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Zenker M (ed) (ed): Noonan Syndrome and Related Disorders - A Matter of Deregulated Ras Signaling. Monogr Hum Genet. Basel, Karger, , vol 17, pp I-X.
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Noonan syndrome, a common genetic disorder occurring in approximately 1 in individuals, is another RASopathy. Individuals with Noonan syndrome may also have wispy scalp hair during infancy that becomes unusually wooly or curly during later childhood. In many males with Noonan syndrome, one or both testes may have failed to descend into the scrotum cryptorchidism.

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In addition, affected individuals often have congenital heart defects, particularly obstruction of the normal flow of blood from the lower right chamber ventricle of the heart to the lungs valvar pulmonary stenosis. Noonan syndrome has autosomal dominant inheritance.

Cases in which a positive family history has not been found are thought to represent new genetic changes mutations that occur randomly, with no apparent cause sporadic. There are now more than 10 genes known to cause Noonan syndrome, with more likely to be reported in the coming years.

In addition, some affected individuals may also have congenital heart defects. Most cases of Costello syndrome occur sporadically, with no family history of the disorder. Such cases are thought to represent new dominant gene mutations. For information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database. In most cases, CFC syndrome is diagnosed during infancy based upon a thorough clinical evaluation, characteristic physical findings, and specialized tests.

Congenital heart defects that may occur in association with CFC syndrome e. For example, in mild asymptomatic cases of pulmonary stenosis, the condition may initially be detected through an abnormal heart murmur heard during such stethoscopic evaluation. X-ray studies may reveal abnormal enlargement of the heart cardiomegaly or malformation of certain heart structures.

An EKG, which records the electrical activities of the heart muscle, may reveal abnormal electrical patterns. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. During cardiac catheterization, a small hollow tube catheter is inserted into a large vein and threaded through the blood vessels leading to the heart. For example, according to the medical literature, computerized tomography CT scanning may help confirm the presence of hydrocephalus or, in some cases, degeneration of the outer layer of the brain cortical atrophy in some individuals with the disorder.

Molecular genetic testing is available for mutations in the four genes known to cause CFC syndrome. Testing can be done by using a multi-gene panel that screens all of the genes currently known to cause a RASopathy since there is a considerable overlap among them or whole exome sequencing can be considered. Consensus guidelines for the management of individuals with CFC were published in and should be referenced in the care of any patient with this diagnosis.

Treatment The treatment of CFC syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Specific therapies for CFC syndrome are symptomatic and supportive. In individuals with CFC syndrome, respiratory infections should be treated promptly and vigorously. Because of the potentially increased risk of bacterial infection of the lining of the heart endocarditis and the heart valves, individuals with atrial septal defects may be given antibiotic drugs before any surgical procedure, including dental procedures such as tooth extractions.

In affected individuals with hydrocephalus, shunts may be implanted to drain excess cerebrospinal fluid away from the brain, relieving pressure. In addition, in some cases, treatment with anticonvulsant drugs may help prevent, reduce, or control seizures. Oftentimes, children who are failing to thrive will require a nasogastic or gastrostomy tube feeding tubes. An increased caloric intake may also be beneficial in conjunction with increase fiber if the affected individual suffers from constipation. In addition, to help alleviate skin abnormalities, physicians may recommend certain lubricating lotions or ointments, such as petroleum jelly.

Applying such lubricants may be particularly effective after bathing while the skin is moist. In affected individuals with hemangiomas, treatment may not be required in some cases. Various removal techniques may be used e. Early intervention may be beneficial in helping children with CFC syndrome reach their potential. Genetic counseling is recommended for affected individuals and their families. Other treatment for the disorder is symptomatic and supportive.

Medications derived from vitamin A retinoids such as tretinoin, etretinate, or acitretin may be effective in relieving some of the symptoms associated with ichthyosis. However, such vitamin A derivatives may interfere with bone growth in children in some cases. Therefore, according to the medical literature, such medications should be avoided in children unless other forms of treatment have failed.

In addition, certain vitamin A derivatives are known to cause severe birth defects; therefore, such medications should not be taken during pregnancy. Further research is needed to determine the long-term safety and effectiveness of vitamin A derivatives in the treatment of ichthyosis such as that occurring in some cases of CFC syndrome. Information on current clinical trials is posted on the Internet at www.

All studies receiving U. For information about clinical trials sponsored by private sources, in the main, contact: www. Inborn Errors of Development. Oxford University Press, New York. Molecular Causes of Cardio-facio-cutaneous Syndrome. In: Monographs in Human Genetics. Volume Noonan Syndrome and Related Disorders. A matter of deregulated Ras signaling. Schmid M. Freiburg, Germany. Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines. Clinical Genetics. Muscle and Nerve. American Journal of Medical Genetics. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: Transmission through four generations.

Am Journal of Medical Genetics. British Journal of Dermatology. Current Opinion in Genetics and Development, ;19 3 Expert Review in Molecular Medicine. Developmental Medicine and Child Neurology. Germline mutations in genes within the MAPK cascade cause cardio-facio-cutaneous syndrome. The cardiofaciocutaneous syndrome. There are clearly many phenotypic similarities in infancy in these syndromes. The facies typically show low set ears, downward slanting eyes and a short neck. Polyhydramnios is common and cystic hygroma is sometimes noted by fetal ultrasound.

It is tempting to blame the cystic hygroma as a likely cause of the facial phenotype. However, an interesting study by Achiron et al. They propose that NS has an evolving phenotype during in utero and postnatal life. Among 46, live born infants only seven newborn and four fetuses were found to have NS while some NS would be expected. Unlike Bekker et al. This observation indicates lymphatic abnormalities are not a sine qua non for a prenatal diagnosis of NS.

