Noonan Syndrome : Epidemiology, Genes Implicated

This syndrome, which affects both boys and females, has a normal karyotype but phenotypically resembles Turner syndrome.

Epidemiology Of Noonan Syndrome

A familial 20% of cases exhibit autosomal dominant inheritance.
In 1 in 1000 to 1 in 2500 live births, it is observed. Equitable in terms of gender. The majority of cases are caused by abnormalities in a particular pathway, the RAS-MAP kinase system. The RAS-MAP kinase pathway is dysfunctional in those suffering from Costello syndrome and neurofibromatosis-1.

Genes Implicated In Noonan Syndrome

• Most common: missense mutation in PTPN- 11 gene on  12 q24.1 (50-65%) 
• SOS-1 gene: 13%
• SHOC-2
• CBL
• K-RAS
• N-RAS
• BRAF
• RAF-1
• RIT-1
• Duplication of 12q24.

Also Read: Genetic Disorders - Basics, Multifactorial/polygenic inheritance 

Clinical Manifestations

1. Phenotypic features similar to Turner Syndrome

Webbed neck; Cubitus Vagus (elbow malformation); Short stature , Nipples hypoplastic. Abnormal chest (the chest is shield-like in Turner syndrome but not in Noonan syndrome). Pectus excavatum or pectus carinatum, or pigeon-like chest, are observed in cases of Noonan syndrome. In the event that both are observed: pectus excavatum, which affects the lower chest, and pectus carinatum, which affects the upper chest.

2. Abnormal Facies

The term "hypertelorism" describes an abnormal increase in the distance between the eyes; • "antimongoloid slant" refers to the downward slanting of the eyelids; • "Bulbus" is the upturned tip of the nose; • "Wide, smooth, abnormal philtrum between the nose and upper lip"; • "Excess bow/cupid shaped upper lip"; • "Small lower jaw and ear abnormality" (backward turning of the ear).

3. Systemic features

SNHL-high frequency; hepatosplenomegaly; lymphatic dysplasia of the lower limbs, lungs, and intestines.  Haematological disorders: irregular coagulation (factor 11 or 12 deficiency), viral-like sickness.  Heart Disease (50–80%).  Pulmonary stenosis (pulmonary valvular stenosis) is the most prevalent congenital cardiac illness, followed by hypertrophic cardiomyopathy (HCM), ASD > VSD, and HCM.

4. Genetic Abnormalities

Hypogonadotropic hypogonadism is the form of hypogonadism observed in Noonan syndrome, which is characterized by primary gonadal failure.
While some patients may have blood levels of testosterone that range from normal to low, male patients' spermatogenesis is significantly diminished.  Small testes B/L and cryptorchidism affect 70–80% of males.  The inhibin-B level is a good indicator of the level of Sertoli cell function in male youngsters. 

5. Mental Status

• Subnormal IQ: range 53–127; average IQ-86
• Performance IQ is inferior to verbal IQ.
• A slight delay in development causes late puberty.

6. Risk of Malignancies

Seven to eight times as many cancer cases as typical youngsters • The most prevalent hematological malignancies are juvenile myelomonocytic leukemia, acute lymphoblastic leukemia, and AML. 

The prognosis for JMML with Noonan syndrome is better than that of JMML in a child without syndrome.  In the event that the prenatal ultrasound reveals drastically reduced femoral length, normal karyotype, and fetal hydrops linked to polyhydramnios. Then, one may suspect Noonan syndrome.

Also Read: Image Based Questions On Genetics

Treatment

Recombinant Human Growth Hormone (sHGH)

Suggested in people with Ht for ages under the third percentile. Dosage: 25–66 micrograms/kg per day. Raises the average SD score from 1.3 to 1.7. Complete growth in height, 9.5–23 cm for men and 9–9.8 cm for women.

The PTPN-11 gene mutation causes a post-signalling malfunction that results in partial GH resistance in NS patients, which is characterized by elevated serum GH and low IGF-1 levels. These individuals also grow less well and respond less effectively to GH medication.

Frequently Asked Questions

Q. Noonan syndrome resembles to-

Ans: Turner's syndrome

Q. Which is the most common cause of Noonan syndrome-

Ans. Autosomal dominant inheritance

Q. Which abnormality involves in Noonan syndrome-

Ans.  Specific pathway (RAS-MAP kinase pathway)

Q. Which is the most common Gene implicated in Noonan Syndrome

Ans. PPTPN-11 gene on 12q.24.1

Q. Webbed neck is the feature of-

Ans. Phenotypic features similar to Turner Syndrome

Q. Pectus carinatum affects the-

Ans. Upper part of the chest

Q. Define Hypertelorism-

Ans. Hypertelorism refers to an abnormal increase in the distance between the eyes

Q. Anti-mogoloid slant also called-

Ans. Downward slanting of the eyelids

Q. Which is the most common congenital syndrome-

Ans. Pulmonary stenosis (pulmonary valvular stenosis)

Q. Which type of hypogonadism is seen in Noonan syndrome-

Ans. Hypogonadotropic hypogonadism

Q. Which is the most common hematological malignancy in Noonan syndrome-

Ans. Juvenile Myelomonocytic leukemia 

Q. What is the treatment of Noonan syndrome-

Ans. Recombinant Human Growth Hormone (sHGH)

Important Points to Remember 

• Recommended in those with Ht for age below 3 percentile
• Dose:25 to 66 microgram/kg/day.
• Increases mean SD score by 1.3 to 1.7
• Absolute increase of height of 9.5 -23 cm in male and 9- 9.8 cm in females.
• NS patients with PTPN-11 gene mutations grow less well and show less response to GH therapy
• Reason in post-signalling defect leading to partial GH resistance, manifesting as raised serum GH and low IGF-1 level

Hope you found this blog helpful for your NEET SS Genetic Disorders preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.