Background
Noonan spectrum disorders include: Noonan, LEOPARD, Cardio-facio-cutaneous, and Costello syndromes, which are a group of related disorders that show clinical and genetic overlap. Common features of these disorders are facial anomalies, heart defects, growth retardation, skeletal anomalies, and variable degrees of mental retardation or developmental delay. The genes that cause these syndromes are all components of the Ras/Raf/MEK/ERK signal transduction pathway, which, when activated, promotes cell growth and division (see image below). The Noonan Spectrum Chip provides the DNA sequence for all eight genes that have been associated with Noonan spectrum disorders (PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, and HRAS).

Individuals with a Noonan spectrum disorder can have very variable phenotypes, even among family members. Features of these disorders can also change with age, which may make it difficult to make an accurate clinical diagnosis. To this point, individuals with a clinical diagnosis of one of the Noonan spectrum disorders have had a molecular etiology that is not consistent with their clinical diagnosis. For example, BRAF mutations have been reported in individuals with a clinical diagnosis of Noonan syndrome and a SOS1 mutation has been reported in an individual with Cardio-facio-cutaneous syndrome (Nystrom et al. 2008). In addition, some of these genes are associated with more than one syndrome (PTPN11, KRAS, and RAF1). As such, molecular diagnostics can help to distinguish between the different Noonan spectrum disorders. Therefore, this comprehensive approach of simultaneously testing all of these genes is beneficial because it provides complete testing while eliminating the need to determine which of these genes to test based on an individual's clinical features, thus reducing the likelihood of missed molecular diagnoses.

Noonan syndrome (NS; OMIM #163950) is an autosomal dominant disorder occurring in about 1 in 1000-2500 live births. It is characterized by short stature, distinct facial features, congenital heart disease, motor delay, learning difficulties or mild mental retardation, hearing loss, chest deformity, scoliosis, undescend testes, pubertal delay and varied coagulation defects and lymphatic dysplasias (www.GeneTests.org/Gene Reviews). Although these are common manifestations of the condition, this syndrome exhibits both inter- and intrafamilial variation.

Noonan syndrome is genetically heterogeneous. Mutations in PTPN11 have been detected in 50% of individuals with a clinical diagnosis of Noonan syndrome (Tartaglia et al. 2001, 2002). All mutations reported thus far are missense changes in the coding region with 90% clustering in exons 3, 8, and 13 (Tartaglia et al. 2005). Of the remaining individuals, mutations in RAF1, SOS1, and KRAS have been observed in 3-17%, 10%, and 1%, respectively (Pandit et al. 2007, Razzaque et al. 2007, Roberts et al. 2007, Tartaglia et al. 2007, Carta et al. 2006, Schubbert et al. 2006). BRAF mutations have been reported in individuals with a clinical diagnosis of Noonan syndrome. However, the detection rate is unknown at this time (Nystrom et al. 2008). PTPN11, RAF1, and SOS1 mutations co-segregate with Noonan syndrome within families; however, variable expressivity has been observed. All KRAS mutations described to date have occurred de novo.

Genotype-phenotype correlation studies demonstrate a statistically significant association between pulmonic stenosis and individuals with PTPN11 or SOS1 mutations (Roberts et al. 2006 and Tartaglia et al. 2002). Individuals with mutations in the CR2 domain in exon 7 of RAF1 have a high incidence of hypertrophic cardiomyopathy (80-95%, Pandit et al. 2007, Razzaque et al. 2007). A lower incidence of mutations in PTPN11 has been found in individuals with Noonan syndrome-associated hypertrophic cardiomyopathy (Tartaglia et al. 2002). PTPN11 and RAF1 mutations have also been observed in individuals with LEOPARD Syndrome and KRAS mutations have been identified in individuals with Cardio-Facio-Cutaneous syndrome (Niihori et al. 2005).

