#163950ICD+ NOONAN SYNDROME 1; NS1

Alternative titles; symbols NOONAN SYNDROME MALE TURNER SYNDROME FEMALE PSEUDO-TURNER SYNDROME TURNER PHENOTYPE WITH NORMAL KARYOTYPE Other entities represented in this entry:

PTERYGIUM COLLI SYNDROME, INCLUDED

Phenotype Gene Relationships
Location 12q24.13 Phenotype Noonan syndrome 1 Phenotype MIM number 163950 Gene/Locus PTPN11 Gene/Locus MIM number 176876

Description
Noonan syndrome (NS) is an autosomal dominant dysmorphic syndrome characterized by hypertelorism, a downward eyeslant, and low-set posteriorly rotated ears (Shah et al., 1999). Other features include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, epicanthic folds, deafness, motor delay, and a bleeding diathesis. Noonan syndrome has an estimated incidence of 1 in 1,000 to 2,500 live births (Tartaglia et al., 2001). Tartaglia et al. (2010) provided a detailed review of the clinical and molecular features of Noonan syndrome. Genetic Heterogeneity of Noonan Syndrome

See also NS3 (609942), caused by mutation in the KRAS gene (190070); NS4 (610733), caused by mutation in the SOS1 gene (182530); NS5 (611553), caused by mutation in the RAF1 gene (164760); NS6 (613224), caused by mutation in the NRAS gene (164790); and NS7 (613706), caused by mutation in the BRAF gene (164757).

See also NS2 (605275) for an autosomal recessive form of NS; Noonan syndromelike disorder with loose anagen hair (NSLH;607721), caused by mutation in the SHOC2 gene (602775); and Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL; 613563), caused by mutation in the CBL gene (165360). Mutations in the neurofibromin gene (NF1; 613113), which is the site of mutations causing classic neurofibromatosis type I (NF1;162200), have been found in neurofibromatosis-Noonan syndrome (NFNS; 601321).

Clinical Features
The disorder now known as Noonan syndrome bears similarities to the disorder described by Turner (1938) and shown by Ford et al. (1959) to have its basis in a 45,X chromosomal aberration. (With considerable justification, Ullrich's name is combined with that of Turner as the designation for the 45,X syndrome. Ullrich described the disorder 8 years before Turner. Wiedemann and Glatzl (1991)provided a follow-up of Ullrich's original patient with Ullrich-Turner syndrome and demonstrated that the restudy in 1987, when the patient was 66 years old, confirmed the 45,X chromosome constitution.) Noonan (1968) reported 19 cases of whom 17 had pulmonary stenosis and 2 had patent ductus arteriosus (see 607411). Twelve were males and 7 were females. Deformity of the sternum with precocious closure of sutures was a frequent feature. Kaplan et al. (1968)described 2 brothers with elevated alkaline phosphatase levels, one of whom also had malignant schwannoma of the forearm. Nora and Sinha (1968) observed mother-to-offspring transmission in 3 families; in 1 family, transmission was through 3 generations. They suggested Xlinked dominant inheritance of either a single mutant gene or a submicroscopic deletion. Among 95 male patients with pulmonary stenosis, Celermajer et al. (1968) found the Turner phenotype in 8. In 5 of these, karyotyping was performed. In 4 the chromosomes were normal. In one an extra acrocentric chromosome was present. Abdel-Salam and Temtamy (1969) reported 2 affected sibs from a first-cousin marriage. A deceased female sib may have been affected also. They suggested autosomal recessive inheritance. Baird and De Jong (1972) described 7 cases in 3 generations. One affected woman had 5 affected children (out of 6) with 2

different husbands. Seizures and anomalous upper lateral incisors may have been coincidental. Diekmann et al. (1967) described 2 brothers and a sister, with normal and unrelated parents, who had somatic characteristics of the Noonan syndrome, particularly pterygium colli and deformed sternum, and had myocardiopathy leading to death at ages 12 and 10 in two of them. Migeon and Whitehouse (1967) described 2 families, each with 2 sibs with somatic features of the Turner syndrome. In 1 family, 2 brothers had webbing of the neck, coarctation of the aorta, and cryptorchidism. In the second, a brother and sister were affected. Simpson et al. (1969) reported experiences suggesting that rubella embryopathy may result in the Turner phenotype, thereby accounting for either the male Turner syndrome or the female pseudo-Turner syndrome. A particularly convincing pedigree for autosomal dominant inheritance was reported by Bolton et al. (1974), who found the condition in a man and 4 sons (in a sibship of 10). Four of the 5 affected persons had pulmonic stenosis. Father-to-son transmission was reported by Qazi et al. (1974). Koretzky et al. (1969) described an unusual type of pulmonary valvular dysplasia which showed a familial tendency with either affected parent and offspring or affected sibs. Although some relatives had pulmonary valvular stenosis of the standard dome-shaped variety, the valvular dysplasia in others was characterized by the presence of three distinct cusps and no commissural fusion. The obstructive mechanism was related to markedly thickened, immobile cusps, with disorganized myxomatous tissue. Other features were retarded growth, abnormal facies (triangular face, hypertelorism, low-set ears and ptosis of the eyelids), absence of ejection click, and unusually marked right axis deviation by electrocardiogram. It now seems clear that the patients of Koretzky et al. (1969) had the Noonan syndrome. Mendez and Opitz (1985) stated that the Watson syndrome (193520) and the LEOPARD syndrome (151100) 'are essentially indistinguishable from the Noonan syndrome.' Witt et al. (1987) reviewed the occurrence of lymphedema in Noonan syndrome. When it does occur, it opens the possibility of prenatal diagnosis by imaging methods or by AFP level. Noonan syndrome was one of the causes found for posterior cervical hygroma in a series of previable fetuses studied by Kalousek and Seller (1987). The authors found, furthermore, that 45,X Turner syndrome lethal in the fetal period showed a constant association of 3 defects, posterior cervical cystic hygroma, generalized subcutaneous edema, and preductal aortic

coarctation. Evans et al. (1991) found a large cutaneous lymphangioma of the right cheek and amegakaryocytic thrombocytopenia in a male infant with Noonan syndrome. Donnenfeld et al. (1991) presented a case of Noonan syndrome in which posterior nuchal cystic hygroma was diagnosed at 13 to 14 weeks of gestation by ultrasonography. The hygroma had regressed by the time of birth leaving nuchal skin fold redundancy and pterygium colli. On the basis of studies of genital tract function in 11 adult males with Noonan syndrome, Elsawi et al. (1994) concluded that bilateral testicular maldescent was a main factor in contributing to impairment of fertility. Four of the 11 men had fathered children. Thrombocytopenia occurs in some cases of the Noonan syndrome (Goldstein, 1979). Partial deficiency of factor XI was described byKitchens and Alexander (1983). Out of 9 patients with Noonan syndrome, de Haan et al. (1988) found 4 with partial deficiency of factor XI (30-65% of normal). They reviewed the other reports of bleeding tendency associated with thrombocytopenia or with abnormal platelet function. Witt et al. (1988) described bleeding diathesis in 19 patients with Noonan syndrome. Several different defects were identified in the coagulation and platelet systems, occurring singly or in combination; for example, 2 patients had factor XI deficiency, 3 had presumptive von Willebrand disease, and 1 had thrombocytopenia. In 5 of the patients an unusually pungent odor of urine and sweat was noted by parents. One of these patients was reported by Humbert et al. (1970) as a case of trimethylaminuria (136131) and another patient was suspected of having this condition. Sharland et al. (1990) also described a variety of coagulation factor deficiencies. The most common abnormality was a partial factor XI deficiency in the heterozygote range, found in 21 of 31 patients. Of 72 patients studied (37 male, 35 female, mean age 11.4 years) by Sharland et al. (1992), 47 (65%) had a history of abnormal bruising or bleeding. In 29 patients (40%), prolonged activated partial thromboplastin time was found. In 36 patients (50%) specific abnormalities were found in the intrinsic pathway of coagulation, i.e., partial deficiency of factor XI:C, XII:C, and VIII:C. Multiple abnormalities among these 36 patients included combined deficiencies of factors XI and XII (4 patients), of factors XI and VIII (4 patients), and of factors VIII, XI, and XII (1 patient). In 5 families, similar coagulation-factor deficiencies were present in first-degree relatives. Sharland et al. (1992) suggested that because of the involvement of several factors, either singly or in combination, there are likely to be regulatory factors that control the intrinsic (contact activation) system; that these factors are