Since the great majority of patients with these syndromes do not have nuchal translucency in utero it is necessary to propose another explanation for the typical facial phenotype. Some infants with NS and related disorders are clearly recognized as dysmorphic at birth. The four fetuses in Achirons report all developed bilateral hydrothorax and generalized edema. All had typical facies of NS. All were very ill and two died in the neonatal period. The seven infants diagnosed at birth or in early infancy had typical clinical findings of NS. This suggests that the other 30 to 40 NS expected among the 46, newborn delivered were mild enough to be unrecognized at least through the first year of life.

It is not uncommon for a diagnosis of NS to be delayed past five to six years of age and sometimes into adulthood. Is it possible that the facial phenotype becomes more typical with time demonstrating that the RAS pathway continues to play a role in an evolving phenotype? The RAS pathway must play a role in this common facial phenotype but it is still unknown. On the other hand it is also clear that the RAS pathway must play a role in early lymphatic development. Lymphatic problems are well recognized in NS. Chylous thorax may be present at birth or appear spontaneously later on or be a complication following heart surgery.

Pulmonary and intestinal lymphangiectasia have been reported. Some cases occur in infancy but may be delayed until adulthood. Lymphedema may present for the first time in adulthood. Bloomfield et al. The infant was born at 33 weeks with severe edema and bilateral pleural effusions which proved to be chylous. The fluid was drained and the baby improved. On day 14 a lymphangiogram was carried out from the right foot. The six lymphatics that filled were dilated and saccular. There was no filling of lymph nodes in the groin or extension into the pelvic or para-aortic lymphatics or thoracic duct.

Clearly the lymphatic system was dysplastic suggesting very abnormal development. Unfortunately the infant had two episodes of viral pneumonia and died at 5 months of age. I have personal knowledge of another infant with persistent chylous thorax who underwent lymphangiography. This demonstrated absence of the thoracic duct with multiple lymphatics draining directly into the chest cavity. There is need for further study of the role of RAS in lymphatic development. Few studies of the lymphatics have been carried out but the lymphangiograms so far performed have shown significant lymphatic abnormalities.

It is very exciting for me to learn that NS and these related disorders disturb the RAS pathway, demonstrating that this pathway plays an important role in development. Once we understand exactly. Already basic scientists are making important progress in understanding the effect of specific mutations on human development. Krenz et al. Nakamura et al. Gauthier et al. The normal Shp2 instructs cell precursors to make neurons and not astrocytes during the neurogenic period of development.

A mouse knockin mutant Shp2 model is a phenocopy of human NS. This model was shown to inhibit basal neurogenesis and caused enhanced astrocyte formation. It will be very important for these patients to have continued long-term follow-up as they age. Am J Dis Child ; J Pediatr ; Am J Med Genet ; Arch Anthropol ; Dtsch Zeitschr Chir ; Registries to follow these patients will be important.

In countries with established registries, it will be essential that these patients be followed long-term. As we follow these adults, we may be able to identify what role the RAS pathway plays in aging. There is plenty of exciting knowledge awaiting investigators as we continue to learn more about the RAS pathway. In the United States, without national registries, three support groups founded by mothers of affected children could play a role.

They hold international meetings every one to two years and families attend with their affected children. At these meetings, information about the syndrome is shared with families and the physicians attending always learn much from the families. The children are able to interact with affected peers which provides a lot of support. These groups have or are in the process of establishing registries which could play a very important role in long-term followup of patients with all these syndromes. Little is known of the natural history of these syndromes. These mutations likely continue to exert an effect on the RAS pathway throughout life.

Z Kinderheilkd ; Endocrinology ; Br J Surg ; Am J Hum Genet ; Am J Med Genet ; Circulation ; Br Heart J ; Radiology ; Arch Dis Child ; Nat Genet ; Am J Med Genet A ; J Med Genet ; NZ Med J ; Aust Paediatr J ; Proc Greenwood Genet Cent ; Clin Genet ; Am J Med Genet A ; Nat Med ; Fetal Diagn Ther ; Pediatr Radiol ; Circ Res ; J Clin Invest ; Neuron ; Jacqueline A.

Abstract Noonan syndrome is an autosomal dominant condition notable both for its common occurrence and phenotypic variability. It is characterized by short stature, congenital cardiac defects, unusual chest shape, broad or webbed neck, cryptorchidism, typical facial appearance and developmental delay of variable extent.

It is frequently overlooked in the mildly affected individual and diagnosis in an adult often follows the birth of a child with more florid manifestations. There are several excellent reviews [1, 39]. The cardinal features of Noonan syndrome are short stature, congenital heart defects, broad or webbed neck, characteristic pectus deformity, a particular facial appearance which changes with age and, in some cases, mild intellectual handicap. This pattern of features was recognized and reported more than 40 years ago by Noonan and Ehmke [1], however it is likely that Kobylinski, in , was the first to publish on the condition [2].

Average age at diagnosis is 9 years [4]. Life expectancy is likely to be normal in the absence of serious cardiac defects. Cause of adult death. Facial appearance changes with age fig. In the newborn, key features include tall forehead, widespaced and down-slanting palpebral fissures, ptosis or thickened eyelids, epicanthal folds, depressed nasal root with upturned nasal tip, deeply grooved philtrum with high, wide peaks of the vermilion border so-called cupids bow shape , low-set and posteriorly angulated ears with thick helices, small chin, and excessive nuchal skin with a low posterior hairline.

During infancy, the head is relatively large in comparison to face size, with a tall and prominent forehead. Hypertelorism, ptosis or thick hooded eyelids remain characteristic. The nose is short and wide with a depressed root. During later childhood, the face may appear coarse or even myopathic. With increasing age, the face lengthens and becomes more triangular in shape with a broad forehead tapering to a small and.

