Noonan Syndrome

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744 Noonan syndrome (NS) is a relatively common but geneti- cally heterogeneous autosomal dominant malformation syndrome. The incidence of Noonan syndrome is estimated to be 1 in 1000 to 1 in 2500 live births.

GENETICS/BASIC DEFECTS

1. Inheritance

a. Autosomal dominant inheritance

b. Many affected individuals with de novo mutations c. Affected parent recognized in 30–70% of families 2. Caused by mutation in the gene PTPN11 (protein-tyrosine

phosphatase, nonreceptor-type 11), mapped on 12q24.1, encoding the protein tyrosine phosphatase SHP-2 a. Heterozygous point mutations in the gene PTPN11

identified in:

i. Families showing linkage to the NS1 locus in 12q24

ii. Some sporadic cases with NS

b. All mutations detected to date: missense mutations c. The majority of mutations found in exons 3 and 8,

which correspond to the interacting regions of the N-SH2 and protein tyrosine phosphatase domains of the gene

3. Genotype–phenotype correlation

a. Increased frequency of PTPN11 mutations observed in individuals with Noonan syndrome with pulmonary stenosis (70%)

b. Infrequent frequency of PTPN11 mutations observed in individuals with hypertrophic cardiomyopathy (6%)

CLINICAL FEATURES

1. Clinical features a. Growth

i. Average length at birth: 47 cm

ii. Generally normal birth weight but can be high due to subcutaneous edema

iii. Prepubertal growth parallel the 3rd centile (40%) with a relatively normal growth velocity iv. Pubertal growth spurt often reduced or absent b. Craniofacial features: change with age (see below) c. Ocular abnormalities (observed up to 95% of cases)

i. Strabismus ii. Refractive errors iii. Amblyopia

iv. Nystagmus

v. Anterior segment and fundal changes d. Congenital heart defects (2/3rd of cases)

i. Pulmonary valvular stenosis (50%)

ii. Hypertrophic cardiomyopathy (20–30%): may be present at birth or appears in infancy or childhood

iii. Atrial septal defect (10%)

iv. Asymmetrical septal hypertrophy (10%) v. Ventricular septal defect (5%)

vi. Persistent ductus arteriosus (3%) vii. Other cardiac defects

a) Pulmonary artery branch stenosis b) Mitral valve prolapse

c) Ebstein anomaly d) Single ventricles e. Genitourinary abnormalities

i. Males: ranging from normal prepubertal viriliza- tion to delayed fertility and inadequate secondary sexual development associated with deficient spermatogenesis secondary to earlier cryp- torchidism (60%)

ii. Females: normal or delayed puberty but fertile in majority of cases

f. Skeletal abnormalities

i. Characteristic pectus deformity (see detail description below)

ii. Common features a) Cubitus valgus (50%)

b) Hand anomalies including clinobrachy- dactyly and blunt fingertips (30%)

c) Vertebral and sternal anomalies (25%) d) Dental malocclusion (35%)

g. Ectodermal abnormalities i. Various skin manifestations

a) Café-au-lait patches (10%) b) Pigmented nevi (25%) c) Lentigines (2%)

d) Keratosis pilaris atrophicans faciei

ii. Several instances of neurofibromatosis and the Noonan phenotype documented

h. Bleeding diathesis (about 1/3rd of cases with a coagulation defect)

i. Factor XI deficiency ii. Von Willebrand disease

iii. Platelet dysfunction which may be associated with trimethylaminuria

i. Lymphatic abnormalities

i. Congenital dysplasia, hypoplasia, or aplasia of lymphatic channels (20%)

ii. General lymphedema iii. Peripheral lymphedema

iv. Pulmonary lymphangiectasia v. Intestinal lymphangiectasia vi. Hydrops fetalis

vii. Cystic hygroma j. Rare associated features

i. Autoimmune thyroiditis ii. Pheochromocytoma iii. Ganglioneuroma

iv. Malignant schwannomas

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v. Congenital contractures

vi. Chiari malformation with syringomyelia vii. Skin and oral xanthomas

viii. Odontogenic keratosis

k. Behavioral and developmental abnormalities i. Failure to thrive in infancy (40%) ii. Motor developmental delay (26%)

iii. Learning disability with specific visual-con- structional problems and verbal-performance discrepancy (15%)

iv. Language delay (20%) secondary to perceptual motor disabilities, mild hearing loss (12%), or articulation abnormalities (72%)

v. Intelligence

a) IQ: 64-127 with a median of 102

b) IQ: 10 points below that of unaffected family members

c) Mild mental retardation reported in up to 35% of cases

2. Changing phenotype with age a. Newborn period

i. Marked edema

a) Contributing to a normal-to-high birth weight

b) Rapid reduction after birth simulating failure to thrive

ii. Excess nuchal skin

iii. Sloping and broad forehead iv. Apparent ocular hypertelorism

v. Downslanting palpebral fissures vi. A deep philtrum

vii. Mild retrognathia

viii. Posteriorly angulated ears with a thick helix b. Neonatal period to 2 years