under chromosomal genetic control; and that abnormalities of this regulation occur in Noonan syndrome. Lee et al. (1992) reviewed the ophthalmologic and orthoptic findings in 58 patients with Noonan syndrome. External features were hypertelorism (74%), downward sloping palpebral apertures (38%), epicanthal folds (39%), and ptosis (48%). Orthoptic examination revealed strabismus in 48%, refractive errors in 61%, amblyopia in 33%, and nystagmus in 9% of cases. Anterior segment changes, found in 63% of patients, included prominent corneal nerves (46%), anterior stromal dystrophy (4%), cataracts (8%), and panuveitis (2%). Fundal changes occurred in 20% of patients and included optic nerve head drusen, optic disc hypoplasia, colobomas, and myelinated nerve fiber layer. Lee et al. (1992) recommended early ophthalmic examination of children with Noonan syndrome. Allanson et al. (1985) studied the changes in facial appearance with age. They pointed out that the manifestations may be subtle in adults. Ranke et al. (1988) analyzed the clinical features of 144 patients from 2 West German centers. The size at birth was normal in both sexes. In both males and females, the mean height followed along the 3rd percentile until puberty, but decreased transiently due to an approximately 2-year delay in onset of puberty. Final height approaches the lower limits of normal at the end of the second decade of life. The mean adult height was 162.5 cm in males and 152.7 cm in females, respectively. Allanson (1987) provided a useful review. The fetal primidone syndrome, occurring in the offspring of mothers taking this anticonvulsant, closely simulates the Noonan syndrome. Baraitser and Patton (1986) reported 4 unrelated children (2 boys, 2 girls) with a Noonan-like syndrome associated with sparse hair as a conspicuous feature. Leichtman (1996) reported a family suggesting that cardiofaciocutaneous syndrome (CFC; 115150) is a variable expression of Noonan syndrome. He described a 4-year-old girl who had all of the manifestations of CFC syndrome (characteristic facial and cardiac anomalies, developmental delay, hypotrichosis, eczematic eruption with resistance to treatment), whose mother had typical characteristics of Noonan syndrome. Lorenzetti and Fryns (1996) reported a 13year-old boy with Noonan syndrome and retinitis pigmentosa. Because similar eye defects are found in CFC syndrome, the authors suggested that CFC and Noonan syndromes might be variable manifestations of the same entity. However, Neri

and Zollino (1996) noted distinctions between the patient reported byLorenzetti and Fryns (1996) and CFC syndrome, and stated that similarity of eye defects is not enough to conclude that CFC and Noonan syndromes are the same condition. Early feeding difficulties are common in Noonan syndrome but often go unrecognized. Shah et al. (1999) studied a consecutive series of children with Noonan syndrome whose diagnosis had been confirmed by a clinical geneticist. Sixteen had poor feeding (poor suck or refusal to take solids or liquids) and symptoms of gastrointestinal dysfunction (vomiting, constipation, abdominal pain, and bloating). All 16 had required nasogastric tube feeding. Seven of the 25 had foregut dysmotility and gastroesophageal reflux. In 4 of these, electrogastrography and antroduodenal manometry demonstrated immature gastric motility reminiscent of that of a preterm infant of 32 to 35 weeks' gestation. Other children had less severe forms of gastric dysmotility. The authors highlighted the importance of recognizing this common, treatable feature of Noonan syndrome. Lemire (2002) described a father, son, and daughter with an apparently autosomal dominant disorder characterized by craniofacial anomalies, coarctation of the aorta, hypertrophic cardiomyopathy, and other structural heart defects with normal psychomotor development. Some clinical features such as webbed neck, low-set ears, low posterior hairline, and widely spaced nipples suggested Noonan syndrome. Alternatively, a previously unrecognized disorder was considered. The paternal age at the father's birth was 50 years. The father presented at age 13 years when postductal coarctation of the aorta was discovered during routine physical examination. Preoperative evaluation showed hypertrophied interventricular septum with pulmonic stenosis and bicuspid aortic valve in addition to the aortic coarctation. At age 22 years, echocardiogram showed marked systolic thickening of interventricular septum and posterior wall of the left ventricle and concentric left ventricular hypertrophy. He later developed atrial flutter and congestive heart failure. His son was recognized at birth to have 2 small ventricular septal defects, mildly hypoplastic aortic arch, and coarctation of the aorta. The coarctation was repaired at age 14 days and bilateral inguinal hernias at age 5 weeks. At age 9 months, he was found to have congestive heart failure due to a restrictive cardiomyopathy. At age 10 months, studies confirmed the presence of spongy myocardium with much impaired diastolic function. He died of early acute graft failure at age 14 months after heart transplantation. Autopsy showed restrictive cardiomyopathy with generalized myocardium

hypertrophy. The daughter was found at birth to have a small ventricular septal defect, small patent ductus arteriosus, aneurysm of the atrial septum, and coarctation of the aorta. Cardiomyopathy was suspected on the basis of excessive thickening of the lower two-thirds of the interventricular septum and of the free wall of the right ventricle. Coarctation of the aorta was repaired surgically at age 19 days. At age 10.5 months, she was noted to have plagiocephaly, facial asymmetry with left side smaller than the right, webbed neck, asymmetric chest with widely spaced nipples, and edema of the dorsum of the feet. At age 2 years, bicuspid aortic valve and diffuse concentric hypertrophy of the left ventricle were noted. Juvenile myelomonocytic leukemia (JMML; 607785) has been observed in some cases of Noonan syndrome (Bader-Meunier et al., 1997; Fukuda et al., 1997; Choong et al., 1999). Holder-Espinasse and Winter (2003) described a 6-year-old girl with clinical features of Noonan syndrome, short stature, and headache who was noted to have Arnold-Chiari malformation (207950) on MRI. They cited 3 previous reports of Noonan syndrome and Chiari malformation and/or syringomelia (Ball and Peiris, 1982; Gabrielli et al., 1990; Colli et al., 2001). Holder-Espinasse and Winter (2003) concluded that Chiari malformation should be considered part of the Noonan syndrome spectrum and that brain and cervical spine MRI should be required in patients with Noonan syndrome, particularly if headaches or neurologic symptoms are present. For a comprehensive review of Turner syndrome, including clinical management, see Ranke and Saenger (2001). Kondoh et al. (2003) described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a 3-month-old Japanese patient with Noonan syndrome and a de novo missense mutation in the PTPN11 gene (176876.0007). Noonan et al. (2003) reported their findings in 73 adults over 21 years of age with Noonan syndrome. In 30%, adult height was in the normal range between the 10th and 90th percentiles. More than half of the females and nearly 40% of males had an adult height below the third percentile. The presence or severity of heart disease was not a factor, and none of the adults with normal height had been

treated with growth hormone. Serial measurements of height over many years through childhood to adulthood were available in only a few patients, but their pattern of growth suggested that catch up may occur in late adolescence. The possible benefit of growth hormone therapy could not be evaluated. Croonen et al. (2008) evaluated ECG findings and cardiographic abnormalities in 84 patients with Noonan syndrome, 54 (67%) of whom were positive for a mutation in the PTPN11 gene. As reported previously, pulmonary stenosis was the most common cardiac abnormality, followed by atrial septal defect and hypertrophic cardiomyopathy. ECG showed at least 1 characteristic finding in 50% of cases, including left axis deviation in 38 (45%), small R waves in the left precordial leads in 20 (24%), and an abnormal Q wave in 5 (6%) Noonan patients; however, these ECG findings were not associated with a PTPN11 mutation or with a specific cardiac anomaly. Among 40 Italian patients with Noonan syndrome, Ferrero et al. (2008) found short stature in 92%, congenital heart defect in 82.5%, isolated pulmonic stenosis in 60.6%, and hypertrophic obstructive cardiomyopathy in 12.2%. Prenatal anomalies were observed in 25% of cases, with polyhydramnios being the most common. PTPN11 mutations were detected in 11 sporadic patients and 1 family, totaling 12 (31.5%) of 38 cases. One patient without a detectable mutation had a Chiari I malformation with seizures. Another of the remaining patients had a mutation in the SOS1 gene.

Other Features
Some patients with Noonan syndrome develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villomoduolar synovitis (PVNS) when occurring in the jaw or joints. Early reports described this as a separate disorder (Leszczynski et al., 1975; Lindenbaum and Hunt, 1977; Wagner et al., 1981); however, it is now considered part of the phenotypic spectrum of Noonan syndrome (Tartaglia et al., 2010). Cohen et al. (1974) described a patient with short stature, ocular hypertelorism, prominent posteriorly angulated ears, short webbed neck, cubitus valgus, pulmonic stenosis, multiple lentigines, and giant cell lesions of both bone and soft tissue. Cohen (1982) presented a photographic montage of the patient. Cohen and Gorlin (1991) reviewed further known cases to a total of 14. Chuong et al. (1986)studied central giant cell lesions of the jaw in 17 patients and noted that 2

of

these

occurred

in

patients

with

Noonan

syndrome.

Ucar et al. (1998) described a patient with Noonan syndrome and PVNS. As indicated by the photographs provided, the patient showed facies and sternal configuration typical of Noonan syndrome. Cubitus valgus, pulmonary valve stenosis, and patent foramen ovale, as well as cryptorchidism, were also present. A central giant cell granuloma was found originating from the lateral wall of the right maxillary sinus and caused the presenting complaint of proptosis of the right eye. (Giant cell granulomas in the head and neck region are called central when they occur in bone and peripheral when they occur in gingiva or alveolar mucosa.) In this family the patient's father also had the phenotype of Noonan syndrome, suggesting autosomal dominant inheritance. Bertola et al. (2001) described a family with typical clinical findings of Noonan syndrome associated with giant cell lesions in maxilla and mandible. The authors raised the possibility that Noonan syndrome and Noonan syndrome-like disorder with multiple giant cell lesions might be allelic disorders. This was indeed demonstrated to be the case by Tartaglia et al. (2002), who found a mutation in the PTPN11 gene (176876.0004), which is the site of mutation in about half of unrelated individuals with sporadic or familial Noonan syndrome.