Female with Noonan syndrome at different ages, showing how facial features change with time. In adolescence and young adulthood, the nose has a thin, prominent bridge and a wide base. The neck is longer with accentuated webbing pterygium colli or a prominent trapezius. In older adults, nasolabial folds are exaggerated and the skin appears thin and transparent [6, 10, 11].

The hair may be wispy or sparse during infancy and curly or woolly in older childhood and adolescence. Despite this subjective impression of age-related facial change, detailed measurements demonstrate the opposite. There is a Noonan-specific pattern of craniofacial widths, lengths, depths and arcs that is maintained over time. Features likely to be seen irrespective of age include blue-green irides, frequently out of keeping with family eye colour, arched or diamond-shaped eyebrows, and low-set posteriorly angulated ears with thickened helices [4, 6].

Malocclusion is common and likely is related to the small chin and oral cavity [6, 10]. Relative or absolute macrocephaly is usual. Mean adult head circumference in males is Since this feature may prompt diagnosis, and because many published reports come from tertiary and quaternary medical centres which place emphasis on serious structural manifestations, there may be bias of ascertainment. It may be isolated or associated with other defects. Other common structural cardiac anomalies include atrial or ventricular septal defects and tetralogy of Fallot.

Many other cardiac defects have been reported less commonly, including atrioventricular septal defect, aortic stenosis or dysplasia, coarctation of the aorta [], bicuspid aortic valve, double chambered right ventricle, mitral valve anomalies [19], Ebstein anomaly, total anomalous pulmonary venous return, supravalvular pulmonary stenosis, coronary artery dilatation, coronary artery fibromuscular dysplasia causing ischemia [20], and giant aneurysms of the sinuses of Valsalva caused by deficiency of medial elastin [21].

Hypertrophy may be mild or severe, and may present before or at birth, in infancy or childhood. It is histologically, echocardiographically and clinically indistinguishable from non-syndromic hypertrophic cardiomyopathy, except that arrhythmia and sudden death appear to be less common. Restrictive cardiomyopathy and dilated cardiomyopathy are reported but uncommon [24 26].

Extreme right axis deviation with superior counter-clockwise frontal QRS loop is likely related to asymmetric septal hypertrophy. Left axis deviation may occur secondary to a conduction abnormality; there may be left anterior hemiblock or an RSR pattern in lead V1. Abnormal findings may occur in a structurally normal heart. In older individuals, arrhythmia and congestive cardiac failure may be more common than previously suspected [27].

Birth weight is usually normal but may be increased due to subcutaneous edema. In this situation there is rapid loss of weight in the neonatal period. They are usually related to hypotonia and poor coordination of oral musculature, however immature gut motility and delayed gastrointestinal motor development are documented in some individuals [28]. It is self-limited and usually resolves by 18 months of age. Average birth length is 47 cm.

Childhood growth tends to follow the general population third centile, with normal growth velocity. The pubertal growth spurt is frequently reduced or absent. Delayed bone maturation is common and allows prolonged growth potential into the 20s. Average adult height in males is Noonan syndrome growth curves are published [29, 30]. Growth hormone production is usually normal but a variety of physiological abnormalities are described which may or may not have consequences for growth or responsiveness to growth hormone [31].

One study suggested that children with more f lorid facial, thoracic and cardiac features of Noonan syndrome had higher peak growth hormone levels [32]. These children did not seem to differ in pre- or post-growth hormone treatment height when compared to children with a milder Noonan syndrome phenotype. Genotype was not reported but may be germane, because higher spontaneous and stimulated growth hormone secretion has been noted in children with PTPN11 mutations [33]. There is a growing body of lite rature on the use of growth hormone therapy in Noonan syndrome [].

Growth velocity is clearly enhanced in the first year of treatment, and, to a lesser extent, in year 2. Growth velocity gradually seems to fall after three years of treatment. The accelerating effect on bone maturation may compromise final height prognosis, although gain in height of 1 SD appears to be sustained. Several studies show improvement in intermediate and final adult height [36, 39, 40].

Use of growth hormone treatment also varies from country to country. Considerable enthusiasm for use remains in the United States. In Canada, growth hormone is only prescribed if growth hormone deficiency is proven. Response to growth hormone therapy may be better in those individuals without PTPN11 mutations [33, 41, 42]. The inferior response to growth hormone, greater likelihood of short stature, and. Gain-of-function mutations in PTPN11 will enhance this effect [33, 43]. Early developmental milestones are often delayed, with average age of sitting at 10 months, first unsupported walking at 21 months and simple two-word phrases at 31 months.

Joint laxity and hypotonia clearly contribute to the motor delay. A large cohort of affected individuals, followed for many years, has demonstrated a strong association between significant feeding difficulties in infancy and intellectual handicap requiring special education [5]. Verbal IQ was slightly higher than performance IQ. Mild to moderate clumsiness and coordination problems were noted in about half the children. Other publications report learning disability with specific visual-constructional problems and verbalperformance discrepancy [44, 46, 47], language delay [4] and strengths in abstract reasoning and social awareness [48].

Studies of behaviour in Noonan syndrome have been somewhat contradictory. One study has suggested an increased likelihood of stubbornness and mood disorders [49]. Another found a majority of a group of 26 individuals to be impulsive, hyperactive and irritable [47]. A more recent study of 48 affected children has shown good self-esteem and has failed to identify a behavioral phenotype [45].

Notably few children are reported with autism,. Few details of psychological health are reported. In males, short stature, hypotonia and reduced athleticism appeared to be predisposing factors. Similar findings were not reported by Shaw et al. Detailed psychological assessment of 10 young adults demonstrated variable levels of intelligence and suggests moderate impairment of social cognition in terms of emotion recognition and alexithymia.

In some individuals there were mild signs of anxiety and lowered mood.

