1. Orthopaedic conditions in RAS/Mapk family disorders Kent Reinker, MD Clinical Professor U. Texas, San Antonio Kent Reinker, MD Clinical Professor U. Texas, San Antonio

2. What’s to be covered? DiagnosisDiagnosis Lower ExtremityLower Extremity Upper ExtremityUpper Extremity SpineSpine GeneralizedGeneralized DiagnosisDiagnosis Lower ExtremityLower Extremity Upper ExtremityUpper Extremity SpineSpine GeneralizedGeneralized

3. We will draw heavily from Orthopaedic Conditions in Ras/MAPK Related Disorders, Reinker, Stevenson, Tsung, J Pediatr Orthop. 2011:599-605.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):94-8Costello syndrome: orthopaedic manifestations and functional health, Yassir, Grottkau, Goldberg. J Pediatr Orthop. 2003 Jan-Feb;23(1):94-8 Orthopaedic Conditions in Ras/MAPK Related Disorders, Reinker, Stevenson, Tsung, J Pediatr Orthop. 2011:599-605.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):94-8Costello syndrome: orthopaedic manifestations and functional health, Yassir, Grottkau, Goldberg. J Pediatr Orthop. 2003 Jan-Feb;23(1):94-8

4. DiagnosisDiagnosis RAS/MAPK disorders overlapRAS/MAPK disorders overlap –Phenotypic overlap Growth delayGrowth delay HypotoniaHypotonia Cardiac AnomalyCardiac Anomaly Characteristic faciesCharacteristic facies RAS/MAPK disorders overlapRAS/MAPK disorders overlap –Phenotypic overlap Growth delayGrowth delay HypotoniaHypotonia Cardiac AnomalyCardiac Anomaly Characteristic faciesCharacteristic facies

5. DiagnosisDiagnosis RAS/MAPK disorders overlapRAS/MAPK disorders overlap –Genotype overlap Noonan GenotypeNoonan Genotype –PTPN, SOS1, KRAS, NRAS, RAF1, BRAF, MEK1, SHOC2, CBL, Unknown CFC GenotypeCFC Genotype –BRAF, MEK1, MEK2, KRAS, Unknown Costello GenotypeCostello Genotype –HRAS, Unknown Leopard GenotypeLeopard Genotype –PTPN, RAF1 RAS/MAPK disorders overlapRAS/MAPK disorders overlap –Genotype overlap Noonan GenotypeNoonan Genotype –PTPN, SOS1, KRAS, NRAS, RAF1, BRAF, MEK1, SHOC2, CBL, Unknown CFC GenotypeCFC Genotype –BRAF, MEK1, MEK2, KRAS, Unknown Costello GenotypeCostello Genotype –HRAS, Unknown Leopard GenotypeLeopard Genotype –PTPN, RAF1

6. Costello Syndrome – Goldberg, JPO 23:94-8,2003 18 Patients18 Patients –16 Short, broad hyperextensible digit Wrists & elbows flexed to 90 degreesWrists & elbows flexed to 90 degrees 10 Decreased elbow ROM10 Decreased elbow ROM –13 Tight heel cords –5 Vertical talus –7 Planovalgus –6 Overriding 2 nd toes –4 Metatarsus adductus 18 Patients18 Patients –16 Short, broad hyperextensible digit Wrists & elbows flexed to 90 degreesWrists & elbows flexed to 90 degrees 10 Decreased elbow ROM10 Decreased elbow ROM –13 Tight heel cords –5 Vertical talus –7 Planovalgus –6 Overriding 2 nd toes –4 Metatarsus adductus

7. Costello Syndrome- Goldberg 3 Plantar flexed great toe3 Plantar flexed great toe 3 Hip subluxations3 Hip subluxations 3 Kyphosis3 Kyphosis 3 Scoliosis3 Scoliosis 1 Radial head subluxation1 Radial head subluxation 1 Pectus excavatum1 Pectus excavatum 3 Plantar flexed great toe3 Plantar flexed great toe 3 Hip subluxations3 Hip subluxations 3 Kyphosis3 Kyphosis 3 Scoliosis3 Scoliosis 1 Radial head subluxation1 Radial head subluxation 1 Pectus excavatum1 Pectus excavatum