Inheritance
Noonan syndrome is inherited in an autosomal dominant pattern (Tartaglia et al., 2010). Wendt et al. (1986) reported a man with polyarticular pigmented villonodular synovitis who had an affected son and daughter.Dunlap et al. (1989) made reference to the fact that the father of one of his cases was affected with Noonan syndrome and PVNS.

Mapping
Exclusion of the NF1 Locus on Chromosome 17q

Using a number of probes at the neurofibromatosis type I locus in the study of 11 families with Noonan syndrome in 2 or 3 generations, Sharland et al. (1992) excluded proximal 17q as the location of the gene. Studying six 2generation families with classic Noonan syndrome, Flintoff et al. (1993) could find no evidence of linkage of this disorder to NF1 on 17q or to NF2 (101000) on 22q.

Linkage

to

Chromosome

12q

By means of a genomewide linkage analysis in a large Dutch kindred with autosomal dominant Noonan syndrome, Jamieson et al. (1994) localized the gene to chromosome 12; maximum lod = 4.04 at theta = 0.0. Linkage analysis using chromosome 12 markers in 20 smaller, 2-generation families gave a maximum lod of 2.89 at theta = 0.07, but haplotype analysis showed nonlinkage in 1 family. These data suggested that a gene for Noonan syndrome is located in the 12q22qter region between markers D12S84 and D12S366. Clinical studies in this kindred were reported by van der Burgt et al. (1994). Brady et al. (1997) further analyzed the 3-generation Dutch family studied by Jamieson et al. (1994) using newly isolated CA-repeat markers derived from the interval between D12S84 and D12S366. In this way they were able to reduce the localization to an interval bounded by markers D12S105 and NOS1 (163731), which has been mapped to 12q24.2-q24.31. Legius et al. (1998) performed linkage analysis in a 4-generation Belgian family with Noonan syndrome in some individuals and CFC syndrome in others. Clinical and linkage data in this family indicated that the 2 syndromes result from variable expression of the same genetic defect. They found a maximum lod score of 4.43 at zero recombination for marker D12S84 in 12q24. A crossover in this pedigree narrowed the candidate gene region to a 5-cM interval between D12S84 and D12S1341. A remarkable feature of the family studied by Legius et al. (1998) was the presence of 3 dizygotic twins in the offspring of 2 affected females. A dizygotic twin pair was observed in the offspring of an affected female in the family in which linkage was studied by Jamieson et al. (1994). It is possible that an increased frequency of dizygotic twinning is associated with NS1/CFC linked to 12q24. The fragile X syndrome (300624) is another mendelian disorder with a possibly increased frequency of dizygotic twinning (Partington et al., 1996; Schwartz et al., 1994). In a study of candidate genes, Ion et al. (2000) excluded the genes EPS8 (600206) and DCN (125255) from the critical region by FISH analysis. They also excluded the MYL2 (160781) and RPL6 (603703) genes by mutation analysis.

Cytogenetics

Robin et al. (1995) described 6 patients with Noonan syndrome who underwent molecular evaluation for submicroscopic deletion of chromosome 22q11. None of these patients presented with conotruncal heart defects. Evidence for 22q11 hemizygosity was demonstrated in only 1 patient. This patient had Noonan-like manifestations without clinical manifestations of DiGeorge (188400) or velocardiofacial (192430) syndromes. Digilio et al. (1996) studied 4 patients with Noonan syndrome and tetralogy of Fallot. Chromosome analysis was normal in all 4 patients. DNA analysis showed no hemizygosity for the 22q11 region in any of the patients. Duplication of Chromosome 12q24.13

Shchelochkov et al. (2008) described a 3-year-old girl with clinical features consistent with Noonan syndrome. She presented with postnatal-onset failure to thrive, microcephaly, velopalatal incompetence, pectus excavatum, aortic coarctation, and atrial and ventricular septal defects. Facial features included ptosis, hypertelorism, epicanthal folds, cupped simple ears, and wide mouth with downturned corners. Speech and fine and gross motor development were at the level of a 12- to 18-month-old child, atypical for a child with Noonan syndrome. Array-CGH showed an interstitial 10-Mb duplication, 12q24.11-q24.23, that includes the genes PTPN11 (176876), TBX5 (601620), and TBX3 (601621). This was confirmed by FISH analysis and chromosome analysis. Sequencing of PTPN11, KRAS (190070), SOS1 (182530), and the coding region of RAF1 (164760) did not reveal any pathogenic mutations.Shchelochkov et al. (2008) proposed that duplications of the region containing PTPN11 may result in a Noonan syndrome phenotype and may account for the basis of Noonan syndrome in some of the 15 to 30% of patients for whom no mutations can be detected by sequencing of components of the RAS/MAPK signaling pathway. Graham et al. (2009) reported another patient with Noonan syndrome caused by an 8.98-Mb duplication on chromosome 12q24.13 encompassing the PTPN11 gene, which was confirmed by FISH analysis. The genomic coordinates of the 12q24.13 duplication were determined to be 104,641,698 to 113,603,100. However, duplications were not observed in a screening of more than 250 Noonan syndrome cases without mutations in known disease-causing genes. Changes affecting the 3-prime untranslated region of the PTPN11 transcript were also not found in 36 patients without disease-causing mutations. In contrast to Shchelochkov et al. (2008), Graham et al. (2009) concluded that duplication of

PTPN11 represents an uncommon cause of Noonan syndrome. However, the rare observation of NS in individuals with duplications involving the PTPN11 locus suggested that increased dosage of this gene may have dysregulating effects on intracellular signaling.

Diagnosis
Butler et al. (2000) used metacarpophalangeal pattern profile (MCPP) analysis to evaluate 15 individuals with Noonan syndrome. Discriminant analysis resulted in the correct classification of 93% of Noonan syndrome patients based on 2 MCPP variables (metacarpal 1 and middle phalanx 3). The authors suggested that MCPP analysis may be useful as a diagnostic tool in screening subjects for Noonan syndrome.

Clinical Management
MacFarlane et al. (2001) reported growth data from the first 3 years of a multicenter study examining the efficacy and safety of recombinant human GH in 23 children with Noonan syndrome. Sixteen male and 7 female patients (aged 9.3 +/- 2.6 years at onset of GH therapy, mean +/- SD; range 4.8-13.7) were each assessed at 1, 2, and 3 years after starting treatment. Comparisons were made with a group of 8 subjects (6 males and 2 females, aged 9.0 +/- 4.1 years; range 4.1-14.8) with Noonan syndrome and not treated with recombinant GH, and measured over the same period. All treated subjects underwent annual cardiac assessment. Height SD score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9 +/- 0.9 three years later. This corresponded to an increase in height from 116.1 +/- 13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4 +/- 1.7 cm/year in the year before treatment to 8.4 +/- 1.7, 6.2 +/- 1.7, and 5.8 +/- 1.8 during the first, second, and third years of GH treatment, respectively. Height acceleration was not significant during the second or third years when pubertal subjects were excluded. The authors concluded that the increase in growth rate in Noonan syndrome resulting from 1 year of GH therapy seems to be maintained during the second year, although height velocity shows a less significant increase over pretherapy values. Possible abnormal anabolic effects of recombinant GH on myocardial thickness were not confirmed, and no treated patient developed features of hypertrophic cardiomyopathy. Kirk et al. (2001) presented data on 66 Noonan syndrome patients (54 males) treated with growth hormone. Treatment improved height velocity in the short term, but longer-term therapy resulted in a waning of effect. The study indicated

that

final

height

is

not

substantially

improved

in

most

patients.

From a study of 14 children with Noonan syndrome who were treated with human growth hormone, half of whom had a missense mutation in the PTPN11 gene, Ferreira et al. (2005) found that those with a PTPN11 mutation had a lower increase in IGF-I (147440) levels during treatment and a significantly lower gain in height SD score after 3 years of treatment compared with those without mutations. Binder et al. (2005) compared GH secretion and IGF-I/IGFBP3 (146732) levels of the PTPN11 mutation-positive (mut+ group) versus the mutation-negative individuals (mut- group). IGF-I and IGFBP3 levels were significantly lower in the mut+ group. In contrast, GH levels showed a tendency to be higher in the mut+ group during spontaneous secretion at night and arginine stimulation. The mean change in height SDS after 1 year of rhGH therapy was +0.66 + 0.21 in the mut+ group (8 individuals), but +1.26 + 0.36 in the mut- group (3 individuals; p = 0.007). The authors concluded that PTPN11 mutations in Noonan syndrome cause mild GH resistance by a post-receptor signaling defect, which seems to be partially compensated for by elevated GH secretion.

