) 0
Scoliosis 18 8 (42%) 9 (35%) 1 (33%) 3 (17%)
Poor hand use 15 3 (16%) 11 (42%) 1 (33%) 16* (89%)
Hypertonia 11 2 (10.5%) 9 (35%) 0 0
Hip dysplasia 8 2 (10.5%) 6 (23%) 0 3 (17%)
Leg pains 8 5 (26%) 2 (8%) 0 0
Elbow contracture 8 2 (10.5%) 5 (19%) 1 (33%) 10 (56%)
Poor shoulder use 7 1 (5%) 6 (23%) 0 0
Knee contracture 7 0 (0%) 6 (23%) 1 (33%) 0
ResultsNoonan CFC Costello Goldberg
Patients number 19 26 3 18
Back pain 5 (26%) 0 (0%) 1 (33%) 0
Kyphosis 1 (5%) 4 (15%) 1 (33%) 3 (17%)
Pes cavus 4 (21%) 2 (8%) 0 (0%) 0
Fem Retroversion 1 (5%) 4 (15%) 1 (33%) 0
Shoulder/neck pain 4 (21%) 0 (0%) 1 (33%) 0
Hip contractures 2 (10.5%) 3 (11.5%) 0 (0%) 0
Pectus carinatum 2 (10.5% 2 (8%) 0 (0%) 0
Foot callouses 0 (0%) 4 (15%) 0 (0%) 0
Arnold-Chiari 3 (16%) 1 (4%) 0 (0%) 0
ResultsNoonan CFC Costello Goldberg
Patients number 19 26 3 18
Toe crowding 0 3 0 6
Hand contracture 0 0 2 0
Excess lordosis 1 1 0 0
Cervical stenosis 1 0 1 0
Foot/knee pain 2 0 1 0
Equinus 2 1 0 13 (72%)
Hallux valgus 0 2 0 0
Femoral anteversion 2 0 0 0
External tibial torsion 1 1 0 0
Internal tibial torsion 1 1 0 0
Club foot 0 0 1 0
Noonan CFC Costello
Patients number 19 26 3
Toe crowding 0 3 0
Hand contracture 0 0 2
Excess lordosis 1 1 0
Cervical stenosis 1 0 1
Foot/knee pain 2 0 1
Equinus 2 1 0
Hallux valgus 0 2 0
Femoral anteversion 2 0 0
External tibial torsion 1 1 0
Internal tibial torsion 1 1 0
Club foot 0 0 1
Results
ResultsNoonan CFC Costello
Patients number 19 26 3
Ataxia 1 1 0
Hydrocephalus 0 1 0
Torticollis 0 1 0
Cervical arthritis 1 0 0
Shoulder instability 1 0 0
Radial head subluxation 0 1 0
Short fingers 1 0 0
Wrist instability 0 1 0
Metatarsus varus 1 0 0
Short metatarsals 0 1 0
Hip labrum tear 1 0 0
ResultsTotal Noonan CFC Costello
Patient # 48 19 26 3
Pes planus 24 5 (26%) 18 (67%) 1 (33%)
Hypotonia 21 6 (31.5% 14 (52%) 1 (33%)
Scoliosis 18 8 (42%) 9 (33%) 1 (33%)
Poor hand use 15 3 (16%) 11 (41%) 1 (33%)
Hypertonia 11 2 (10.5%) 9 (33%) 0
Hip dysplasia 8 2 (10.5%) 6 (22%) 0
Leg pains 8 5 (26%) 2 (7%) 0
Elbow contracture 8 2 (10.5%) 5 (18.5%) 1 (33%)
Poor shoulder use 7 1 (5%) 6 (22%) 0
Knee contracture 7 0 (0%) 6 (22%) 1 (33%)
ResultsNoonan CFC Costello
Patients number 19 26 3
Back pain 5 (26%) 0 (0%) 1 (33%)
Kyphosis 1 (5%) 4 (15%) 1 (33%)
Pes cavus 4 (21%) 2 (8%) 0 (0%)
Fem Retroversion 1 (5%) 4 (15%) 1 (33%)
Shoulder/neck pain 4 (21%) 0 (0%) 1 (33%)
Hip contractures 2 (10.5%) 3 (11.5%) 0 (0%)
Pectus carinatum 2 (10.5% 2 (8%) 0 (0%)
Foot callosities 0 (0%) 4 (15%) 0 (0%)
Arnold-Chiari 3 (16%) 1 (4%) 0 (0%)
Syringomyelia 2 (10.5%) 0 (0%) 0%
New findings - Stevenson
• Decreased bone density is found in many patients with MAPK disorders– Metabolic bone disorder?– Disuse?
• Decreased grip strength is found in many patients with MAPK disorders– Myopathy?
Discussion
• Orthopaedic disorders in MAPK syndromes come in 3 flavors– Intrinsic to the disorder– Secondary to something else– Unrelated
• Probably the most common• MAPK disorders do not immunize patients
against other medical problems
Discussion
• Treatment of these disorders should take into account the syndrome– What’s the pathophysiology?
• Encephalopathy, myopathy, neuropathy?
– Is treatment likely to be complicated by other things going on?• Clotting disorders, spinal cord anomaly,
myopathy?
Discussion
• Few orthopaedic surgeons are likely to be familiar with these syndromes– You may need to help them
Discussion
• A few disorders of special interest– Spinal Cord
abnormalities• High number of
these in Noonan, CFC, and Costello
• Need to look for them with neurologic exam and MRI
Discussion• Disorders of special interest
– Pain syndromes in Noonan adults• Common & puzzling
– Neuropathy? – Spinal cord anomaly?– Bone turnover?
Disorders of special interest
• Scoliosis surgery– Workup should
include:• Spinal MRI• Neck x-rays• Clotting studies in
Noonan• Anesthesiologist
ready for hyperthermia
Disorders of special interest
• Hand anomaly in Costello– Unique– Treatment?
Thanks for your attention