Noonan syndrome

Noonan Syndrome (NS) is characterised by short stature, typical facial dysmorphology and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births.

The main facial features of NS are hypertelorism with down-slanting palpebral fissures, ptosis and low-set posteriorly rotated ears with a thickened helix. The cardiovascular defects most commonly associated with this condition are pulmonary stenosis and hypertrophic cardiomyopathy. Other associated features are webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding tendency and lymphatic dysplasias. The syndrome is transmitted as an autosomal dominant trait.

In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Recently, mutations in the KRAS gene have been identified in a small proportion of patients with NS.

A DNA test for mutation analysis can be carried out on blood, chorionic villi and amniotic fluid samples. NS should be considered in all foetuses with polyhydramnion, pleural effusions, oedema and increased nuchal fluid with a normal karyotype.

Types

  Noonan syndrome type 1 (NS1) (PTPN11 at 12q24.1) (MIM.163950)
 Noonan syndrome type 2 (NS2) (MIM.605275)
 neurofibromatosis-Noonan syndrome (NF1 at 17q11.2) (MIM.162200)
 NS3 (MIM.609942)

Synopsis

 short stature
 webbed neck
 pectus excavatum
 cubitus valgus
 pulmonary valve stenosis
 patent foramen ovale
 characteristic face appearance
 cryptorchidism
 short stature (postnatal onset)
 failure to thrive in infancy
 specific growth curves are available
 triangular face with age
 low-set ears
 posteriorly rotated ears
 nerve deafness
 ptosis
 hypertelorism
 down-slanting palpebral fissures
 epicanthal folds
 myopia
 blue-green irides
 deeply grooved philtrum
 high peaks of upper lip vermilion border
 high arched palate - micrognathia
 dental malocclusion
 low posterior hairline
 webbed neck
 cystic hygroma
 congenital heart defect
 atrial septal defects
 ventricular septal defects
 pulmonic stenosis
 patent ductus arteriosus
 shield chest
 pectus carinatum superiorly
 pectus excavatum inferiorly
 occasional hypogonadism
 cryptorchidism
 male infertility in individuals with bilateral cryptorchidism
 vertebral abnormalities
 cubitus valgus
 clinodactyly
 brachydactyly
 blunt fingertips
 wooly-like consistency of hair
 lmphedema
 aticulation difficulties
 mental retardation (25%)
 megakaryocytic thrombocytopenia
 Von Willebrand disease
 bleeding tendency
 transient abnormal myelopoiesis (12468921)

 tumoral predisposition

• malignant schwannoma
• juvenile myelomonocytic leukemia (JMML) (10598665)
• embryonal rhabdomyosarcoma (17483716, 12679651, 8544198, 12661943)

Laboratory

 Partial deficiency of factor XI:C
 Partial deficiency of factor XII:C
 Partial deficiency of factor XIII:C
 Thrombocytopenia

 rare autoimmune diseases

• systemic lupus erythematosus
• celiac disease
• Hashimoto thyroiditis

 central giant cell granuloma (giant cell granuloma of the jaws) (9660063)

Etiology

This autosomal dominant disease is caused mainly by mutations in the protein tyrosine phosphatase, nonreceptor-type, 11 gene (PTPN11) (MIM.176876).

 germline mutations in

• PTPN11 gene (MIM.176876) (50%) -(Allelic with LEOPARD syndrome MIM.151100)
• NF1 gene coding for neurofibromin (MIM.162200) in neurofibromatosis-Noonan syndrome (NFNS) (MIM.601321)
• KRAS gene

References

 van der Burgt I. Noonan syndrome. Orphanet J Rare Dis. 2007 Jan 14;2:4. PMID: 17222357

 Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007 Apr;7(4):295-308. PMID: 17384584

References

 Limal JM, Parfait B, Cabrol S, Bonnet D, Leheup B, Lyonnet S, Vidaud M, Le Bouc Y. Noonan syndrome: relationships between genotype, growth, and growth factors. J Clin Endocrinol Metab. 2006 Jan;91(1):300-6. Epub 2005 Nov 1.PMID: 16263833