8. MethodsMethods 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 authorsWe 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

9. ResultsResults TotalNoonanCFCCostelloGoldberg Patient #491926318 Pes planus245 (26%)18 (69%)1 (33%)7 (39%) Hypotonia216 (31.5%14 (54%)1 (33%)0 Scoliosis188 (42%)9 (35%)1 (33%)3 (17%) Poor hand use153 (16%)11 (42%)1 (33%)16* (89%) Hypertonia112 (10.5%)9 (35%)00 Hip dysplasia82 (10.5%)6 (23%)03 (17%) Leg pains85 (26%)2 (8%)00 Elbow contracture82 (10.5%)5 (19%)1 (33%)10 (56%) Poor shoulder use71 (5%)6 (23%)00 Knee contracture70 (0%)6 (23%)1 (33%)0

10. ResultsResults NoonanCFCCostelloGoldberg Patients number1926318 Back pain5 (26%)0 (0%)1 (33%)0 Kyphosis1 (5%)4 (15%)1 (33%)3 (17%) Pes cavus4 (21%)2 (8%)0 (0%)0 Fem Retroversion1 (5%)4 (15%)1 (33%)0 Shoulder/neck pain4 (21%)0 (0%)1 (33%)0 Hip contractures2 (10.5%)3 (11.5%)0 (0%)0 Pectus carinatum2 (10.5%2 (8%)0 (0%)0 Foot callouses0 (0%)4 (15%)0 (0%)0 Arnold-Chiari3 (16%)1 (4%)0 (0%)0

11. ResultsResults NoonanCFCCostelloGoldberg Patients number1926318 Toe crowding0306 Hand contracture0020 Excess lordosis1100 Cervical stenosis1010 Foot/knee pain2010 Equinus21013 (72%) Hallux valgus0200 Femoral anteversion2000 External tibial torsion1100 Internal tibial torsion1100 Club foot0010

12. NoonanCFCCostello Patients number19263 Toe crowding030 Hand contracture002 Excess lordosis110 Cervical stenosis101 Foot/knee pain201 Equinus210 Hallux valgus020 Femoral anteversion200 External tibial torsion110 Internal tibial torsion110 Club foot001ResultsResults

13. ResultsResults NoonanCFCCostello Patients number19263 Ataxia 110 Hydrocephalus 010 Torticollis010 Cervical arthritis100 Shoulder instability100 Radial head subluxation010 Short fingers100 Wrist instability010 Metatarsus varus100 Short metatarsals010 Hip labrum tear 100

14. ResultsResults TotalNoonanCFCCostello Patient #4819263 Pes planus245 (26%)18 (67%)1 (33%) Hypotonia216 (31.5%14 (52%)1 (33%) Scoliosis188 (42%)9 (33%)1 (33%) Poor hand use153 (16%)11 (41%)1 (33%) Hypertonia112 (10.5%)9 (33%)0 Hip dysplasia82 (10.5%)6 (22%)0 Leg pains85 (26%)2 (7%)0 Elbow contracture82 (10.5%)5 (18.5%)1 (33%) Poor shoulder use71 (5%)6 (22%)0 Knee contracture70 (0%)6 (22%)1 (33%)

15. ResultsResults NoonanCFCCostello Patients number19263 Back pain5 (26%)0 (0%)1 (33%) Kyphosis1 (5%)4 (15%)1 (33%) Pes cavus4 (21%)2 (8%)0 (0%) Fem Retroversion1 (5%)4 (15%)1 (33%) Shoulder/neck pain4 (21%)0 (0%)1 (33%) Hip contractures2 (10.5%)3 (11.5%)0 (0%) Pectus carinatum2 (10.5%2 (8%)0 (0%) Foot callosities0 (0%)4 (15%)0 (0%) Arnold-Chiari3 (16%)1 (4%)0 (0%) Syringomyelia2 (10.5%)0 (0%)0%

16. New findings - Stevenson Decreased bone density is found in many patients with MAPK disordersDecreased bone density is found in many patients with MAPK disorders –Metabolic bone disorder? –Disuse? Decreased grip strength is found in many patients with MAPK disordersDecreased grip strength is found in many patients with MAPK disorders –Myopathy? Decreased bone density is found in many patients with MAPK disordersDecreased bone density is found in many patients with MAPK disorders –Metabolic bone disorder? –Disuse? Decreased grip strength is found in many patients with MAPK disordersDecreased grip strength is found in many patients with MAPK disorders –Myopathy?

