Noonan syndrome is a genetically heterogeneous multiple malformation syndrome. It was formerly known as 'Turner-like syndrome' due to the similar phenotypic features of the two diseases. However, Noonan syndrome is associated with a normal karyotype, unlike the 45,XO karyotype of Turner's. The main features of this syndrome are webbed and short neck, down-slanting eyes, hypertelorism, strabismus, refractive errors, amblyopia, low-set ears, deeply grooved philtrum, micrognathia, abnormalities in the sternum like pectus excavatum, congenital heart disease, mental retardation in 25% cases, short stature, and delayed puberty.
Approximately 1 in every 1000 to 2500 live births is affected by Noonan syndrome. The disease affects people of all ethnicities and both the sexes equally. The inheritance of the disease has been seen to be either in an autosomal dominant fashion, or through sporadic mutations. Diagnosis of the disease involves evaluation of the physical features, katyotypic analysis to rule out Turner's syndrome, and gene tests for both the PTPN11 and KRAS genes. Treatment is mostly symptomatic. Growth hormone has been administered to accelerate growth in patients.
More than 50% of individuals affected with Noonan syndrome have been shown to have mutations in the Protein-Tyrosine Phosphatase, Nonreceptor-Type, 11 (PTPN11) gene. This gene maps to chromosome 12 and codes for a tyrosine phosphatase, the activity of which is important in signal transduction of cells, especially during the embryonic development of heart, blood cells, and other tissues. It also plays a pivotal role in cell movement, and cell specialization. Mutations in the gene lead to its constitutive activation and constitutive production of the protein, causing misregulation of cell division and growth.
Approximately 5-10% of patients with Noonan syndrome who do not have any mutations in the PTPN11 gene show mutations in the V-KI-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) gene. The protein product of this gene is also involved in the signal transduction in cells.
In a review of the spectrum of genetic diseases in Bahrain, Al-Arrayed (1999) found an increased rate of families with Noonan syndrome. In 2006, Al-Arrayed reported 10 cases of NS from Bahrain; including four Bahraini boys and six Pakistani girls (3 alive and 3 deceased). One of the Bahraini boys was a sporadic case, while the other three were siblings of one family. It was conjectured that the father could be the transmitting parent as he had ptosis, but was normal mentally. A changing phenotype with age was found to manifest in this family (Allanson et al., 1985). The 2- year old boy had more severe edema, ptosis and a round face whereas the eldest boy had EEG abnormality and seizures.
Aglan et al. (2003) compared the clinical features of 14 Egyptian patients (eight males and 6 females) diagnosed with NS, with patients diagnosed with CFC syndrome. Analysis involved three generation pedigree construction, clinical examination, anthropometric and IQ measurements, cytogenetic studies, echocardiography, and ultrasound examination. Except for one case, where two of the patient's cousins were reported to have clinical symptoms of NS, all other cases were sporadic. Parental consanguinity was observed in 42.8% of the cases. Aglan et al. (2003) showed that in the cases they studied, clinical features could be used to differentiate between NS and CFC. The important features which were found in a significantly higher frequency in NS cases, compared to CFC were antimongoloid staining (57% NS, 17% CFC), ptosis (50% NS, 17% CFC), neck webbing (71% NS, absent in CFC), and shieldchest (64% NS, 17% CFC). On the other hand, features like gastrointestinal problems (7% NS, 66% CFC), bitemporal constriction (66% CFC, absent in NS), short nose (29% NS, 100% CFC), sparse hair (absent in NS, 100% CFC), and relative macrocephaly (7% NS, 100% CFC) were present in higher frequencies in CFC cases. One of the patients with NS had factor XI deficiency. Undescended testicles and hypogonadism were observed in three of the NS male patients. Mental retardation was observed in 50%, and absolute microcephaly in 14% of the cases. Aglan et al. (2003) proposed that comprehensive clinical examination and scoring indices are important towards identifying cases of NS, and differentiating them from other symptoms with overlapping manifestations.
Mansour et al. (2005) conducted a retrospective study of 240 consecutive patients with congenital heart disease. In all, 105 syndromic subjects included the velocardiofacial syndrome (18), Down's syndrome (17), CHARGE association (6), DiGeorge syndrome (5), Williams syndrome (3), Edwards syndrome (3), Noonan syndrome (3), VACTERL association (2), and Patau syndrome (trisomy 13) (2).
Soliman et al. (1998) compared auxological and endocrine data from 12 prepubertal children (3 males, 9 females) with Noonan syndrome (NS) with those of 15 children with constitutional short stature (CSS), 20 children with partial GH deficiency (GHD), and 6 children with Turner syndrome (TS). Four children with NS were treated with human growth hormone (hGH) (n = 4) (25 units/m2 week, divided on daily s.c. doses). In children with NS, the peak serum GH response to clonidine (5.4 +/- 2.7 ug/L) and glucagon (7.4 +/- 3.4 ug/L) were significantly lower than those for children with CSS (14.8 +/- 3.4 and 12.8 +/- 2.8 ug/L respectively). Nine out of the 12 (75%) children with NS did not mount normal GH peak (10 ug/L or more) after provocation. The 12-h integrated GH secretion in the 3 children with NS who had normal GH response to provocation (2.7 +/- 0.7 ug/L) was markedly lower compared to that for children with CSS (6.7 +/- 1.2 ug/L). On the other hand, the serum insulin-like growth factor-1 (IGF-I) concentrations were lower in children with NS (67 +/- 32 ng/ml) vs CSS (165 +/- 35 ng/ml), but not different from those for GHD children (59 +/- 33 ng/ml). In 4 children with NS, hGH therapy for a year increased height growth velocity from 4.1 +/- 0.3 cm/yr to 7.4 +/- 0.6 cm/yr and height standard deviation score (Ht SDS) from -2.2 +/- 0.6 to -1.45 +/- 0.3. This growth acceleration was accompanied by an increase in IGF-I concentration (from 52 +/- 21 ng/ml to 89 +/- 25 ng/ml). Soliman et al. (1998) concluded that in children with NS there exists a defect of the GH secretion and suggested that GH therapy has an important role in the management of their short stature.
Sawardekar (2005) conducted a study to establish the prevalence of major congenital malformations in children born during a 10-year period in an Omani hospital in Nizwa. Of the 21,988 total births in the hospital, four children were born with Noonan Syndrome. Sawardekar (2005) hinted for a possible genetic contribution in these children.
Eapen et al. (1998) carried out a screening program among school-going children in Al-Ain, United Arab Emirates, to identify children with learning disorders. During the course of one academic year, 34 such children were identified. The cause was judged to be prenatal in 18 cases (53%). Eight cases exhibited dysmorphic features including a case with Noonan syndrome.
Topley et al (1995) reviewed the case of eight infants with choanal atresia or with choanal stenosis. Interestingly, all had at least one other congenital anomaly. Identifiable syndromes included Noonan syndrome in one case probably born to non-consanguineous parents from the United Arab Emirates. Topley et al. (1995) suggested that choanal atresia and the associated anomalies were thought to be the consequences of the interference with the migration of neural crest cells, and the influence of chemical and genetic factors.
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