Molecular Genetics
In more than 50% of patients with Noonan syndrome, Tartaglia et al. (2001) identified mutations in the PTPN11 gene (see, e.g.,176876.0001176876.0003). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 (Src homology 2) domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP2 activity underlie the pathogenesis of Noonan syndrome. After germline mutations in PTPN11 (176876) were demonstrated in the Noonan syndrome, Tartaglia et al. (2003) investigated defects in PTPN11 in myeloid disorders including cases of juvenile myelomonocytic leukemia (JMML; 607785) in children with Noonan syndrome. Specific mutations in PTPN11 associated with isolated JMML occurred as somatic changes and had never been observed as germline defects, leading Tartaglia et al. (2003) to speculate that these molecular

defects are stronger and associated with embryonic lethality. Conversely, most mutations in PTPN11 associated with Noonan syndrome, which were sufficient to perturb developmental processes, were not fully leukemogenic, suggesting a milder gain-of-function effect. In 10 affected members from a large 4-generation Belgian family with Noonan syndrome and some features suggestive of CFC syndrome, Schollen et al. (2003) identified a missense mutation in the PTPN11 gene (176876.0018). The mutation was not found in 7 unaffected relatives or 3 spouses. Musante et al. (2003) screened the PTPN11 gene for mutations in 96 familial or sporadic Noonan syndrome patients and identified 15 missense mutations in 32 patients (33%). No obvious clinical differences were detected between subgroups of patients with mutations in different PTPN11 domains. Analysis of the clinical features of their patients revealed that several patients with facial abnormalities thought to be pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely varying phenotypes among the 64 patients without PTPN11 mutations indicated further genetic heterogeneity. Musante et al. (2003) also screened 5 sporadic patients with CFC syndrome and found no mutations in the PTPN11 gene. Bertola et al. (2004) described a young woman with clinical features of Noonan syndrome but with some characteristics of CFC as well, including prominent ectodermal involvement (sparse and very coarse hair, and sparse eyebrows and eyelashes), developmental delay, and mental retardation. They identified a T411M mutation in the PTPN11 gene (176876.0019); the same mutation was found in her mother and older sister, not initially considered to be affected but who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies. Bertola et al. (2004) suggested that all first-degree relatives of patients with confirmed Noonan syndrome, even those with no signs of the disorder, be screened for PTPN11 mutations in order to provide accurate assessments of recurrence risk. Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. Sequence analysis of the coding exons 1 through 15 of PTPN11 revealed a novel 3-bp deletion (176876.0024) and 10 recurrent missense mutations in 18 patients. The authors estimated that PTPN11 mutations account for approximately 40% of Japanese Noonan syndrome patients.

Jongmans et al. (2005) performed mutation analysis of the PTPN11 gene in 170 Noonan syndrome patients and identified a mutation in 76 (45%) of them. They described the distribution of these mutations, as well as genotype-phenotype relationships. The usefulness of the Noonan syndrome scoring system developed by van der Burgt et al. (1994) was demonstrated; when physicians based their diagnosis on the scoring system, the percentage of mutation-positive patients was higher. Mutations in the KRAS gene (190070) can also cause Noonan syndrome (NS3; 609942). One patient with a T58I mutation (190070.0011) also had a myeloproliferative disorder resembling juvenile myelomonocytic leukemia (JMML) (Schubbert et al., 2006). Tartaglia et al. (2006) proposed a model that splits NS- and leukemia-associated PTPN11 mutations in the 2 major classes of activating lesions with differential perturbing effects on development and hematopoiesis. The results documented a strict correlation between the identity of the lesion and disease, and demonstrated that NS-causative mutations have less potency for promoting SHP2 gain of function than do leukemia-associated ones. Roberts et al. (2007) and Tartaglia et al. (2007) investigated sizable groups of patients with Noonan syndrome but no mutation in PTPN11, which accounts for approximately 50% of such cases. They found that many had missense mutations in the SOS1 gene (182530) and that the SOS1-positive case patients represented approximately 20% of cases of Noonan syndrome. The phenotype of Noonan syndrome caused by SOS1 mutation, while within the Noonan syndrome spectrum, appears to be distinctive (see NS4,610733). Kontaridis et al. (2006) examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK (see 176948)-mediated signaling.Kontaridis et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation.

In a prospective multicenter study in 35 Noonan syndrome patients with growth retardation, Limal et al. (2006) compared growth and hormonal growth factors before and during recombinant human GH therapy in patients with and without PTPN11 mutations. Sequencing of the PTPN11 coding sequence revealed 12 different heterozygous missense mutations in 20 of the 35 patients (57%). The results showed that among NS1 patients with short stature, some neonates had birth length less than -2 SDS. Growth of patients with mutations was reduced and responded less efficiently to GH than that of patients without mutations. Limal et al. (2006) concluded that the association of low IGF1 (147440) and insulin-like growth factor-binding protein, acid-labile subunit (IGFALS; 601489) with normal IGFBP3 (146732) levels could explain growth impairment of children with mutations and could suggest a GH resistance by a late postreceptor signaling defect. In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007) identified compound heterozygosity for the N308S (176876.0004) and Y63C (176876.0008) mutations in the PTPN11 gene. The mother and father, who exhibited facial features of Noonan syndrome and had both undergone surgical correction of pulmonary valve stenosis, were heterozygous for N308S and Y63C, respectively. A second pregnancy resulted in the birth of a boy with Noonan syndrome carrying the paternal Y63C mutation. Ferrero et al. (2008) identified PTPN11 mutations in 31.5% of 37 sporadic patients and 1 family with a clinical diagnosis of Noonan syndrome. One of the remaining patients had a mutation in the SOS1 gene. Cooccurrence of NF1 and PTPN11 Mutations

Bertola et al. (2005) provided molecular evidence of the concurrence of neurofibromatosis and Noonan syndrome in a patient with a de novo missense mutation in the NF1 gene (613113.0043) and a mutation in the PTPN11 gene (176876.0023) inherited from her father. The proposita was noted to have cafeau-lait spots at birth. Valvar and infundibular pulmonary stenosis and aortic coarctation were diagnosed at 20 months of age and surgically corrected at 3 years of age. As illustrated, the patient had marked hypertelorism and proptosis as well as freckling and cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a pilocytic astrocytoma in the suprasellar region involving the optic chiasm (first presenting symptomatically at 2 years of age), was partially resected.

The father, who was diagnosed with Noonan syndrome, had downslanting palpebral fissures and prominent nasal labial folds. He was of short stature (159 cm) and had pectus excavatum. Electrocardiogram showed left-anterior hemiblock and complete right bundle branch block. Thiel et al. (2009) reported a patient with features of both neurofibromatosis I and Noonan syndrome who was compound heterozygous for mutations in both the NF1 (162200.0044) and PTPN11 (176876.0027) genes. The PTPN11 mutation occurred de novo, and the NF1 mutation was inherited from the patient's mother, who had mild features of neurofibromatosis I, including the absence of optic gliomas. The proband developed bilateral optic gliomas before age 2 years, suggesting an additive effect of the 2 mutations on the Ras pathway. The proband also had short stature, delayed development, sternal abnormalities, and valvular pulmonary stenosis.

Nomenclature
Dunlap et al. (1989) referred to Noonan syndrome with multiple giant cells lesions as the Noonan syndrome-cherubism association.Cohen and Gorlin (1991) recommended that it not be called Noonan syndrome, pigmented villonodular synovitis, central giant cell granuloma, or cherubism, because each of these is a specific diagnostic entity sui generis and the use of such terms results in nosologic blinders that tend to limit the workup of patients.

Animal Model
In a mouse model of Noonan syndrome in which transgenic mice carried a cardiomyocyte-specific gain-of-function Q79R mutation in the PTPN11 gene (176876.0018), Nakamura et al. (2007) demonstrated that the developmental effects of Q79R cardiac expression are stage-specific and that ablation of subsequent ERK1/2 (see 176948) activation prevented the development of cardiac abnormalities.

