Costello syndrome: Further clinical delineation, natural history, genetic definition, and nosology

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Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well‐characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G → A transition in codon 12. Less frequent mutations included 35G → C (codon 12) and 37G → T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G → A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G → C had cardiac arrhythmias whereas one patient with a 37G → T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G → A mutation. Loss of the wild‐type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio‐facio‐cutaneuos (CFC) syndromes, the HRAS coding region was sequenced in a well‐characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes. © 2005 Wiley‐Liss, Inc.

Section: Discussionmentioning

confidence: 99%

HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy

Estep

Tidyman

Teitell

et al. 2005

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157

“…On subsequent imaging studies and on clinical follow up, no neuroblastoma or other catecholamine secreting tumor was identified. We proposed to use the urine assay for HVA/VMA as a screening test for neuroblastoma in the Costello syndrome population [Gripp et al, 2002], because of the apparently increased incidence of neuroblastoma in this patient group [Zampino et al, 1993;Flores-Nava et al, 2000;Moroni et al, 2000]. Neuroblastoma screening in the general population is controversial, because of the identification of preclinical neuroblastoma which remains asymptomatic and matures without medical intervention.…”

Section: Discussionmentioning

confidence: 99%

Elevated catecholamine metabolites in patients with Costello syndrome

Gripp

Kawame

Viskochil

et al. 2004

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 confirmation of 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. © 2004 Wiley‐Liss, Inc.

“…The characteristic growth pattern in this condition is one of increased birth weight and macrocephaly, followed by postnatal growth retardation and failure to thrive [Zampino et al, 1993]. Young children with Costello syndrome often require placement of enteral feeding tubes due to poor oral motor coordination.…”

Section: Introductionmentioning

confidence: 99%

“…Young children with Costello syndrome often require placement of enteral feeding tubes due to poor oral motor coordination. In time, weight gain improves but there is a persistence of linear growth deficiency [Zampino et al, 1993].…”

Section: Introductionmentioning

confidence: 99%

Growth hormone deficiency in Costello syndrome

Legault

Daneman

Weksberg

et al. 2004

We report on three patients with Costello syndrome and isolated growth hormone (GH) deficiency treated with biosynthetic GH. To our knowledge, these are the only patients with Costello syndrome who have been successfully treated for GH deficiency. We review the pathophysiology of Costello syndrome and highlight the recent recommendations of tumor screening and cardiac surveillance in this population, of particular relevance to those receiving GH therapy.