Noonan Syndrome
Etiology
The term Noonan syndrome has been applied to males and females with normal karyotypes who have certain phenotypic features that occur also in females with Turner syndrome (although the genetic causes are completely distinct). Noonan syndrome occurs in 1 in 1,000-2,500 live births. Approximately 20% of the cases are familial and exhibit autosomal dominant inheritance. Males and females are equally affected. Several mutations in the renin–angiotensin system (RAS)–mitogen-activated protein kinase (MAPK) pathway can cause Noonan syndrome and other related disorders and such mutations are currently detected in approximately 70% of the cases of Noonan syndrome. Missense mutations in PTPN11 —a gene on chromosome 12q24.1 encoding the nonreceptor protein tyrosine phosphatase SHP-2—are seen in about half the cases. Mutations in other genes in this pathway, including SHOC2 , CBL , SOS1 , KRAS , NRAS , BRAF , and RAF1 as well as duplications of the 12q24 region are also seen. Phenotypic features of Noonan syndrome therefore overlap with other syndromes involving the RAS-MAPK pathway, such as Leopard syndrome, Costello syndrome, and cardiofaciocutaneous syndrome.
Clinical Manifestations
The most common abnormalities are short stature, webbing of the neck, pectus carinatum or pectus excavatum, cubitus valgus, right-sided congenital heart disease, and characteristic facies. Hypertelorism, epicanthus, downward-slanting palpebral fissures, ptosis, micrognathia, and ear abnormalities are common. Other abnormalities such as clinodactyly, hernias, and vertebral anomalies occur less frequently. The mean IQ of school-age children with Noonan syndrome is subnormal at 86, with a range of 53-127. Verbal IQ tends to be better than performance IQ. High-frequency sensorineural hearing loss is common. The cardiac defect is most often pulmonary valvular stenosis, hypertrophic cardiomyopathy, or atrial septal defect. Hepatosplenomegaly and several hematologic diseases―including low clotting factors XI and XII, acute lymphoblastic leukemia, and chronic myelomonocytic leukemia―are noted. Noonan-like features can be part of the phenotypic variation of the NF1 (neurofibromatosis) gene mutation, possibly because of common involvement of the RAS-MAPK pathway in both diseases. Males frequently have cryptorchidism and small testes. Testosterone secretion may be low or normal, but spermatogenesis may be affected even in those with normal testosterone (and normal secondary sexual characteristics). Serum inhibin-B is a useful marker of Sertoli cell function in these patients. Puberty is delayed, and adult height is achieved by the end of the second decade; it usually reaches the lower limit of the normal population. Prenatal diagnosis should be suspected in fetuses with normal karyotype, edema, or hydrops and short femoral length.
Treatment
Human growth hormone results in improvement in growth velocity in many Noonan syndrome patients, comparable to that seen in patients with Turner syndrome, and studies show a mean increase in height standard deviation score ranging from 1.3 to 1.7, corresponding to 9.5-13 cm for males and 9.0-9.8 cm for females. Many patients with Noonan syndrome reach normal height without growth hormone therapy, but treatment is recommended for those who fall below the 3rd percentile for height. The recommended dose is up to 66 µg/kg/day of recombinant growth hormone. Patients with Noonan syndrome and demonstrable PTNP11 mutations grow less well and are less responsive to growth hormone treatment than those without mutations. They have lower insulin-like growth factor-1 and higher growth hormone levels, suggesting partial growth hormone resistance because of post–receptor-signaling defects.
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