17. DiscussionDiscussion Orthopaedic disorders in MAPK syndromes come in 3 flavorsOrthopaedic disorders in MAPK syndromes come in 3 flavors –Intrinsic to the disorder –Secondary to something else –Unrelated Probably the most commonProbably the most common MAPK disorders do not immunize patients against other medical problemsMAPK disorders do not immunize patients against other medical problems Orthopaedic disorders in MAPK syndromes come in 3 flavorsOrthopaedic disorders in MAPK syndromes come in 3 flavors –Intrinsic to the disorder –Secondary to something else –Unrelated Probably the most commonProbably the most common MAPK disorders do not immunize patients against other medical problemsMAPK disorders do not immunize patients against other medical problems

18. DiscussionDiscussion Treatment of these disorders should take into account the syndromeTreatment of these disorders should take into account the syndrome –What’s the pathophysiology? Encephalopathy, myopathy, neuropathy?Encephalopathy, myopathy, neuropathy? –Is treatment likely to be complicated by other things going on? Clotting disorders, spinal cord anomaly, myopathy?Clotting disorders, spinal cord anomaly, myopathy? Treatment of these disorders should take into account the syndromeTreatment of these disorders should take into account the syndrome –What’s the pathophysiology? Encephalopathy, myopathy, neuropathy?Encephalopathy, myopathy, neuropathy? –Is treatment likely to be complicated by other things going on? Clotting disorders, spinal cord anomaly, myopathy?Clotting disorders, spinal cord anomaly, myopathy?

19. DiscussionDiscussion Few orthopaedic surgeons are likely to be familiar with these syndromesFew orthopaedic surgeons are likely to be familiar with these syndromes –You may need to help them Few orthopaedic surgeons are likely to be familiar with these syndromesFew orthopaedic surgeons are likely to be familiar with these syndromes –You may need to help them

20. DiscussionDiscussion A few disorders of special interestA few disorders of special interest –Spinal Cord abnormalities High number of these in Noonan, CFC, and CostelloHigh number of these in Noonan, CFC, and Costello Need to look for them with neurologic exam and MRINeed to look for them with neurologic exam and MRI A few disorders of special interestA few disorders of special interest –Spinal Cord abnormalities High number of these in Noonan, CFC, and CostelloHigh number of these in Noonan, CFC, and Costello Need to look for them with neurologic exam and MRINeed to look for them with neurologic exam and MRI

21. DiscussionDiscussion Disorders of special interestDisorders of special interest –Pain syndromes in Noonan adults Common & puzzlingCommon & puzzling –Neuropathy? –Spinal cord anomaly? –Bone turnover? Disorders of special interestDisorders of special interest –Pain syndromes in Noonan adults Common & puzzlingCommon & puzzling –Neuropathy? –Spinal cord anomaly? –Bone turnover?

22. Disorders of special interest Scoliosis surgeryScoliosis surgery –Workup should include: Spinal MRI Spinal MRI Neck x-raysNeck x-rays Clotting studies in NoonanClotting studies in Noonan Anesthesiologist ready for hyperthermiaAnesthesiologist ready for hyperthermia Scoliosis surgeryScoliosis surgery –Workup should include: Spinal MRI Spinal MRI Neck x-raysNeck x-rays Clotting studies in NoonanClotting studies in Noonan Anesthesiologist ready for hyperthermiaAnesthesiologist ready for hyperthermia

23. Disorders of special interest Hand anomaly in CostelloHand anomaly in Costello –Unique –Treatment? Hand anomaly in CostelloHand anomaly in Costello –Unique –Treatment?

24. Thanks for your attention