LEOPARD syndrome (OMIM# 151100) is an autosomal dominant disorder whose clinical features include multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness (Digilio et al. 2002, Pandit et al. 2007). There is clinical overlap with features of Noonan syndrome (facial anomalies, distinct congenital heart defects, pectus deformity, hearing loss and growth retardation). Mutations in exons 7, 12, and 13 of PTPN11 have been detected in the majority of individuals with LEOPARD syndrome (90-100%) (Digilio et al. 2002; Legius et al. 2002). As many as 33% of patients with PTPN11-negative LEOPARD syndrome have mutations in RAF1 (Pandit et al. 2007).

Cardio-Facio-Cutaneous syndrome (CFC; OMIM# 115150) is characterized by congenital heart defects and ectodermal anomalies. Sparse, curly, or slow-growing hair and skin abnormalities such as atopic dermatitis and hyperkeratosis with ichthyosis-like lesions are distinguishing. Cardiac features occur in 77% of cases and include atrial septal defects, pulmonic stenosis, and hypertrophic cardiomyopathy. Characteristic facial features include macrocephaly, a large prominent forehead, bitemporal narrowing, down-slanting palpebral fissures, epicanthal folds, hypertelorism, ptosis, exophthalmos, short upturned nose, prominent philtrum, posteriorly rotated, low-set ears, and webbed neck. Mild to severe mental retardation is observed in 80% of Cardio-facio-cutaneous syndrome cases. Postnatal growth deficiency is common. Cardio-facio-cutaneous syndrome has been reported to share features with Noonan syndrome, Costello syndrome, and Kabuki syndrome. An increased risk of malignancy has not been reported in individuals with Cardio-facio-cutaneous syndrome.

Mutations in several components of the Ras/Raf/MEK/ERK signal transduction pathway have been reported in individuals with a clinical diagnosis of Cardio-facio-cutaneous syndrome. BRAF mutations have been identified in up to 78% of individuals (Niihori et al. 2006 and Rodriguez-Viciana et al. 2006). BRAF-negative individuals have been reported to have mutations in KRAS (up to 7%), MEK1 (up to 8%), and MEK2 (up to 4%) (Niihori et al. 2006 and Rodriguez-Viciana et al. 2006). SOS1 mutations have also been reported in individuals with a clinical diagnosis of Cardio-facio-cutaneous syndrome. However, the detection rate is unknown at this time (Nystrom et al. 2008). All mutations reported thus far have occurred de novo.

Costello syndrome (CS; OMIM# 218040) is characterized by typical craniofacial features, failure to thrive, developmental delay, cardiac anomalies, skeletal anomalies, and a predisposition to neoplasia. Facial features are coarse and typically include macrocephaly with a prominent forehead, epicanthal folds, down-slanting palpebral fissures, a short nose with a depressed nasal bridge and broad tip, and low-set posteriorly rotated ears with thickened helices and lobes. The cheeks may be full and the mouth large with full lips. The hair is typically curly. Deep palmar and plantar creases, hyperpigmentation and nasal papillomas are evident. Cardiac features are observed in up to 52% of cases and include pulmonary valve stenosis, ventricular septal defect, atrial septal defect, thickening of the intraventricular septum, hypertrophic cardiomyopathy, or rhythm disturbances. Developmental delay ranges from mild to severe and feeding difficulties (poor suck and swallow) are common. Predisposition to malignancy has been observed, with the most common being rhabdomyosarcoma, transitional cell carcinoma of the bladder, and neuroblastoma. Costello syndrome has been reported to share features with Noonan syndrome and Cardio-facial cutaneous syndrome.

Mutations in HRAS have been reported in several cohorts of Costello syndrome patients. The combined data from four studies indicates that 115/132 (87%) individuals with clinically diagnosed Costello syndrome had HRAS mutations (Estep et al. 2006, Gripp et al. 2006, Aoki et al. 2005, Kerr et al. 2006). The majority of mutations identified were in codon 12, although at least one mutation has been reported in another region of the gene. No HRAS mutations have been identified in individuals with Cardio-facio-cutaneous syndrome (74/74) or PTPN11 negative-Noonan syndrome (33/33). It is not clear yet whether the individuals with a clinical diagnosis of Costello syndrome and no HRAS mutation can be attributed to locus heterogeneity or overlapping clinical features with a different disorder. All mutations thus far reported have occurred de novo.

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