History
Cole (1980) pointed out that the blacksmith in the famous painting 'Among Those Left' by Ivan Le Lorraine Albright appears to have had Noonan syndrome. The contour of the sternum, the low-set ears, and the short stature are suggestive. Genetic confirmation was provided by studies of a great-grandson with general features of the Noonan syndrome and cardiac abnormalities consistent with that diagnosis (pulmonic stenosis and regurgitation, abnormal architecture of the left

ventricular musculature). Opitz and Pallister (1979)reproduced the first published illustration of the Noonan syndrome by Kobylinski (1883), and Opitz (1985) republished the photograph of Rickey E., the first patient with 'her' syndrome studied at the State University of Iowa by Jacqueline A. Noonan. See Also: Alslev and Reinwein (1958); Char et al. (1972); Duncan et al. (1981); Fisher et al. (1982); Golabi et al. (1985); Hall et al. (1982); Levy et al. (1970); Linde et al. (1973); Miller and Motulsky (1978); Nora et al. (1974); Pierini and Pierini (1979); Sharland et al. (1992);Wiedemann (1991); Witt et al. (1985)

http://omim.org/entry/163950

Sndrome de Noonan
Es un trastorno gentico que causa desarrollo anormal de mltiples partes del cuerpo. Se le sola llamar sndrome similar a Turner, debido a que ciertos sntomas, como membranas en el cuello y trax con forma anormal, se asemejan a los que se observan en el sndrome de Turner. Causas Los defectos en cuatro genes (KRAS y PTPN11, RAF1, SOS1) pueden causar el sndrome de Noonan. Aproximadamente la mitad de las personas afectadas por este sndrome tienen una mutacin en el gen PTPN11. Las personas con una anomala en el gen KRAS presentan una forma ms severa del sndrome de Noonan. Aquellas personas con anomalas en el gen RAF1 tienden a tener un problema cardaco particular (miocardiopata hipertrfica). Los problemas con estos genes hacen que ciertas protenas involucradas en el crecimiento y desarrollo se vuelvan hiperactivas. El sndrome de Noonan es hereditario, lo cual significa que se transmite de padres a hijos. Es una afeccin autosmica dominante, lo cual significa que slo uno de los padres tiene que aportar el gen defectuoso para que el beb tenga el sndrome. Sin embargo, el hecho de que algunos nios no tengan un padre con el sndrome de Noonan probablemente quiere decir que algunos casos no son hereditarios. Sntomas

Retardo en la pubertad Ojos de base amplia o inclinados hacia abajo Hipoacusia (vara) Orejas de implantacin baja o de forma anormal

Retardo mental leve (slo en aproximadamente el 25% de los casos) Prpados cados (ptosis) Estatura baja Pene pequeo Criptorquidia Forma inusual del trax (generalmente un trax hundido llamado trax excavado) Cuello con pliegues y de apariencia corta

Pruebas y exmenes El examen puede mostrar un pliegue extra de la piel por encima de los ojos cerca de la nariz (epicanto) y brazos que pueden estar sostenidos en un ngulo inusual. Puede haber signos de cardiopata congnita (especialmente estenosis pulmonar y en ocasionescomunicacin interauricular). Los exmenes de sangre para mirar el conteo de plaquetas y factores sanguneos pueden revelar signos de una tendencia al sangrado. Los exmenes especficos dependen de cules son los sntomas; por ejemplo, si hay signos de cardiopata, se puede recomendar un ECG, una radiografa del trax o una ecocardiografa. Se recomiendan pruebas auditivas para aquellas personas que tengan signos de disminucin de la audicin. Las pruebas genticas pueden identificar mutaciones en los cuatro genes que causan el sndrome de Noonan. Tratamiento No hay un tratamiento nico para el sndrome de Noonan. El tratamiento se centra en los sntomas individuales. La hormona del crecimiento se ha utilizado con xito en algunas personas con este sndrome para tratar la estatura baja. Grupos de apoyo The Noonan Syndrome Support Group, Inc .: www.noonansyndrome.org. Pronstico El pronstico esperado depende de la magnitud y gravedad de los sntomas. Los pacientes pueden llevar una vida normal. Posibles complicaciones

Acumulacin de lquido en los tejidos corporales (linfedema, higroma qustico) Retraso en el desarrollo en los bebs Autoestima baja Infertilidad masculina en los que presentan los dos testculos no descendidos Problemas con la estructura del corazn Estatura baja

Dificultades sociales relacionadas con los problemas fsicos

Cundo contactar a un profesional mdico Esta afeccin se puede detectar en los primeros exmenes que se le hacen al beb. Con frecuencia, es necesaria la evaluacin por parte de un genetista experimentado para determinar el diagnstico de este sndrome. Prevencin Las parejas con antecedentes familiares de sndrome de Noonan pueden pensar en solicitar una asesora gentica antes de tener hijos. Referencias Rapaport R. Hypofunction of the Ovaries. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds.Nelson Textbook of Pediatrics. 18th Ed. Philadelphia, Pa: Saunders Elsevier; 2007: chap 587. Actualizado: 8/26/2009 Versin en ingls revisada por: Chad Haldeman-Englert, MD, Wake Forest University School of Medicine, Department of Pediatrics, Section on Medical Genetics, WinstonSalem, NC. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc. Traduccin y localizacin realizada por: DrTango, Inc.

http://www.nlm.nih.gov/medlineplus/spanish/ency/article/001656.htm

SNDROME DE NOONAN Joaqun Fernndez Toral (*), Julia Barreiro Davia (**), Mario Pestaa Garca (***) (*) Profesor Titular de Pediatra de la Universidad de Oviedo y Jefe de Seccin de Gentica Peditrica del Hospital Central de Asturias. (**) Mdico Pediatra. Hospital Central de Asturias. (***) Servicio de Proceso de Imgenes y Tecnologas Multimedia de la Universidad de Oviedo. Francisco de Goya y Lucientes pint este cuadro entre 1786 y 1788 para la Real Fbrica de Tapices. Se titula "Los pobres en la fuente" y actualmente est en el Museo del Prado. El nio de la derecha, que pudiera guardar sus manos para calentarlas entre el pecho y la chaqueta, tiene unos rasgos especiales en la cara: las hendiduras palpebrales son llamativamente "antimongoloides", el prpado superior cubre el ojo ms de lo normal, la conformacin del macizo crneo-facial es triangular, parece tener hipoplasia malar, la punta de la nariz es ancha, el cuello pudiera ser corto -aunque cabe que estuviera encogido por el fro o enfadado-, y los hombros se ven redondeados. Tambin parece de baja estatura pues el cenit de su cabeza llega a la altura del ombligo de la mujer adulta, que para aquellos aos

poda medir unos 160 cm., y as, su talla sera de unos 100 cm (que poda ser la de un nio espaol de entonces de unos 5 aos), pero al desconocer su edad real, no podemos ms que elucubrar que acaso era hipocrecido. Quedndonos con los rasgos faciales, evidentes de una disstosis facial bilateral (como tendra las orejas y la implantacin del pelo nucal?), tambin por los mismos se puede sospechar la posibilidad de un sndrome de Noonan, que tras el de Down es la causa gentica ms comn de hipocrecimiento. Febrero de 2002 INTRODUCCIN. La palabra sndrome significa "ir juntos", y en medicina se usa para describir un grupo de signos y sntomas clnicos que dndose en una enfermedad tienen valor diagnstico porque su suma implica una peculiaridad. Con frecuencia llevan el nombre del autor o autores que lo describieron por primera vez, con mayor precisin u otros motivos (S. de Patau para la trisoma 13...), aunque tambin pueden hacer referencias a la patologa que conllevan (S. adrenogenital para la hiperplasia suprarrenal virilizante...), o ser un complejo de sntomas y sntomas generales (S. febril, S. gripal...). Sin embargo, el uso vulgarizado del trmino cuando se refiere a un paciente con rasgos anatmicos inhabituales (la consulta frecuentemente se hace como de "posible sndrome"), lo ha convertido en un trmino peyorativo y preocupante para los padres. Uno de los ms frecuentes (1/1.000 a 1/.2.500 recin nacidos vivos), es el llamado de Noonan (Jacqueline Noonan y D.A. Ehmke en 1963), de gran polimorfismo expresivo y en el que el signo gua ms importante para el diagnstico son los peculiares rasgos faciales a los que se asocian en combinacin variable al menos uno de los siguientes: talla baja, piel redundante en cuello, implantacin baja del pelo en la regin occipital, deformidad esternal, cardiopata (fundamentalmente estenosis de la vlvula pulmonar), criptorquidia... y en algunos casos, dficit mental. Todo ello en un fenotipo que va cambiando evolutvamente (Allanson) y con una frmula citogentica normal. (Ver ms adelante la valoracin de los criterios diagnsticos). Cara triangular, frente amplia, epicantus, ptosis palpebral, hendiduras palpebrales hacia abajo punta de nariz gruesa, orejas dismrficas, cuello corto... (tomado de Goodman y Gorlin) Sin embargo, autores anteriores a la seora Noonan haban publicado pacientes con caractersticas de tal cuadro, plantendolo como diagnstico diferencial del S. de Turner -con el que comparte varios rasgos-, mas con el distingo de su normalidad cromosmica en ambos sexos (a partir de la descripcin citogentica del S. de Turner con frmula 45,X0). As se le denominaba "Fenotipo Turner con cariotipo normal", "S. de Turner masculino" (en el caso de varones), "S. de Ullrich", "Fenotipo Turner familiar" (por el hallazgo de varias familias con tales rasgos)... La virtud de Jacqueline Noonan fue que adems de indicar los signos clnicos mayores, observ que la cardiopata ms frecuente era la estenosis pulmonar (17 en

