Hematologic abnormalities associated with patients with cardio-facio-cutaneous syndrome

Yuka Saito1, Yoko Aoki1, Tetsuya Niihori1, Akira Ohtake2, Atsushi Shibuya2, Kazuhito Sekiguchi,3, So-ichi Suenobu3, Taturo Izumi3, Hideki Muramatsu4, Seiji Kojima4, Shigeo Kure1,5, Shigeru Tsuchiya5, Yoichi Matsubara1
1) Dept Med Genet, Tohoku Univ Sch Med, Sendai, Japan; 2) Dept Pediatr, Saitama Med Univ, Moroyama, Saitama, Japan. 3) Dept Pediatr and Child Neurol, Oita Univ Facul Med, Oita, Japan 4) Dept. Pediatr, Nagoya Univ Graduate Sch Med, Nagoya, Japan 5) Dept. Pediatr. Tohoku Univ Sch Med

Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome. Mutations in KRASBRAF and MAP2K1/2 (MEK1/2) have been identified in patients with CFC syndrome. By age 20, the cumulative incidence of cancer was approximately 4% for Noonan syndrome and 15% for Costello syndrome (Christian P. Kratz. AJMD, 2011). For Costello syndrome, tumor-screening protocols have been proposed. In contrast, little attention has been paid to the development of tumors in patients with CFC syndrome. We have previously reported three CFC patients with BRAF mutations who developed hematologic malignancies: two patients with acute lymphoblastic leukemia, 1 with non-Hodgkin lymphoma. A patient with a MAP2K1 mutation, who developed hepatoblastoma, has also been reported. Here we report additional patient with CFC syndrome who developed juvenile myelomonocytic leukemia (JMML)-like myeloproliferative disorder. He was delivered by caesarian section at 32 weeks’ gestation due to non-immune hydrops fetalis. He had curly hair, low-set ears, atrial septal defect, hepatosplenomegaly, pulmonary arteriovenous fistula and portosystemic shunt. At one month age, the patient showed marked monocytosis and decrease in platelet count. The diagnosis of JMML was made on bone marrow cell culture studies. Hematological abnormalities resolved spontaneously at three month of age. Sequencing of genomic DNA from the patient showed a heterozygous p.T241P (c.721A>C) mutation. This is the first report that a patient with CFC syndrome developed JMML-like myeloproliferative disorder. The clinical features of JMML-like disorder in the patient are similar with those of JMML-like disorder/Noonan syndrome. Germline mutations in BRAF possibly contribute to leukemogenesis and JMML-like abnormalities with spontaneous regression in early infantile period. These results suggest the importance of molecular diagnosis and careful observation in children with CFC syndrome.