Cancer in Noonan, Costello, Cardiofaciocutaneous and LEOPARD Syndromes
CHRISTIAN P. KRATZ,* SUTHEE RAPISUWON, HELEN REED, HENRIK HASLE, AND PHILIP S. ROSENBERG
Noonan syndrome (NS), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and LEOPARD syndrome (now also referred to as Noonan syndrome with multiple lentigines or NSML) are clinically overlapping dominant disorders that are caused by mutations in RAS signaling pathway genes. The spectrum of cancer susceptibility in this group of disorders has not been studied in detail. We identified more than 1900 cases of NS, CS, CFCS, or NSML reported in the literature between 1937 and 2010; 88 cancers were reported. The most common cancers reported in 1051 NS subjects were neuroblastoma (n¼8), acute lymphoblastic leukemia (n¼8), low grade glioma (n¼6), and rhabdomyosarcoma (n¼6). These associations are biologically plausible, given that somatic RAS pathway mutations are known to occur in these specific cancers. In addition, 40 childhood cases of myeloproliferative disease were described in individuals with NS, several of whom experienced a benign course of this hematologic condition. We confirmed the previously described association between CS and cancer in 268 reported individuals: 19 had rhabdomyosarcoma, 4 had bladder cancer, and 5 had neuroblastoma. By age 20, the cumulative incidence of cancer was approximately 4% for NS and 15% for CS; both syndromes had a cancer incidence peak in childhood. The cancers described in CFCS and NSML overlapped with those reported in NS and CS. Future epidemiologic studies will be required to confirm the described cancer spectrum and to estimate precise cancer risks.
Costello Syndrome and the Importance of Cancer Screening
Costello syndrome is a rare congenital syndrome first described in 1971.1 Since then, approximately 115 cases have been reported in the literature.1 The syndrome presents with failure to thrive, developmental delay, and unique facial characteristics. These include macrocephaly, downward-slanted palpebral fissures, curly hair, lowset ears, depressed nasal bridge, large tongue, and hypertrophied gingiva.2 Overall, these phenotypic features give rise to the characteristic coarse facial appearance.
Costello syndrome also affects multiple organsystems, includingmusculoskeletal,skin, and cardiac. These manifest as joint hypermobility, tightness of achillestendon,redundant skin on the neck, hands, and feet, and cardiac abnormalities, suchasdysrhythmias and hypertrophic cardiomyopathy. The most intriguing feature of Costello syndrome is the predisposition to certain malignant tumors.Ofthese,rhabdomyosarcomas involving the abdomen, pelvis, and urogenital areas are the mostcommon. We describe a case of nasopharyngeal rhabdomyosarcoma in a patient with Costello syndrome.
Elevated Catecholamine Metabolites in Patients With Costello Syndrome
Karen W. Gripp,1* Hiroshi Kawame,2 David H. Viskochil,3 and Linda Nicholson1
1 Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware
2 Division of Medical Genetics, Nagano Children’s Hospital, Nagano, Japan
3 Division of Medical Genetics, University of Utah, Salt Lake City, Utah
Costello syndrome is a rare congenital anomaly syndrome with a predisposition to specific tumors, including neuroblastoma, rhabdomyosarcoma, and transitional cell carcinoma of the bladder. The increased risk for solid tumors led to the proposal of a tumor screening protocol. A screening test for neuroblastoma consists of measuring catecholamine metabolites in urine, an assay that may also be used for diagnostic confirmationof a suspected catecholamine secreting tumor. We report eight patients with Costello syndrome with elevated catecholamine metabolites, vanillylmandelic acid (VMA) and/or homovanillic acid (HVA), in urine. Each patient had additional laboratory and/or imaging studies.
None of the patients was found to have a neuroblastoma or another catecholamine secreting tumor. In two cases, the assays were performed because the patients were symptomatic with diaphoresis and hypertension, respectively, and in the other six cases the assays were performed in order to screen for neuroblastoma. The pathophysiology for the catecholamine metabolite abnormality in these patients with Costello syndrome remains unclear. However, it appears that in this patient group an elevation above the normal limit, defined as 2 standard deviations (SD) above the mean for age, is more likely to be a variant, rather than a sign of a neuroblastoma. Thus, it may be prudent not to use this assay as a screening test, and to take the frequently elevated results into consideration when interpreting diagnostic assays.
Tumor Predisposition in Costello Syndrome
KAREN W. GRIPP
Costello syndrome (CS) is a rare congenital anomaly syndrome. Although it may be classified as an ‘‘overgrowth’’ syndrome due to slightly increased birth weight and relative macrocephaly, it is characterized by severe postnatal failure to thrive and short stature. Patients with CS have an increased risk for malignant tumors, a hallmark of several model overgrowth syndromes. The most common tumor in CS is rhabdomyosarcoma (RMS), followed by neuroblastoma and bladder carcinoma. The occurrence of bladder carcinoma in adolescents is distinctly unusual as this is typically a neoplasm of older adults and is not seen with increased frequency in other tumor predisposition syndromes. The increased tumor frequency in CS led to the proposal of a screening protocol, consisting of abdominal and pelvic ultrasounds, and urine studies for catecholamine metabolites and hematuria.
It has since become apparent that patients with CS have an increased excretion of catecholamine metabolites in urine without the presence of an identifiable catecholamine secreting tumor. Thus, the urine assay for catecholamines is unhelpful as a screening test for neuroblastoma and should not be used in this population. The benefit of abdominal and pelvic ultrasound and urinalysis for hematuria as screening tests remains to be shown. A timely diagnosis of CS is a necessary prerequisite for awareness of the increased tumor risk. Once a malignancy has been identified, treatment should follow standard protocols. Additional medical problems characteristic for CS,