i. Head

a) Relatively large appearance b) Flat malar eminence

c) Bitemporal narrowing accentuated by lateral supraorbital fullness

d) “Coarse” and occasional asymmetric facial appearance

ii. Eyes

a) Prominent and round b) Ocular hypertelorism c) Telecanthus

d) Lessening down slanting of the palpebral fissures

e) Occasional strabismus

f) Thick eyelid hooding the upper iris g) Sharp arched eyebrows

iii. Nose

a) Depressed nasal root b) Low nasal bridge c) Wide nasal base d) Bulbous nasal tip e) Anteverted nares f) Short columella iv. Deep philtrum

v. Arched upper lip with high and wide peaks of the vermilion border

vi. Ears

a) Posteriorly rotated

b) Occasionally small or square vii. Neck

a) Short

b) Less excess skin than in the newborn period c) A low posterior hairline

viii. Often failure to thrive and hypotonia

ix. Occasional hepatosplenomegaly, swarthy skin, and wispy hair

x. 12–18 months of age

a) Changing body shape with stocky and square upper body

b) Occasional presence of an umbilical hernia or diastasis recti

c) The limbs becoming relatively longer and thinner secondary to resolving edema d) Blunt finger tips

c. Childhood i. Face

a) Appearance remaining coarse

b) Becoming more triangular as the chin lengthens

c) Forehead becoming lower and may be bossed

d) Flatter malar eminence ii. Eyes

a) Less prominent eyes with reduced epican- thus

b) Increasing ptosis

c) Increasing lateral supraorbital fullness d) Higher nasal root and bridge

iii. Full lips with sublabial protrusion iv. Neck

a) Appearing longer b) Accentuating webbing c) Prominent trapezius v. Thorax

a) Broad

b) An inverted pyramid shape c) Increasing pectus

d) Upper chest length increases with relatively low-set nipples and axillary webbing which persist to adulthood

vi. Scapula

a) Round shape b) Winged scapulae vii. Limbs

a) Thin

b) Marked cubitus valgus c) Flat feet

viii. Skin

a) Lentigines b) Nevi

c) Café-au-lait spots

ix. Often markedly curly or woolly hair d. Teenage and young adulthood

i. Facial shape becoming increasingly triangular ii. Facial features becoming sharper

iii. Less prominent eyes with occasional ptosis

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iv. Nose a) Thinner b) A pinched root c) Higher bridge d) Wide base e) Pointed tip

f) A longer columella v. Eyebrows becoming sparse e. Older adulthood

i. Prominent nasolabial folds ii. Higher anterior hairline iii. Occasional sloping forehead

iv. Transparent wrinkled skin f. Prominent abnormalities at all ages

i. Striking blue or blue-green irides ii. Increased number of fingertip whorls iii. Posteriorly angulated ears with a thick helix

iv. Characteristic pectus deformity a) Pectus carinatum superiorly b) Pectus excavatum inferiorly

DIAGNOSTIC INVESTIGATIONS

1. Growth curves for males and females with Noonan syndrome now available

2. Echocardiography for previously described congenital heart defects

3. Electrocardiography a. A wide QRS complex b. Left axis deviation c. Giant Q wave

d. A negative pattern in the left precordial leads 4. Radiography: pectus deformity

5. Renal ultrasound for renal anomalies 6. Coagulation studies when needed 7. Chromosome analysis: normal karyotype 8. Molecular genetic testing available clinically

a. Mutations in the gene PTPN11 identified in 50% of patients (familial and sporadic cases)

b. Germline mutations

i. Detected in 59% of patients with familial Noonan syndrome

ii. Detected in 37% of individuals with sporadic Noonan syndrome

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib

i. 50% if a parent is affected

ii. Low risk (<1%) if parents are not affected unless gonadal mosaicism is present in a parent b. Patient’s offspring: 50% affected

2. Prenatal diagnosis

a. Ultrasonography for pregnancies at 50% risk: no definitive ultrasonographic diagnostic criteria early in gestation

i. Septated cystic hygroma ii. Scalp edema

iii. Polyhydramnios iv. Facial features

a) Posteriorly angulated, apparently low-set ears b) Depressed nasal bridge

v. Pleural and pericardial effusions vi. Cardiac defects

a) Pulmonic stenosis

b) Hypertrophic cardiomyopathy vii. Ascites

viii. Hydrops fetalis

b. Molecular genetic testing of fetal DNA extracted from amniocentesis or CVS for PTPN11 mutations.