19 pacientes) (Noonan 1968) frente a la cardiopata que se presenta en el estado 45,X0 que es la coartacin de la aorta. ETIOLOGA: Desde hace unos pocos aos se ha identificado el locus donde se ubica el gen que condiciona el fenotipo de al menos un gran porcentaje de personas con S. de Noonan y que se sita en 12q24 (Jamieson). Se haba visto que haba familias en donde el sndrome apareca en varios miembros, bajo una transmisin vertical, con rasgos diferentes de unos a otros e incluso con generaciones saltadas (dominancia irregular), pero con un predominio de herencia por va materna. Una de estas familias, alemana en este caso, con transmisin fenotpica autosmica dominante fue la que permiti a Jamieson y cols. hallar la ubicacin del gen. En Espaa, Zubeldia y cols. en el estudio de 29 pacientes hallaron que en el 57% haba rasgos de S. de Noonan en la familia, y en todos los casos se daban en la rama materna. Sin embargo existen nios nacidos de parejas consanguneas en los que el cuadro clnico no parece diferir llamatvamente de la forma dominante salvo que tienen con alta frecuencia miocardiopata hipertrfica obstructiva manifestada muy precozmente (Burgt, Maximilian). RASGOS CLNICOS: Parece afectar ms a varones (o se diagnostica ms en ellos debido a la criptorquidia): van der Burgt halla en 100 pacientes que 61 eran del sexo masculino, y con una frecuencia del 29% encuentra rasgos identificativos de S. de Noonan en los padres: 21 veces en la madre y 8 en el padre. Crecimiento: La longitud media neonatal es de 47cm y a partir de ese momento la estatura media va a ir paralela y bajo el percentil 3 en el 83% de los pacientes (Nora). Sharland en 151 personas afectadas vio que el 50% estaban bajo el percentil 3 y el 68% bajo el 10. El brote puberal es habitualmente de poca intensidad y unos 2 aos ms tarde que en la poblacin general (Limal), siendo la talla final disminuida en ambos sexos: 162.5 +- 5.4cm. y 152.7 +- 5.7cm. para hombres y mujeres respectivamente en la poblacin alemana segn un estudio de 144 pacientes (Ranke). Tablas de crecimiento en el S. de Noonan (Ranke) La velocidad de crecimiento est disminuida en relacin a la de la poblacin general, pero en la edad puberal se diferencia del S. de Turner pues s tiene lugar un pequeo brote de crecimiento "estirn", aunque tardo. (Ranke) Los estudios de hormona de crecimiento no son concluyentes, pues en la mayora de los pacientes con talla baja no se encuentran alteraciones (Ahmed). El peso neonatal puede estar aumentado debido a los edemas linfticos (un 15% superaba el percentil 97) (van der Burgt, 2001). Por otro lado, los problemas de alimentacin son frecuentes en la infancia (los muestran el 76% de los estudiados por Sharland).

Rasgos crneo-facio-cervicales: Ya desde el nacimiento llaman la atencin las caractersticas de la cara y cuello, pues los ojos estn separados (hipertelorismo ocular), siendo los prpados superiores algo cados o "cargados" (leve ptosis) y frecuentemente de forma asimtrica con hendiduras horizontales o ligeramente hacia abajo y afuera.

Hipertelorismo y ligera caida palpebral (ms implantacin baja del pelo en la nuca, orejas malconformadas, trax ancho, posible estenosis pulmonar, edemas de pies, uas pequeas... y cariotipo normal) permiten el diagnstico del S. de Noonan en el periodo neonatal (Gen 1.399, Gen 17.815, Gen 4.329), aunque muchos pasan desapercibidos por no reunir entonces suficientes rasgos clnicos para el diagnstico, como por ej. el hipocrecimiento, cbitus valgus, criptorquidia.... La raz nasal es ancha y la punta redondeada, las orejas dismrficas por toscas, bajas, y con lbulos prominentes y rotados hacia adelante con frecuencia. La regin malar es hipoplsica. La piel de la nuca es sobrante e incluso puede apreciarse "pterigium colli", y el pelo se extiende hacia la espalda en su implantacin, sobre todo lateralmente, todo ello en un cuello que frecuentemente es corto y que an lo parece ms por el exceso de piel lateral, apreciable sobre todo al mirarlo por detrs.

Gen 456: Imagen lateral y posterior en las que se aprecian orejas grandes con lbulos prominentes y antevertidos, e implantacin baja del pelo nucal. A la derecha, Gen 23.532 con pterigium discreto y baja implantacin del pelo. Evolutvamente la cara se hace frecuentemente triangular por ser la frente amplia (Allanson), la mandbula fina, el pelo se ensortija, las cejas se arquean, los ojos se vuelven algo prominentes y las hendiduras palpebrales se hacen llamativamente "antimongoloides". Y todo ello acaba ofreciendo una imagen de cierta tosquedad. Gen 10: Frente amplia, ptosis palpebral, hendiduras "antimongoloides", piel redundante cervical. Gen 10.124: Cuello palmeado, pelo llamativamente bajo, hombros redondeados. Aqu, sin embargo, el cuello parece ms largo de lo normal.

Gen 1.494: Ptosis asimtrica, lbulos auriculares prominentes, inclinacin de fisuras palpebrales, trax ancho, estenosis pulmonar, surco de 4 dedos, talla muy baja... deficiencia intelectual, consanguinidad parental y cariotipo 46,XY. Trax y corazn: La deformidad esternal ms comn es el excavamiento inferior en un trax habitualmente ancho, a veces con los hombros redondeados y las mamilas separadas y bajas. Se refiere en la literatura la prominencia superior "en pichn", que en mi experiencia es excepcional frente a la alta frecuencia de la depresin inferior. Depresin esternal media-inferior y trax llamativamente ancho. En 2/3 de los pacientes se descubre cardiopata de los que en el 50% se trata de estenosis valvular pulmonar por ser displsica o gruesa, 20% defectos septales, 20% cardiomiopata hipertrfica... (Allanson, Jones, van der Burgt 2001). Tan slo era normal el ECG en el 12.5% de los 151 pacientes de Sharland. Zubeldia y cols. estudiaron 19 mujeres y 10 hombres con S. de Noonan y hallaron cardiopata en 14 (50%), de las que 11 eran estenosis pulmonar, 5 comunicacin interauricular, 3 miocardiopata hipertrfica y 3 comunicacin interventricular. El ECG caracterstico muestra una gran aberracin del complejo QRS, comprendiendo alguno o todos de los 4 rasgos (Snchez-Cascos): -Desviacin del eje llamativamente hacia la izquierda, -Ensanchamiento del QRS, -Grandes W en muchas derivaciones representado a veces ms de la mitad de la anchura total del QRS, -Predominio de W o de S en derivaciones precordiales izquierdas. ECG caracterstico (Snchez-Cascos) Se han descrito algunos pacientes hijos de padres consanguneos o no, con formas genealgicas autosmicas recesivas y en los que los rasgos clnicos no parecen distintos de la forma dominante, salvo que muestran con mucha mayor frecuencia miocardiopata hipertrfica obstructiva (Burgt, Maximilian). Genital: La criptorquidia se da en un 60%-75% de pacientes masculinos (Allanson) lo que puede llevar en formas bilaterales a favorecer la esterilidad masculina (50%) (Limal), con acaso menor grado de desarrollo de caracteres sexuales secundarios en la pubertad, y elevacin de los niveles de gonadotropinas con bajos valores de testosterona. El pene no suele mostrar alteraciones y es ms, puede estar aumentado de tamao (Goodman). Nistal hall en los estudios bipsicos testiculares, disminucin del ndice tubular medio y de clulas de Sertoli llegando a la conclusin de que adems de las lesiones propias del testculo criptorqudico, hay signos de

disgenesia primaria. En las mujeres, la pubertad y la fertilidad suelen ser normales. Por estas razones parece explicarse que sea habitualmente la va materna la transmisora. Hiposiquismo, ptosis palpebral unilateral, cbitus valgus, hipocrecimiento, criptorquidia bilateral... llev al diagnstico de s. de Noonan en este nio. Urinario: Un 11% pueden presentar anomalas tales como urter doble, agenesia renal unilateral, duplicacin... (Sharland) por lo que la ecografa reno-ureteral est indicada. Inteligencia: En 1/4 a 1/3 se aprecia dficit mental moderado (Jones, Mndez y Opitz), siendo el CI medio de 102 con valores extremos de 64 a 127 (Money). Goodman y Gorlin refieren que ms de la mitad muestran retraso de ligero a CI menor de 50 y Limal y cols. indican que afecta solamente al 10%. Se ha descrito un fenotipo conductual: torpeza, tozudez, irritabilidad, con difcil comunicacin y siendo caprichosos con la comida (Wood). Sharland vio que el tiempo medio de la sedestacin era a los 10 meses y el de la deambulacin a los 21. Esqueleto: Adems de lo visto en el trax, el cbitus valgus se aprecia en el 50%, clinobraquidactilia de algunos dedos y puntas romas con uas pequeas y a veces cuadradas en un 30%, con forma coiloniquica (en cuchara) y crecimiento hacia arriba frecuentemente, anomalas vertebrales en 25%. Hipoplasia ungueal (Gen 1.399) Coiloniquia: uas cncavas, que crecen hacia arriba (Gen 3.162) Piel: Manchas "caf con leche" y lntigos son apreciables en un 10% (Allanson), y queratosis atrfica folicular con posible alopecia parcial de cejas. Es frecuente el engrosamiento y acortamiento distal de los dedos con formacin de almohadillas digitales en el pulpejo (Sharland). Una asociacin caracterstica es la de rasgos de Noonan con Neurofibromatosis I o sndrome de Watson (Mndez). Rasgos de Neurofibromatosis y S. de Noonan (S. de Watson) Vascular-Hematolgico: Edemas de causa linftica por hipoplasia de los vasos pueden apreciarse en los recin nacidos y persistir durante meses. Edemas e hipoplasia de uas Otras localizaciones son la linfagiectasia pulmonar y la intestinal. Prenatalmente pueden ser apreciados en forma de higroma qustico cervical, y precisamente es la dilatacin cervical secundaria la que hace manifestar la piel redundante en el cuello y el pterigium colli. La tendencia a sangrar aparece en el 20% de los pacientes y su causa puede ser el dficit del factor XI (la ms frecuente), plaquetopenia, disfuncin plaquetaria...(Kitchens, Witt).

