Prevalence and clinical features of Costello syndrome and cardio‐facio‐cutaneous syndrome in Japan: Findings from a nationwide epidemiological survey

Abstract

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.

Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp

“…The female patient described by Aoki et al [2005] was reevaluated at age 18 years [Abe et al, 2012]. Photographs were available for the patients reported by Digilio et al, 2008 (age 3 months) and Limongelli et al, [2008] (age 15 years).…”

Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

“…2,36 These are usually accompanied by severe feeding problems including gastroesophageal reflux, suck/swallow dysfunction, and oral aversion ( Table 3). The swallowing difficulties are reflected early by prenatal polyhydramnios that, after birth, is followed by difficulty in maintaining adequate oral caloric intake.…”

“…Although the worldwide prevalence of CFC is unknown, the prevalence of CFC in Japan is estimated at 1 in 810 000 individuals. 2 It is often challenging to differentiate CFC from other RASopathies; therefore, CFC International convened an international conference on November 5-6, 2012, composed of health care providers and physician-scientists with expertise in CFC to aid in establishing a correct diagnosis and provide optimum clinical management to patients. The goal of this conference was to review the most current medical and scientific information about CFC, and develop guidelines for its diagnosis and clinical management.…”

Cardiomyopathies in Noonan syndrome and the other RASopathies

“…For cardiofaciocutaneous syndrome, two studies contained adequate numbers of individuals with BRAF mutations or MEK defects (either MEK1 or MEK2) to permit a comparison of hypertrophic cardiomyopathy [31, 32]. The prevalence of hypertrophic cardiomyopathy was not significantly different ( BRAF 35% and MEK 21%).…”