Diagnosis of Noonan syndrome and related disorders using target next generation sequencing

Key elements of this behavioral phenotype are deficiencies in social and emotional recognition and expression [51]. Ocular anomalies are among the most common findings in Noonan syndrome and have been well studied in two large cohorts [5, 52]. Anterior segment changes prominent corneal nerves, anterior stromal dystrophy, cataracts, and panuveitis are frequently found, while coloboma [52, 53], retinitis pigmentosa [54], congenital fibrosis of extraocular muscles [55] and spontaneous corneal rupture [53, 56] are rare associations.

Optic nerve hypoplasia is occasionally reported, in contrast to cardiofaciocutaneous syndrome, which shares many characteristics with Noonan syndrome, and in which optic nerve hypoplasia appears fairly common. The hearing loss described in Noonan syndrome is usually a mild conductive loss secondary to recurrent otitis media, however sensorineural and.

Qui et al. Temporal bone anomalies are reported [59]. The thorax usually displays pectus carinatum superiorly and pectus excavatum inferiorly due to precocious closure of sternal sutures fig. The chest is also broad with wide-spaced nipples. Shoulders are rounded and the upper chest appears long; with low-set nipples and axillary webbing. This chest phenotype provides a good clue to diagnosis. Cubitus valgus, brachydactyly and blunt fingertips are frequently found. There are less common reports of talipes equinovarus, joint contractures, scoliosis, vertebral and rib anomalies, and radio-ulnar synostosis.

The association between Noonan syndrome and malignant hyperthermia is poorly understood. Malignant hyperthermia has been linked to a Noonan phenotype and designated as King syndrome []. The possibility of malignant hyperthermia is of greater concern in individuals with significant muscular pathology or elevated creatine kinase. Giant cell lesions of the jaws identical to those found in cherubism are described []. Cherubism may occur as an isolated autosomal dominant disorder caused by mutations in SH3BP2 [72], or as part of neurofibromatosis. In Ramon syndrome cherubism is associated with juvenile rheumatoid arthritis polyarticular pigmented villonodular synovitis.

Giant cell granulomas, and bone and joint anomalies that include polyarticular pigmented villonodular synovitis, are now recognized to be part of the Noonan syndrome spectrum, and have been reported in individuals with PTPN11 and KRAS mutations [66, 73, 74]. Polyarticular pigmented villonodular synovitis. The chest phenotype showing wide-spaced and low-set nipples, pectus deformity with pectus carinatum superiorly and pectus excavatum inferiorly, and rounded shoulders. Zenker - English / Genetics / Evolution: Books

Reinker, personal communication. This is intriguing given the bleeding diathesis that can accompany Noonan syndrome. Structural anomalies of the central nervous system are unusual. Communicating hydrocephalus is generally described and Clericuzio and colleagues hypothesize that this may be related to extra-cranial lymphatic dysplasia [75]. They refer to studies documenting the drainage of cerebrospinal fluid from the subarachnoid space along the olfactory nerves to the nasal lymphatics, and from there to cervical lymph nodes [79]. There are several reports of Chiari I malformation in Noonan syndrome and additional individuals are known to the author [80, 81].

Other less common structural brain anomalies include schwannoma, Dandy-Walker malformation, and lateral meningocele [82]. Cerebrovascular anomalies have been described in a few individuals []. In males, pubertal development varies from normal virilization with subsequent fertility, to delayed but normal pubertal development, to inadequate sexual development associated with early cryptorchidism and deficient spermatogenesis [90]. Mean age of onset of puberty is Most females are fertile [6, 90].

Rare findings include xanthomas of the skin and oral mucous membranes, leukokeratosis of the lips and gingiva, molluscoid scalp skin, and vulvar angiokeratoma. The cause is unknown, but one might suspect an association with congestive heart failure or myelodysplasia on occasion. Rarely reported anomalies include choledochal cyst and midgut rotation [89]. Dorsal limb lymphedema is the most common finding. It may contribute to increased birth weight, and usually resolves in childhood. Less common abnormalities include generalized lymphedema, pulmonary lymphangiectasia, chylous effusions in pleural or peritoneal spaces, intestinal or testicular lymphangiectasia, and localized lymphedema of scrotum or vulva.

Adolescent or adult onset does occur. Lymphangioma is a rare complication [98, 99]. The most common underlying pathology is lymph vessel hyperplasia with or without a thoracic duct abnormality. Lymphatic aplasia, hypoplasia and megalymphatics are also described. Various skin manifestations are seen in Noonan syndrome including caf-au-lait spots, pigmented nevi, and lentigines [91]. Keratosis pilaris atrophicans has been noted in several instances, predominantly over extensor surfaces and the face [92].

On occasion facial keratosis is severe enough to cause absence of eyebrows and lashes, as seen in cardiofaciocutaneous syndrome. Ectodermal features seem to be more prevalent when Noonan syndrome is caused by mutations in SOS1 [93, 94].

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Prominent fetal fingertip pads are often seen [4]. Multiple subcutaneous granular cell schwannomas are occasionally reported. Several different coagulopathies may occur, either alone or in combination [, ]. They affect about one third of individuals, however, many more will have a history of abnormal bleeding or easy bruising. The range of manifestations is broad, from severe surgical hemorrhage to asymptomatic laboratory abnormalities.

There is poor correlation between bleeding history and actual defect. Laboratory findings include factor XI deficiency, factor XII deficiency, factor VIII deficiency [, ], von Willebrand disease, and platelet dysfunction, which may be associated with trimethylaminuria or acyclooxygenase deficiency [, ]. Some factor deficiencies. There is no evidence of hepatic dysfunction or vitamin K-dependent coagulation factor deficiency. Aspirin-containing medications should be avoided.