The disease-causing allele of an affected family mem- ber must be identified before prenatal testing can be performed

3. Management

a. Plotting of growth parameters on growth charts for Noonan syndrome

b. Ophthalmological care

c. Cardiac management of congenital heart defects and hypertrophic cardiomyopathy

d. Hearing evaluation and management

e. Physical and occupational therapies for hypotonia f. Speech therapy for articulation deficiencies g. Infant stimulation program for developmental delay h. Multidisciplinary developmental intervention pro-

gram

i. Hearing aids for sensorineural hearing loss

j. Orthopedic management of musculoskeletal abnormalities

k. Growth hormone treatment of short stature: final height not improved substantially in most patients l. Successful pregnancy possible in women with

Noonan syndrome

REFERENCES

Abuelo DN, Meryash DL: Neurofibromatosis with fully expressed Noonan syndrome. Am J Med Genet 29:937–941, 1988.

Achiron R, Heggesh J, Grisaru D, et al.: Noonan syndrome: a cryptic condition in early gestation. Am J Med Genet 92:159–165, 2000.

Allanson JE: Noonan syndrome. J Med Genet 24:9–13, 1987.

Allanson JE: Noonan syndrome. In Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes. New York: Wiley-Liss, 2001. pp 253–268.

Allanson JE: Noonan syndrome. Gene Reviews 2003. http://www.genetests.org Allanson JE, Hall JG, Hughes HE, et al.: Noonan syndrome: the changing phe-

notype. Am J Med Genet 21:507–514, 1985.

Burch M, Sharland M, Shinebourne E, et al.: Cardiologic abnormalities in Noonan syndrome: phenotypic diagnosis and echocardiographic assess- ment of 118 patients. J Am Coll Cardiol 22:1189–1192, 1993.

Collins E, Turner G: The Noonan syndrome—a review of the clinical and genetic features of 27 cases. J Pediatr 83:941–950, 1973.

Kirk JM, Betts PR, Butler GE, et al.: Short stature in Noonan syndrome:

response to growth hormone therapy. Arch Dis Child 84:440–443, 2001.

Kosaki K, Suzuki T, Muroya K, et al.: PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab 87:3529–3533, 2002.

Maheshwari M, Belmont J, Fernbach S, et al.: PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. Hum Mutat 20:298–304, 2002.

Mendez HM, Opitz JM: Noonan syndrome: a review. Am J Med Genet 21:493–506, 1985.

Musante L, Kehl HG, Majewski F, et al.: Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet 11:201–206, 2003.

Noonan JA: Noonan syndrome. An update and review for the primary pediatri- cian. Clin Pediatr (Phila) 33:548–555, 1994.

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Noonan JA, Raaijmakers R, Hall B: Adult height in Noonan syndrome. Am J Med Genet 123A:68–71, 2003.

Nora JJ, Nora AH, Sinha AK, et al.: The Ullrich-Noonan syndrome (Turner phenotype). Am J Dis Child 127:48–55, 1974.

Ogata T, Sato S, Hasegawa Y, et al.: Lymphstasis in a boy with Noonan syndrome: implication for the development of skeletal features. Endocr J 50:319–324, 2003.

Opitz JM: The Noonan syndrome. Am J Med Genet 21:515–518, 1985.

Patton MA: Noonan syndrome: a review. Growth Horm 10:1–3, 1994.

Ranke MB, Heidemann P, Knupfer C, et al.: Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr 148:220–227, 1988.

Romano AA, Blethen SL, Dana K, et al.: Growth hormone treatment in Noonan syndrome: the National Cooperative Growth Study experience. J Pediatr 128:S18–S21, 1996.

Sharland M, Morgan M, Smith G, et al.: Genetic counselling in Noonan syndrome. Am J Med Genet 45:437–440, 1993.

Tartaglia M, Kalidas K, Shaw A, et al.: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype–phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 70:1555–1563, 2002.

Tartaglia M, Mehler EL, Goldberg R, et al.: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465–468, 2001.

Witt DR, Hoyme HE, Zonana J, et al.: Lymphedema in Noonan syndrome:

clues to pathogenesis and prenatal diagnosis and review of the literature.

Am J Med Genet 27:841–856, 1987.

Witt DR, Keena BA, Hall JG, et al.: Growth curves for height in Noonan syndrome. Clin Genet 30:150–153, 1986.

Witt DR, McGillivray BC, Allanson JE, et al.: Bleeding diathesis in Noonan syndrome: a common association. Am J Med Genet 31:305–317, 1988.

Zenker M, Buheitel G, Rauch R, et al.: Genotype–phenotype correlations in Noonan syndrome. J Pediatr 144:368–374, 2004.

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Fig. 1. Two boys (A-D;E-F) with Noonan syndrome showing various features: down slanting palpebral fissures, hypertelorism, short and webbed neck with a low posterior hair line, pectus, and cubitus valgus.

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Fig. 2. A boy with Noonan syndrome showing characteristic facial fea- tures and webbed neck.

Fig. 3. Familial Noonan syndrome in a mother and a daughter.