Recommended panel testing at Breda Genetics for this condition:
Summary
Noonan syndrome (NS) is an autosomal dominant disorder characterized by congenital heart defects, short stature, characteristic facies, and variable developmental delay. NS is the most common of the group of disorders known as RASopathies, with an estimated prevalence of 1 in 2,500 individuals.
Detailed clinical description
NS patients are usually shorter than average and display characteristic facial features including a triangle-shaped face with broad forehead and small chin, hypertelorism, ptosis of the eyelids, short and webbed neck, low hairline at the back of the head, and low-set, posteriorly rotated ears. NS patients may have a deformity of the chest with superior pectus carinatum and inferior pectus excavatum. Cardiovascular anomalies are observed in 50% to 80% of affected individuals, with the most common defect being pulmonary valve stenosis observed in 20%-50% of NS cases. Other structural cardiac defects include atrial or ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Hypertrophic cardiomyopathy occurs in 20%-30% affected individuals. Other features include cryptorchidism in males, blood coagulation defects, lymphatic dysplasias of lungs, bowels or lower extremities, hypotonia and joint hyperextensibility in infancy/childhood. Skin changes such as cafè-au-lait spots and lentigines are common in NS patients. Early developmental milestones may be delayed, intellectual performance may be slightly lowered. Language impairment is more common in NS patients than in the general population.
Molecular genetics
Many, but not all, individuals with NS have a de novo pathogenic variant in one of the following genes: PTPN11 (50% of cases), SOS1 (~10%), RAF1 (5%), RIT1 (5%), KRAS (<5%), BRAF (2%), MAP2K1 (2%), and NRAS (rare). Other genes that have been associated to a NS-like phenotype include RRAS2, RASA2, A2ML1, SOS2, and LZTR1. Due to variable expressivity and possibly incomplete penetrance of the disorder, as many as 50% of individuals diagnosed with NS have a mildly affected parent or relative, who are recognized to have NS only after a diagnosis is established in a more obviously affected index case.
Differential diagnosis
The genetic differential diagnosis of Noonan syndrome includes the following:
Turner syndrome (45,X): in addition to short stature, cardiac anomalies, webbed neck, ptosis and low hairline, affected females have gonadal dysgenesis and often display renal anomalies such as horseshoe kidney and renal agenesis that are not found in NS individuals.
Noonan-like syndrome with loose anagen hair: affected individuals display the characteristic NS features, together with growth hormone deficiency, distinctive hyperactive behavior, easily pluckable, sparse, thin hair, skin with eczema or ichthyosis. Heterozygous mutations in SHOC2 or PPP1CB cause this syndrome.
Noonan-like syndrome with or without juvenile myelomonocytic leukemia: this syndrome is due to heterozygous mutations in the CBL gene, which is characterized by a lower prevalence of cardiac abnormalities and short stature, and a high predisposition to juvenile myelomonocytic leukemia.
Cardio-facio-cutaneous (CFC) syndrome: mutations in BRAF, KRAS, MAP2K1 and MAP2K2 may cause this syndrome which is characterized by cardiac and lymphatic findings very similar to NS. Intellectual disability is usually more severe compared to classic NS. Skin abnormalities are more evident as well.
Costello syndrome: this syndrome shares many features with NS and CFC syndromes, but it is characterized by severe feeding difficulties and failure to thrive in infancy, typical deep palmar and plantar creases, skin hyperpigmentation, facial papillomas and a high predisposition to develop tumors. The only gene currently known to cause this syndrome is HRAS.
LEOPARD syndrome (Lentigines – ECG abnormalities – Ocular hypertelorism – Pulmonary stenosis – Abnormal genitalia – Retardation of growth – Deafness): also known as NS with multiple lentigines, is characterized by prominent skin pigmentary changes such as café-au-lait spots, nevi, and lentigines. Sensorineural hearing loss is observed in about 20% of affected individuals. Mutations in PTPN11, RAF1 and BRAF cause this disorder.
Neurofibromatosis (NF) and Legius syndrome: NF and NS share some features such as short stature, learning difficulties, and more importantly the skin pigmentary anomalies (cafè-au-lait spots and freckles). However, NF is characterized by multiple cutaneous neurofibromas which are not present in NS patients. Mutations in the NF1 gene cause neurofibromatosis and its allelic variant Watson syndrome. Legius syndrome, caused by mutations in the SPRED1 gene, is very similar to NF, however iris Lisch nodules, neurofibromas and central nervous system tumors are usually absent.
Recommended testing workflow
Considering the phenotypic overlap between the distinct RASopathies, it is recommended to proceed with the analysis of a panel of genes that have been associated to NS and to disorders belonging to its differential diagnosis by means of next generation sequencing. Breda Genetics offers NS genes in panels based on either Mendeliome, exome or full genome sequencing. As rare duplication of the 12q24.1-q24.23 region which includes the PTPN11 gene have been reported in individuals with NS-like features, targeted deletion/duplication testing for this gene may be required if the panel result is negative.
Recommended panel testing at Breda Genetics for this condition:
Recommended panel testing at Breda Genetics for this condition:
References
Noonan Syndrome. Allanson JE, Roberts AE. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2001 Nov 15 [updated 2016 Feb 25]. PMID: 20301303
Costello Syndrome. Gripp KW, Lin AE. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2006 Aug 29 [updated 2012 Jan 12]. PMID: 20301680
Cardiofaciocutaneous Syndrome. Rauen KA. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2007 Jan 18 [updated 2016 Mar 3]. PMID: 20301365
Noonan Syndrome with Multiple Lentigines. Gelb BD, Tartaglia M. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2007 Nov 30 [updated 2015 May 14]. PMID: 20301557
Neurofibromatosis 1. Friedman JM. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 1998 Oct 2 [updated 2018 May 17]. PMID: 20301288