Congenital bone marrow hypoplasia, congenital hypoplastic anemia, and pancytopenia have been reported rarely [, ]. A low frequency association with myeloproliferative disorders MPD exists. These include, in particular, juvenile myelomonocytic leukemia JMML , but, more rarely, acute lymphoblastic leukemia [], chronic myelomonocytic leukemia [, ] and proliferation of erythroid precursors [].

JMML associated with Noonan syndrome tends to have an earlier onset and milder presentation than sporadic JMML and spontaneous remission may occur []. Solid tumours such as pheochromocytoma, malignant schwannoma, vaginal and orbital rhabdomyosarcoma, and neuroblastoma have been reported rarely [].

Other autoimmune disorders, such as lupus, celiac disease, vitiligo, anterior uveitis and vasculitis are described infrequently [4, ]. In addition, levels of anti-thyroglobulin and anti-microsomal thyroid antibodies seem to be higher than in the general population []. Antiphospholipid syndrome with Moyamoyalike vascular changes is reported [, ]. During pregnancy certain features may suggest the diagnosis of Noonan syndrome. Lack of septation of the cystic hygroma and regression prior to mid second trimester are associated with more favorable prognosis than those with later regression [, ].

Chorioangiomas are described and may contribute to formation of edema through decreased fetal oncotic pressure secondary to loss of alpha-fetoprotein into amniotic fluid. Arch Dis Child ;92; Birth Defects ; Clin Pediatr ; J Clin Endocrinol Metab ; J Craniofac Genet Dev Biol ; Proc Greenwood Genet Ctr ; Acta Paediatr Jpn ; J Am Coll Cardiol ; Hum Genet ; Eur J Pediatr ; Hum Pathol ; Eur J Cardiothorac Surg ; Am Heart J ; Heart ; Int J Cardiol ; New York, Guilford Press, , pp Eur J Pediatr ; Clin Endocrinol ; J Pediatr Endocrinol Metab ; J Clin Endocrinol Metab ; Acta Paediatr Scand ; Endocr J ; Acta Paediatr ; Horm Res ;53 Suppl 1 Acta Pediatr ; Mol Endocrinol ; Dev Med Child Neurol ; Genet Couns ; Arch Dis Child ; J Intellect Disabil Res ; Am J Med Genet ;A Eye ; Eur J Ophthalmol ; J Postgrad Med ; A case report.

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Molecular Genetics of Noonan Syndrome M. Tartagliaa B. The disorder is generally transmitted as an autosomal dominant trait, although many cases result from de novo mutations. The more than 60 mutations that have been reported are almost all missense changes, and promote upregulation of protein function. While the former are generally more activating compared to the NS-causing mutations, the latter cause loss of catalytic activity of the phosphatase.

As documented for PTPN11, the distributions of affected residues and amino acid substitutions in NS and cancer appear to be largely mutually exclusive. NS-causing SOS1 mutations are activating and affect residues placed. Since binding at residue Ser stabilizes RAF1s catalytically inactive conformation and impairs its translocation to the plasma membrane, mutations affecting this motif promote increased RAF1 activity.

Additional studies are required to fully understand the functional consequences of mutations affecting residues placed within the other two mutational hot spots within the activation segment region of the kinase domain and at the C-terminus. Autosomal dominant inheritance was apparent for the majority of families with the disorder, although evidence suggestive of an autosomal recessive form had been reported [1].

Genetic mapping studies for this disorder were performed with small kindreds with the first report appearing in Since NS shares some features with neurofibromatosis, markers flanking the NF1 and NF2 genes were tested and excluded allelism of NS to those traits [2, 3]. Next, Jamieson and co-workers studied a large Dutch kindred transmitting the trait to perform a genome-wide scan and observed linkage with several markers at chromosome 12qqter, which they named NS1 [4].

They also documented that NS was genetically heterogeneous, based on linkage exclusion to NS1 in some kindreds. The NS1 locus was refined to a region of approximately 7. Legius and co-workers studied a fourgeneration Belgian family transmitting the trait, achieving independent linkage to NS1, and refining the critical interval further to approximately 5 cm [6]. PTPN11 was considered an excellent candidate because it mapped to the NS1 critical region and because its protein product, SHP-2, occupied a critical role in several intracellular signal transduction pathways controlling diverse developmental processes, including cardiac semilunar valvulogenesis [9].

Subsequent studies performed with large, clinically well-characterized cohorts provided an estimate of the relative importance of PTPN11 mutations in the epidemiology of NS, defined the spectrum of molecular defects in the disorder, and established genotype-phenotype correlations []. Based on those efforts, it has. Based on the higher prevalence of pediatric myeloproliferative disorders and leukemias in NS, Tartaglia and co-workers discovered that a different class of missense mutations in PTPN11 occurs as somatic events in myeloid and lymphoid malignancies [], and the identity of PTPN11 mutations conferring susceptibility to these hematological disorders was characterized [17, 20].

While the spectrum and distribution of NS-causing and leukemia-associated mutations provided the first hint about their possible consequences on SHP-2 function, biochemical characterization of a relatively large panel of germline or somatic mutations identified multiple mechanisms promoting SHP-2 gain of function [17, ]. This candidate gene approach represented the best available gene hunting strategy since no sufficiently informative PTPN11 mutation-negative family transmitting the trait had been identified to support a linkage study. Mutation analysis of candidate genes has allowed the identification of.

The syndromes and their mutated proteins are as indicated. The double ovals in dark grey and the light grey ovals represent generic dimerized cell-surface receptors binding to their ligand. The initial structural and biochemical characterization of mutations in these genes has provided evidence for their activating effects on protein function as well as on the hyperactivation of the RAS-MAPK transduction pathway [].