Massarano hall en 18 pacientes que 10 tenan tiempo de tromboplastina parcial alargado y valores bajos de factores XI y XII particularmente. El uso de la aspirina, dada la disminucin de la agregacin plaquetaria que origina, ha de ser valorado en un paciente en el que se sospecha coagulopata por defecto. Otros: Se han citado en ms de una ocasin en la literatura mdica la asociacin con tiroiditis autoinmune (Vesterhus), y con hipertermia maligna (Kaplan), hipoacusia neurosensorial, maloclusin dental, defectos oculares... (Cruz). Algunos pacientes muestran trimetilaminuria lo que les da un olor especial, siendo estos los que con frecuencia muestran disfuncin plaquetaria (Allanson). DIAGNSTICO: van del Burgt clasifica 6 rasgos clnicos en Mayores y Menores y los valora mediante una puntuacin que segn su criterio es diagnstica si reune la cara tpica ms otro signo mayor o dos menores. Igualmente si los rasgos faciales son sugestivos y a ellos se suman dos criterior mayores o tres signos menores. RASGOS MAYORES MENORES CARA CARACTERSTICA SUGERENTE CORAZN ESTENOSIS PULMONAR y/o ECG TPICO OTRAS CARDIOPATAS ESTATURA MENOR DEL PERCENTIL 3 MENOR DEL PERCENTIL 10 TRAX PECTUM CARINATUM / EXCAVATUM ANCHO HISTORIA FAMILIAR PADRE O MADRE CON S. DE NOONAN DEM CON ALGN RASGO OTROS LOS TRES CRITERIOS EN NIOS (DOS EN NIAS): DFICIT MENTAL /CRIPTORQUIDIA/ DISPLASIA LINFTICA UNO DE ELLOS El diagnstico prenatal solamente cabe en forma de sospecha ante la presencia de higroma qustico nucal o linfedema, cuando el cariotipo es 46,XX o 46,XY, pero no existen criterios ultrasonogrficos para la identificacin precoz (Achiron). DIAGNSTICO DIFERENCIAL Y VARIANTES DEL S. DE NOONAN. En las nias, fundamentalmente con el S. de Turner y en ambos sexos es preciso excluir sobre todo la embrio-fetopata por alcohol y por primidona, amn de otros cuadros con algunos rasgos comunes como el S. de Aarskog o la trisoma del brazo corto del cromosoma 8. Rasgos apreciables en la forma clsica del Noonan a los que se suman otros, se dan en el S. de Watson (rasgos de NF1 y estenosis pulmonar), LEOPARD (Lentiginosis, ECG con signos de anomala de conduccin, hipertelorismo Ocular, estenosis Pulmonar, Anomalas genitales, Retraso en el crecimiento, sordera (Deafnes); Cardio-Facio-Cutneo (CFC) (frecuente retraso mental y del crecimiento, hipotricosis, eczema resistente al tratamiento....), Costello (...)... lo que complica la precisin del diagnstico en situaciones como la descrita

por Leichtman en que una madre con rasgos de Noonan tuvo una nia con CFC. Lentiginosis en el acrnimo LEOPARD (tomado de Baraitser) Pelo rizoso, frente amplia, ojos saltones y separados, orejas bajas, cardiopata... en S. CardioFacio-Cutneo. Pigmentacin oscura, surcos profundos y papilomas peribucales en el S. de Costello (tomado de Baraitser). CONSEJO GENTICO: Tras el nacimiento de un afectado, si se trata de una forma espordica en donde los progenitores no muestran rasgos de S. de Noonan, el riesgo emprico de recurrencia es el 5%, y si uno de los dos rene criterios para afirmarlo, la recurrencia para siguientes hijos es del 50% considerndose que para que se manifieste como forma grave es el 14% (Sharland). Si ambos conyuges fueran consanguneos, el riesgo de recurrencia es el 25% con la consideracin de la mayor probabilidad de que el sndrome curse con miocardiopata hipertrfica obstructiva. SEGUIMIENTO Y TRATAMIENTO Tras el diagnstico neonatal fenotpico externo se impone la evaluacin cardiolgica como primera medida a seguir. Se refiere que hasta un 6% fallecen cada ao por arritmia (G.A.E.P.). Luego, la valoracin cardiolgica, y la observancia evolutiva del crecimiento estatoponderal y del desarrollo sicomotor. Por lo dems, como cualquier otro nio aunque pueden darse dificultades para la alimentacin (anorexia, reflujo gastro-esofgico...) (Shah). No hay que olvidarse de la mayor frecuencia de defectos de refraccin, tiroiditis, posible hipertermia maligna en caso de anestesia, hipoacusia, maloclusin dental.... El uso de la hormona de crecimiento es eficaz a corto plazo aumentando la velocidad de crecimiento aunque sin que al parecer se incremente de forma ostensible la talla final: media de + 3.1cm (-1.1 a 6.5cm) (Kirk). No se ha constatado riesgo de cardiomiopata hipertrfica bajo el tratamiento en el curso de 3 aos de teraputica (Cotterill). En la pubertad, mxime los varones que tuvieron criptorquidia bilateral, han de ser evaluados gonadalmente tanto clnica (desarrollo de caracteres sexuales secundarios) como hormonalmente (determinacin de valores de testosterona y gonadotropinas), dada la posibilidad de hipofuncin. El tratamiento con administracin de testosterona en parche diario o de depsito (cada 21 das) ha de ser individualizado para por un lado evitar la osteoporosis, y por otro lado que no se de una libido potencialmente peligrosa si no se controla con una inteligencia y educacin suficientes.
http://www.noonansyndrome.org/span.htm
Sndrome de Noonan
Se conoce con el nombre de sndrome de Noonan a un trastorno gentico que afecta mayoritariamente a

varones y que produce un anormal desarrollo en mltiples partes del cuerpo. En particular, se presentan membranas en el cuello y diferentes formas del trax que recuerdan al sndrome de Turner (que slo afecta a mujeres). Estas caractersticas bsicas suelen ser acompaadas de anomalas faciales, enfermedad cardaca congnita (especialmente estenosis pulmonar), retardo mental leve en aproximadamente el 25% de los casos, prdida auditiva variable, malformaciones genitales y bajo crecimiento. Si bien los tratamientos son variados, se enfocan en atender las distintas afecciones por separado. Actualmente los trastornos de desarrollo se pueden tratar con hormona de crecimiento.

El sndrome de Noonan es un trastorno gentico que afecta mayoritariamente a varones y produce un desarrollo anormal de mltiples partes del cuerpo. En particular, se presentan membranas en el cuello y diferentes formas del trax que lo relacionan directamente con el sndrome de Turner, que slo afecta a mujeres. Diversos aspectos clnicos, cardiolgicos, las enseanzas aportadas por la ecografa fetal y finalmente los datos genticos aclaran una parte de este sndrome, que no ha mostrado an todos sus secretos. Los primeros 19 casos del sndrome que reunan todas las caractersticas y sntomas hoy asignados, fueron reportados por la Dra. Jacqueline A. Noonan en el ao 1968. Sin embargo en 1883 Kobilinsky describi el caso de un hombre joven que ya reuna las caractersticas bsicas del sndrome y en 1928 Weissenberg contribuy con una completa descripcin de la patologa. La Dra. Noonan, en colaboracin con D. A. Ehmke redescubre, aos ms tarde, la condicin del sndrome y establece la relacin del mismo con la estenosis pulmonar. El sndrome de Noonan es un desorden heterogneo y por ello debe ser manejado en forma multidisciplinaria. Debido al gran riesgo de complicaciones se debe hacer un diagnstico precoz de la enfermedad y asimismo un manejo oportuno de la sintomatologa. Incidencia, causas y factores de riesgo El sndrome de Noonan se puede heredar de una forma autosmica dominante afectando al menos a 1 de cada 2.500 nios. El gen PTPN1 es el primero que produce el sndrome de Noonan y fue descubierto recientemente, en el ao 2001. El sndrome tiene la particularidad de poseer un gran polimorfismo expresivo , en el que el signo gua ms importante para el diagnstico son los peculiares rasgos faciales a los que se asocian en combinacin variable al menos uno de los siguientes: talla baja, piel redundante en cuello, implantacin baja del pelo en la regin occipital, deformidad esternal, cardiopata (fundamentalmente estenosis de la vlvula pulmonar), criptorquidia, y en algunos casos, dficit mental. Todo ello en un fenotipo que va cambiando en forma evolutiva y con una frmula citogentica normal. Cara triangular, frente amplia, epicantus, ptosis palpebral, hendiduras palpebrales hacia abajo, punta de nariz gruesa, orejas dismrficas, cuello corto. Sin embargo, autores anteriores a la Dra. Noonan haban publicado sobre pacientes con caractersticas de tal cuadro, plantendolo como diagnstico diferencial del sndrome de Turner, pero distinguiendo la normalidad cromosmica en ambos sexos. La virtud de Jacqueline Noonan fue que adems de indicar los signos clnicos mayores, observ que la cardiopata ms frecuente era la estenosis pulmonar (17 en 19 pacientes) (Noonan 1968) frente a la cardiopata que se presenta en el estado 45,X0 que es la coartacin de la aorta. Las anomalas que se ven con ms frecuencia incluyen formacin de membranas en el cuello, cambios en el esternn (generalmente un trax hundido llamado trax excavado), anomalas faciales y enfermedad cardaca congnita (especialmente estenosis pulmonar ). Debido a que estas anomalas se asemejan a las del sndrome de Turner. Generalmente se presenta un retardo en la pubertad y los hombres pueden tener testculos no descendidos y un pene pequeo. Por lo general, existe una disminucin de la estatura del adulto. Sntomas

