Orthopaedic conditions in RAS/Mapk family disorders

Kent Reinker, MDClinical 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 18Toe crowding 0 3 0 6Hand contracture 0 0 2 0

Excess lordosis 1 1 0 0Cervical stenosis 1 0 1 0

Foot/knee pain 2 0 1 0Equinus 2 1 0 13 (72%)

Hallux valgus 0 2 0 0

Femoral anteversion 2 0 0 0External 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 0Cervical stenosis 1 0 1

Foot/knee pain 2 0 1

Equinus 2 1 0Hallux 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 0Hydrocephalus 0 1 0Torticollis 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