Genotype-phenotype correlation analyses have also documented that mutations in these genes are associated with distinct phenotypes. While other genes are expected to be identified in the next following years, mutational screening efforts focused on genes that encode transducers participating in the RAS-MAPK signaling pathway and are mutated in disorders clinically related to NS have allowed the identification of additional molecular lesions involved in NS pathogenesis.

Indeed, a single missense mutation in MEK1, which encodes a dual specificity kinase. The numbers below that cartoon indicate the amino acid boundaries of those domains. Residues affected by germline left or somatically acquired right mutations are shown with their lateral chains colored according to the classification proposed by Tartaglia et al.

Next, we will briefly review current knowledge on the molecular genetics of NS. Specifically, we discuss the function of the identified disease. It encodes SHP-2,. Table 1. Both the N-SH2 and C-SH2 domains selectively bind to short amino acid motifs containing a phosphotyrosyl residue and promote SHP2s association with cell surface receptors, cell adhesion molecules and scaffolding adapters.

As these subdomains show negative cooperativity, the N-SH2 domain functions as an intramolecular switch controlling SHP-2 catalytic activation. Binding of the N-SH2 phosphopeptide-binding site to a phosphotyrosyl ligand promotes a conformational change of the domain that weakens the auto-. Although it has been demonstrated that SHP2 can either positively or negatively modulate signal flow depending upon its binding partner and interactions with downstream signaling networks, it is now established that SHP-2 positively controls the activation of the RAS-MAPK cascade induced by a number of growth factors and cytokines [].

In most cases, SHP-2s function in intracellular signaling appears to be distal to activated receptors and upstream to RAS. While the mechanisms of SHP-2s action and its physiological substrates are still poorly defined, accumulated evidence supports the view that both membrane translocation and PTPase activity are required for SHP-2 function.

Available records based on more than germline defects indicate that NS-causing PTPN11 mutations are almost always missense changes and are not randomly distributed throughout the gene [27]. Mutations have been classified into six major groups on the basis of their predicted effect on protein function table 1 and fig. Most of the mutations affect.

These mutations are predicted to up-regulate SHP-2 physiological activation by impairing the switch between the active and inactive conformation, favoring a shift in the equilibrium toward the latter, without altering SHP-2s catalytic capability. Recent biochemical and molecular modeling data consistently support this view [24, 27, 42]. A number of mutations, however, affect residues contributing to the stability of the catalytically inactive conformation but also participating in catalysis or controlling substrate specificity.

Finally, a few missense mutations affect residues located in the phosphopeptide binding cleft of each SH2 domain. Experimental evidence supports the idea that these amino acid substitutions promote SHP-2 gain of function by increasing the affinity of the protein for the phosphorylated signaling partners [24, 27] our unpublished observations. Like many autosomal dominant disorders, a significant but not precisely determined percentage of cases results from de novo mutations. To investigate the parental origin of de novo mutations in NS, Tartaglia and co-workers studied 46 families, each consisting of an affected individual heterozygous for a PTPN11 mutation and unaffected parents [43].

Among the fourteen informative families identified in the study, the mutation was of paternal origin in all cases. Moreover, advanced paternal age was noted among fathers of sporadic NS cases with or without PTPN11 mutations, consistent with many, but not all, other autosomal dominant disorders with paternal origin of spontaneous mutations. Notably, a sex-ratio bias in transmission of the PTPN11 mutations was also observed within families transmitting. NS as well as for individuals with sporadic NS.

This bias favored males by a factor of The available data point to this bias being attributable to sex-specific developmental effects of PTPN11 mutations that favor survival of affected male embryos compared to female ones. Among families transmitting the trait, there were more transmitting mothers than fathers, a significant difference that can be ascribed to reduced fertility of male individuals with NS [44]. In this family, two siblings had lesions in the mandible while their mother only had typical features of NS [45].

The same mutation has been observed in individuals with sporadic NS and families segregating the condition without any bony involvement. More recently, mutational analysis of three unrelated families inheriting this disorder revealed PTPN11 mutations in two [14]. Consistent with this view, this trait is genetically heterogeneous.

Missense PTPN11 mutations have also been identified in LS [15, 16], a developmental disorder closely related to NS, with major features including multiple lentigines, short stature, distinctive face, cardiac defects and electrocardiographic conduction abnormalities, abnormal genitalia and sensorineural deafness [47, 48].


Analysis of several unrelated individuals with a phenotype fitting or suggestive of LS has confirmed the presence of a heterozygous PTPN11 mutation in the vast majority of cases. TyrCys and ThrMet represent the most common defects, even though additional mutations have been documented see. The elucidation of the pathogenesis of NS, particularly with respect to the developmental perturbations, depends upon studies of animal models. Araki and co-workers generated and characterized a knock-in mouse bearing the Asp61Gly mutation in the Ptpn11 gene [49].

Both homozygous and heterozygous mice had a conspicuous phenotype. The former genotype was an embryonic lethal. At day E Myocardial development was grossly normal. The other half of these embryos had mitral valve enlargement. Other aspects of the NS phenotype were also observed in the heterozygotes, including proportional growth failure, cardiofacial dysmorphism, and a mild leukocytosis with increased neutrophils and lymphocytes in adult mice.

Splenomegaly was present due to extramedullary hematopoiesis. There was a myeloid expansion in the bone marrow and spleen. Hence, this genetic defect engendered a mild myeloproliferative disease similar to that observed in some NS patients. New information concerning gain-of-function Shp-2 and development has emerged through work with transgenic flies [50]. The Drosophila homolog of PTPN11, corkscrew csw , acts downstream of several receptor tyrosine kinases.