- Cuello con pliegues y de apariencia corta. - Anomalas del esternn (trax excavado y ocasionalmente trax en quilla). - Prpados cados. - Ojos de base amplia o inclinados hacia abajo. - Orejas de implantacin baja o de forma anormal. - Testculos no descendidos/esterilidad. - Retardo en la pubertad. - Retardo mental en slo una cuarta parte de los pacientes. - Estatura baja. Profundizacin de signos y exmenes Ya desde el nacimiento llaman la atencin las caractersticas de la cara y cuello, pues los ojos estn separados (hipertelorismo ocular), siendo los prpados superiores algo cados o cargados (le-ve ptosis) y frecuentemente de forma asimtrica con hendiduras horizontales o ligeramente hacia abajo y afuera. La raz nasal es ancha y la punta redondeada, las orejas dismrficas por toscas, bajas, y con lbulos prominentes y rotados hacia adelante con frecuencia. La regin malar es hipoplsica. La piel de la nuca es sobrante e incluso puede apreciarse pterigium colli, y el pelo se extiende hacia la espalda en su implantacin, sobre todo lateralmente, todo ello en un cuello que frecuentemente es corto y que an lo parece ms por el exceso de piel lateral, apreciable sobre todo al mirarlo por detrs. Evolutivamente la cara se hace frecuentemente triangular por ser la frente amplia, la mandbula fina, el pelo se ensortija, las cejas se arquean, los ojos se vuelven algo prominentes y las hendiduras palpebrales se hacen llamativamente antimongoloides. Y todo ello acaba ofreciendo una imagen de cierta tosquedad. La deformidad esternal ms comn es el excavamiento inferior en un trax habitualmente ancho, a veces con los hombros redondeados y las mamilas separadas y bajas. Se refiere en la literatura la prominencia superior en pichn, que es excepcional frente a la alta frecuencia de la depresin inferior. En cuanto a los trastornos genitales, la criptorquidia se da en un 60%-75% de pacientes masculinos lo que puede llevar en formas bilaterales a favorecer la esterilidad masculina en alrededor de un 50%, con acaso menor grado de desarrollo de caracteres sexuales secundarios en la pubertad, y elevacin de los niveles de gonadotropinas con bajos valores de testosterona. El pene no suele mostrar alteraciones y puede estar aumentado de tamao. Segn se hall en los estudios bipsicos testiculares, suele aparecer una disminucin del ndice tubular medio y de clulas de Sertoli llegando a la conclusin de que, adems de las lesiones propias del testculo criptorqudico, hay signos de disgenesia primaria. En las mujeres, la pubertad y la fertilidad suelen ser normales. Por estas razones parece explicarse que sea habitualmente la va materna la transmisora. Un 11% pueden presentar anomalas tales como urter doble, agenesia renal unilateral, por lo que la ecografa reno-ureteral est indicada. En cuanto al desarrollo seo, adems de lo visto en el trax, el cbitus valgus, se aprecia en el 50%, clinobraquidactilia de algunos dedos y puntas romas con uas pequeas y a veces cuadradas en un 30%, con forma en cuchara y crecimiento hacia arriba frecuentemente, anomalas vertebrales en 25%. Los exmenes pueden evidenciar en los brazos un ngulo inusual (cbito valgo). Tambin puede presentarse una tendencia al sangrado, demostrado en el bajo recuento de plaquetas o en los exmenes de coagulacin y en la medicin de los niveles de factores especficos de coagulacin en la sangre (factores XI-XIII). Si existen signos de enfermedad cardaca, suele recomendarse un ECG, radiografa del trax o ecocardiograma. Se ordenan tambin exmenes de audicin si existe algn signo de disminucin de sta. La evaluacin gentica puede identificar mutaciones causales en el gen PTPN11, entonces se utiliza un cariotipo para confirmar que una nia no porta en realidad el sndrome de Turner. Tambin se han descrito problemas de piel, manchas, edemas de causa linftica por hipoplasia, tiroiditis autoinmune,

maloclusin dental y defectos oculares. En cuanto a los valores de inteligencia, en 1/4 a 1/3 se aprecia dficit mental moderado, siendo el CI medio de 102 con valores extremos de 64 a 127. Goodman y Gorlin refieren que ms de la mitad muestran retraso de ligero a CI menor de 50 y Limal y Cols indican que afecta solamente al 10%. Se ha descrito un fenotipo conductual: torpeza, tozudez, irritabilidad, con difcil comunicacin y siendo caprichosos con la comida (Wood). Sharland vio que el tiempo medio de la sedestacin era a los 10 meses y el de la deambulacin a los 21. Tratamiento No se puede hablar de un tratamiento nico para el sndrome de Noonan debido a la diversidad de sntomas. El tratamiento se centra en los distintos trastornos que se presentan. Como primera medida a seguir, tras el diagnstico neonatal fenotpico externo se impone la evaluacin cardiolgica. Se refiere que hasta un 6% fallecen cada ao por arritmia (G.A.E.P.). Luego, la valoracin cardiolgica, y la observancia evolutiva del crecimiento estatoponderal y del desarrollo sicomotor. Por lo dems, como cualquier otro nio aunque pueden darse dificultades para la alimentacin como la anorexia, reflujo gastro-esofgico, etc. No hay que olvidarse de la mayor frecuencia de defectos de refraccin, tiroiditis, posible hipertermia maligna en caso de anestesia, hipoacusia o maloclusin dental. El uso de la hormona de crecimiento es eficaz a corto plazo aumentando la velocidad de crecimiento, aunque sin que al parecer se incremente de forma ostensible la talla final: media de + 3.1cm (-1.1 a 6.5cm) segn Kirk. No se ha constatado riesgo de cardiomiopata hipertrfica bajo el tratamiento en el curso de 3 aos de teraputica (Cotterill). En la pubertad, mxime los varones que tuvieron criptorquidia bilateral, han de ser evaluados gonadalmente tanto clnica (desarrollo de caracteres sexuales secundarios) como hormonalmente (determinacin de valores de testosterona y gonadotropinas), dada la posibilidad de hipofuncin. El tratamiento con administracin de testosterona en parche diario o de depsito (cada 21 das) ha de ser individualizado para, por un lado, evitar la osteoporosis, y por otro lado que no se d una libido potencialmente peligrosa si no se controla con una inteligencia y educacin suficientes. El pronstico esperado depende de la extensin y gravedad de los sntomas existentes. Los pacientes pueden llevar una vida normal y, si se presenta retardo mental, generalmente es leve, dando muchas esperanzas a las familias de lograr un abordaje temprano. Se recomienda tambin la participacin de padres en grupos de apoyo con el fin de compartir experiencias, alternativas de abordaje y contencin afectiva y profesional. En nuestro pas pueden contactarse con la Asociacin Civil Creciendo (http://www.creciendo.org. ar) o consultar en la asociacin central de Noonan Syndrome (www.noonansyndro me.org). Prevencin Es fundamental que aquellas personas con antecedentes familiares de sndrome de Noonan pueden acercarse a un equipo mdico especializado antes de decidir tener hijos. La prevencin de complicaciones, tales como enfermedad cardaca, depende de la deteccin a tiempo y el cuidado continuo de un cardilogo. Ya que no debemos olvidar que se observan defectos cardiacos congnitos en dos tercios de los pacientes: anomalas de la vlvula pulmonar (50%), defectos septales auriculares (10%), defecto septal ventricular (5%) y conducto arterial persistente (3%), se han descrito otras anomala menos comunes. Fuentes: - Asociacin Civil Creciendo. - Wellpath.

http://www.elcisne.org/ampliada.php?id=98

http://www.sepeap.org/imagenes/secciones/Image/_USER_/636-647%20Noonan.pdf

Rev Chil Pediatr 75 (4); 383-389, 2004 EDUCACIN CONTINUA

Manejo de Sndromes malformativos

Mariana Aracena A.1 1. Unidad de Gentica Hospital Luis Calvo Mackenna.

http://viaclinica.com/article.php?pmc_id=1781428