Chromosome: 18q21.1
Gene affected: SMAD4, involving isoleucine at position 500 (similar to mothers against decapentaplegic family member 4, previously known as mothers against decapentaplegic homolog 4 or MADH4)
Inheritance: sporadic (de novo mutation)
Clinical features:
(1) short stature
(2) short hands and feet
(3) generalized muscular hypertrophy
(4) thickened/stiff skin
(5) deafness
(6) facial dysmorphism (narrow palpebral fissures, midface hypoplasia, small mouth, thin upper lip, prognathism)
(7) joint stiffness
(8) skeletal anomalies (thick skull bones, platispondyly, large vertebrae with abnormal pedicles, broad ribs, hypoplastic iliac wings, brachydactyly)
(9) cryptorchidism in males
(10) cognitive deficits
(11) behavioral problems
(12) variable cleft lip and/or palate
(13) variable congenital heart defects
(14) variable ocular defects
Mutations in SMAD4 have been associated with pancreatic cancer, juvenile polyposis and hereditary hemorrhagic telangiectasia (HHT).