While ubiquitous expression of leukemia-associated csw transgenic alleles engendered embryonic or larval lethality, expression of an NS-causing allele, ND, resulted in ectopic wing vein formation. Activation of Ras was necessary but not sufficient for the expression of these phenotypes. Since the ectopic wing vein phenotype closely resembled that observed with Egfr gain of function, epistatic studies with genes relevant for Egfr-Ras-Mapk signaling showed that the ND allele interacted genetically with nearly all genes in the pathway, documenting dependence on the activation of the receptor by its ligand for ectopic wing vein formation [50].

Children with NS are predisposed to a spectrum of hematologic abnormalities, including juvenile myelomonocytic leukemia JMML , a clonal myeloproliferative disorder of childhood characterized by excessive proliferation of immature myelomonocytic cells that infiltrate hematopoietic and non-hematopoietic tissues [52, 53]. PTPN11 mutation analysis on a relatively large number of children with NS and JMML has demonstrated the presence of germline mutations in the majority of cases, as well as the occurrence of genotype-phenotype correlations [17, 20, 22].

In particular, one mutation, a C-to-T transition at position Thr73Ile , was observed to occur in a large percentage of children, a striking finding since that lesion has a very low prevalence among NS-causing mutations. Indeed, somatic missense mutations in PTPN11 have been demonstrated to occur in approximately one-third of isolated JMML as well as variable proportions of other myeloid and lymphoid malignancies of childhood [, 22, 27, 54, 55].

The prevalence of PTPN11 mutations among adult patients with myeloid or lymphoid disorders appears to be considerably lower than observed among pediatric cases [27, ] our unpublished data , even though SHP-2 overexpression has been documented in adult human leukemia [60]. Similarly, PTPN11 is only rarely mutated in non-hematologic cancers [59, 61].

As observed in NS, the vast majority of PTPN11 lesions identified in this heterogeneous group of hematologic malignancies are missense changes that alter residues located at the interface between the N-SH2 and PTP domains. Remarkably, the available molecular data indicate that specificity in the amino acid substitution is relevant to the functional deregulation of SHP-2 and disease pathogenesis table 1 and fig. Indeed, comparison of the molecular spectra observed with the NS and leukemias indicate a clear-cut genotypephenotype correlation, strongly supporting the idea that the germline transmitted PTPN11 mutations have different effects on development and hematopoiesis than those acquired somatically.

Consistent with this, the biochemical behavior of SHP-2 mutants associated with malignancies tend to be more activating than observed with the NSassociated mutant proteins [24, 27, 42]. Moreover, the leukemia-associated PTPN11 mutations upregulate RAS signaling and induce cell hypersensitivity to growth factors and cytokines more than the NS defects do [17, 22, 23, 25].

Overall, the available genetic, modeling, biochemical and functional data support a model in which distinct gain-of-function thresholds for SHP-2 activity are required to induce cell-, tissue- or developmental-specific phenotypes, each depending on the transduction network context involved in the phenotype. According to this model, SHP The diversity of mutations associated with these developmental disorders as well as their phenotypic spectrum have been investigated further, refining the picture of a clustered distribution of germline disease-associated KRAS defects, and confirming the high clinical variability [35, 37].

KRAS gene organization and protein domain structure. The conserved domain G domain is indicated, together with the motifs required for signaling function PM1 to PM3 indicate residues involved in binding to the phosphate groups, while G1 to G3 are those involved in binding to the guanine base. The hypervariable region is shown in grey, together with the C-terminal motifs that direct post-translational processing and plasma membrane anchoring dark grey.

The numbered black and grey boxes indicate the invariant coding exons and exons undergoing alternative splicing, respectively. As previously documented for PTPN11, the distributions of affected residues and amino acid substitutions in NS and cancer appear to be largely mutually exclusive table 2 and fig. Exon 1 contains most of the 5 untranslated region, with the last few bases of it residing in exon 2 along with the translation initiation ATG shared by the two mRNAs. For the KRASA transcript, exon 5 contains the stop codon and a portion of the 3 untranslated region,. For the KRASB transcript, exon 5 is skipped so exon 6 comprises a portion of the coding region, the stop codon and the entire 3 untranslated region.

Table 2. RAS proteins share a structure that includes a conserved domain residues 1 to , known as the G domain, which is required for its signaling function, and a less conserved C-terminal tail, called the hypervariable region, that guides posttranslational processing and plasma membrane anchoring fig.

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Consistent with these data, cells expressing each of the two mutants were hyper-responsive to hematopoietic growth factors. Although these studies documented a complex pattern of intrinsic biochemical properties, expression of these mutants in COS-7 cells promoted higher levels of phosphorylated MEK and ERK proteins, indicating hyperactivation of the MAPK cascade [34]. Consistent with these findings, expression of these mutants in murine fetal liver cells conferred variable hyper-responsive behavior to GM-CSF.

It should be noted that, different from what observed for cells expressing the cancer-associated Gly12Asp mutants, cell growth in these cells remained dependent on growth factor stimulation [34]. In general, the C-termini of RAS proteins are subjected to post-translational modifications, which have important implications for their functions [67].

This differential processing of the two KRAS isoforms leads to alternative trafficking pathways to the plasma membrane and distinct membrane localization [63]. Moreover, recent evidence demonstrates that the two KRAS isoforms play distinct roles in development. Although KRAS mutations affecting domains shared by the two isoforms can cause NS and CFCS, the identification of exon 6 mutations documented that isolated KRASB gain of function is sufficient for disease pathogenesis, further evidence that isoform B plays the major role in development. Cell surface tyrosine kinase receptors activate RAS proteins by recruiting GEF proteins to the cytoplasmic side of the plasma membrane.

Exons 2 to 24 encompass the open reading frame that encodes a large multidomain protein of 1, residues [74].


