Other Publications

  • Home / Other Publications

Other Publications

Costello and Cardio-Facio-Cutaneous Syndromes Moving Toward Clinical Trials in RASopathies


The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen-activated protein kinase (MAPK)  pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two of the more rare RASopathies. CS is caused by activating mutations in HRAS, and CFC is  caused by dysregulation of signaling in the Ras/MAPK pathway due to mutations in BRAF, MEK1, or MEK2. The Ras/MAPK pathway, which has been well-studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics that specifically inhibit the pathway. With many inhibitors of the Ras/MAPK pathway in clinical trials, the notion of using these molecules to ameliorate developmental defects in CS and CFC is under consideration. CS and CFC, like other syndromes in their class, have a progressive phenotype and may be amenable to inhibition or normalization of signaling

Costello syndrome: A Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

Karen W. Gripp, MD1, and Angela E. Lin, MD2


Costello syndrome (OMIM# 218040) is a distinctive rare multisystem disorder comprising a characteristic coarse facial appearance, intellectual disabilities, and tumor predisposition. Although the diagnosis can be suspected clinically, confirmation requires identification of a heterozygous mutation in the proto-oncogene HRAS. In contrast to somatic oncogenic mutations in neoplasia, the Costello syndrome changes are typically introduced in the paternal germline. The predicted amino acid substitutions allow for constitutive or prolonged activation of the HRAS protein, resulting in dysregulation of the Ras/ mitogen activated protein kinase pathway. Dysregulation of this signaling pathway is the disease mechanism shared among Costello syndrome and other rasopathies, including neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. The Ras/mitogen activated protein kinase pathway governs cell proliferation and differentiation, and its dysregulation affects cardiac and brain development, accounting for the significant overlap in physical and developmental differences and common medical problems among rasopathies. Unlike the genetically heterogeneous Noonan syndrome and cardio-facio-cutaneous syndrome, Costello syndrome is caused by HRAS mutations only. Patients, clinicians, and researchers may benefit from a multidisciplinary “rasopathy clinic,” which serves patients with more common conditions such as Noonan syndrome and neurofibromatosis and those affected by rare conditions such as Costello syndrome.

Prevalence and Clinical Features of Costello Syndrome and Cardio-Facio-Cutaneous Syndrome in Japan: Findings From a Nationwide Epidemiological Survey

Yu Abe,1 Yoko Aoki,1* Shinichi Kuriyama,2 Hiroshi Kawame,3 Nobuhiko Okamoto,4 Kenji Kurosawa,5  Hirofumi Ohashi,6 Seiji Mizuno,7 Tsutomu Ogata,8 Shigeo Kure,9 Tetsuya Niihori,1 Yoichi Matsubara1 and Costello and CFC syndrome study group in Japan

1 Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan

2 Department of Molecular Epidemiology, Tohoku University School of Medicine, Sendai, Japan

3 Department of Genetic Counseling, Ochanomizu University, Tokyo, Japan

4 Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan

5 Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan

6 Division of Medical Genetics, Saitama Children’s Medical Center, Saitama, Japan

7 Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai, Aichi, Japan

8 Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

9 Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan

Costello syndrome and cardio-facio-cutaneous (CFC) syndrome are congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, and intellectual disability. Germline mutations in HRAS cause Costello syndrome, and mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) cause CFC syndrome. Since the discovery of the causative genes, approximately 150 new patients with each syndrome have been reported. However, the clinico-epidemiological features of these disorders remain to be identified. In order to assess the prevalence, natural history, prognosis, and tumor incidence associated with these diseases, we conducted a nationwide prevalence study of patients with Costello and CFC syndromes in Japan. Based on the result of our survey, we estimated a total number of patients with either Costello syndrome or CFC syndrome in Japan of 99 (95% confidence interval, 77–120) and 157 (95% confidence interval, 86–229), respectively. The prevalences of Costello and CFC syndromes are estimated to be 1 in 1,290,000 and 1 in 810,000 individuals, respectively. An evaluation of 15 adult patients 18–32 years of age revealed that 12 had moderate to severe intellectual disability and most live at home without constant medical care. These results suggested that the number of adult patients is likely underestimated and our results represent a minimum prevalence. This is the first epidemiological study of Costello syndrome and CFC syndrome. Identifying patients older than 32 years of age and following up on the patients reported here is important to estimate the precise prevalence and the natural history of these disorders.

Understanding Growth Failure in Costello Syndrome: Increased Resting Energy Expenditure

Chiara Leoni, MD1, Roberta Onesimo, MD1, Valentina Giorgio, MD2, Antonella Diamanti, MD3, Daniela Giorgio, RD1, Lucilla Martini, MD1, Aurora Rossodivita, MD1, Marco Tartaglia, PhD4, and Giuseppe Zampino, MD1

Costello syndrome is a rare multisystem disorder caused by mutations in the proto-oncogene HRAS. Failure to thrive is one of its cardinal clinical features. This study documents that individuals with Costello syndrome have increased resting energy expenditure. We speculate this could be one of the potential mechanisms causing failure to thrive. (J Pediatr 2016;170:322-4).

Costello syndrome (OMIM# 218040) is a rare developmental  disorder caused by germline activating mutations in the proto-oncogene HRAS,1,2 which encodes amember of the RAS subfamily of small monomeric GTPases controlling several intracellular signaling pathways with roles in cell proliferation, differentiation, and survival. Clinically, Costello syndrome3 is recognizable by a distinctive facies, reduced postnatal growth, intellectual disability, and cardiac and musculoskeletal anomalies. The growth phenotype presents with severe failure to thrive and swallowing / sucking difficulties after birth, followed by a mild improvement in gaining weight usually occurring after the third year of life.3 Most infants require nasogastric or gastrostomy tube feeds because of the severe feeding difficulties.3 During childhood, individuals are able to take oral feeds, yet they continue to have growth failure.

Herein we report the results of a case/control study evaluating the energy balance in Costello syndrome to further investigate the mechanisms underlying failure to thrive.