SOS1 domain structure and location of affected residues in NS. Residues affected by mutations are indicated with their lateral chains histone folds, violet; HD, blue; PH, green; helical linker, red; Rem, orange; Cdc25, cyan. Based on Sondermann et al. Additional anchorage sites on the membrane are provided by the phosphatidylinositol phosphate-binding site within the PH domain [77], and an extended positively charged surface of the HD domain [78].

Sos1 is widely expressed, and different from Sos2, which is dispensable for mouse development, loss of Sos1 function results in a range of embryonic defects, including cardiovascular abnormalities, causing mid-gestational lethality [79]. Thus far, all of the mutations identified are missense and affect multiple domains, clustering in specific regions of the protein fig. Whereas the former is located entirely within the Cdc25 domain, the allosteric site is bracketed by the Cdc25 domain and REM domains.

The mechanism of activation of the protein is complex: in basal conditions, the interaction between the DH and REM domains stabilizes SOS1 in its catalytically inactive conformation by masking the allosteric binding site for RAS. Following SOS1 translocation to the membrane,. Remarkably, most of NS-associated SOS1 mutations reside in regions within the molecule that are predicted to contribute structurally to the maintenance of the catalytically autoinhibited conformation. Specifically, structural data indicate that Arg interacts directly with the side chains of Asp and Asp in the histone domain of SOS1 [78].

A similar perturbing effect is predicted for the other amino acid substitutions involving residues located in the helical linker connecting the PH and REM domains fig. While the mutation cluster affecting residues to may disrupt the autoinhibited conformation by destabilizing the PH domains conformation, the third cluster of mutations affects residues MR, WL and IF located in the interacting surfaces of the DH and REM domains. Among them, Trp interacts directly with Met, thereby positioning the DH domain in its autoinhibitory conformation.

Biochemical data confirmed these predictions and demonstrated that NS-causing SOS1 mutations promote gain-of-function. A fifth mutant TyrCys was unstable and did not accumulate significantly. In starved cells, ArgGly and TrpLeu expression resulted in modest. The proto-oncogene RAF1 also known as CRAF kinase was identified through its homology to the v-Raf oncogene contained in certain oncogenic murine and avian retroviruses [82]. Furthermore, based on the murine knock-out models, they appear to have unique roles during development []. CR2 contains a negative regulatory domain controlling protein translocation to the membrane and its catalytic activation, while the C-terminal CR3 comprises the kinase domain of the protein [83].

RAF1 is required during development since loss of its function is embryonic lethal [87]. RAF1 mutations affected residues clustered in three regions of the protein fig. Of note, Arg, Ser, Ser and Pro, which are the invariant residues within this motif, were all found to be mutated. Interestingly, several BRAF missense mutations detected in solid tumors alter the activation segment, including some AspGly and ThrIle homologous to those identified in subjects with NS [83]. They identified a single missense mutation ThrIle in a male patient who had been diagnosed with HCM at age 3 years [30].

Since this cohort included only 10 individuals with HCM presenting before age 13, additional studies of pediatric HCM may be warranted. RAF1 catalytic activation is complex. In its inactive conformation, the N-terminal portion of the protein is thought to interact with and inactivate the kinase domain at the C-terminus. This autoinhibited conformation is stabilized by 14 33 protein dimers that bind to phosphorylated Ser and Ser []. Dephosphorylation of Ser, which is possibly mediated by protein phosphatase 2A PP2A or protein phosphatase 1C PP1C , is required for stable interaction with GTP-RAS, allowing protein translocation to the plasma membrane and further interaction with other still uncharacterized proteins.

To examine the functional consequences of RAF1 mutations, Pandit and co-workers expressed mutants from each of the three. RAF1 domain structure and location of affected residues in human disease. BRAF domain structure below is reported for comparison, together with location of residues altered in developmental disorders black or those more commonly mutated in human cancers prevalence higher than 1.

In contrast, AspAsn and ThrIle, representing the mutation cluster in the activation segment and not associated with HCM, were observed to be kinase impaired [30]. Their pathogenetic mechanism awaits explanation. Pandit and co-workers also investigated the status of binding for the ProSer and LeuVal RAF1 mutants, and demonstrated that the increased activation promoted by the.

This finding is consistent with the data obtained by Light and co-workers who engineered SerLeu Raf1 and demonstrated that this mutant protein had normal phosphorylation at Ser but failed to bind and had increased kinase activity [93]. On the contrary, the LeuVal mutant bound to normally at Ser and had normal phosphorylation of Ser so the mechanism through which mutations in this cluster activated RAF1s MEK kinase activity remains to be explained.

Of note, even though MEK kinase activity is necessary for cell transformation via the MAPK cascade [97], and constitutively active MEK mutants promote transformation [98], mutations in these genes have not been reported in human cancers [99]. Functional characterization of the three mutants documented that their transient expression in T cells were more active than the wild type protein in stimulating ERK phosphorylation basally. A missense mutation in MEK1, predicting the Asp67Asn amino acid substitution, has recently been reported in two unrelated subjects with sporadic NS [37].

One additional previously unreported variant Glu44Gly , which was identified in a third sporadic case and her apparently clinically unaffected mother but not in population-matching controls, is likely to represent a private polymorphism. The MEK proteins share a conserved structure including a negative regulatory domain at the N-terminus and a single protein kinase domain.

In particular, genetic evidence from. These steps are preludes to developing improved diagnostics and therapeutics for this genetic disorder. Acknowledgements The authors apologize to colleagues whose work was not cited due to limited space. Eur J Hum Genet ; J Med Genet ;e Am J Hum Genet ; Blood ; Hum Mutat ; Implications for disease phenotypes. J Biol Chem ; Cancer Cell ; Mol Cell Biol ; Trends Biochem Sci ; Curr Opin Hematol ; Cell ; Proteins ; Birth Defects Orig Artic Ser ; Am J Med ; Hum Mol Genet ; Dev Biol ; Mol Med Today ;