Noonan syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul, Ayokunle Olubaniyi, M.B,B.S [2]

Noonan Syndrome (NS) is a relatively common congenital genetic condition which affects both males and females. It used to be referred to as the male version of Turner’s syndrome;^[1] however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart malformation, short stature, learning problems, indentation of the chest, impaired blood clotting, and a characteristic configuration of facial features. The syndrome is named after Dr Jacqueline Noonan.

It is believed that between approximately 1 in 1,000 and 1 in 2,500 children worldwide are born with NS. It is one of the most common genetic syndromes associated with congenital heart disease, similar in frequency to Down syndrome. However, the range and severity of features can vary greatly in patients with NS. Therefore, the syndrome is not always identified at an early age.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul

Jacqueline Noonan was the first to describe the syndrome we now know as Noonan syndrome in 1963 when she noticed that children with a rare type of heart defect, valvular pulmonary stenosis, often had a characteristic physical appearance with short stature, webbed neck, wide spaced eyes, and low-set ears.

Jacqueline Noonan was practicing as a pediatric cardiologist at the University of Iowa when she noticed that children with a rare type of heart defect, valvular pulmonary stenosis, often had a characteristic physical appearance with short stature, webbed neck, wide spaced eyes, and low-set ears. Both boys and girls were affected. Even though these characteristics were sometimes seen running in families, chromosomes appeared grossly normal. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1963 presented a paper: “Associated non-cardiac malformations in children with congenital heart disease”. This described 9 children who in addition to congenital heart disease had characteristic faces, chest deformities and short stature. Both males and females were found to be similarly affected, and the chromosomes were apparently normal. ^[1]

Dr John Opitz, a former student of Dr Noonan, first began to call the condition “Noonan Syndrome” when he saw children who looked like those whom Dr Noonan had described. Dr Noonan later produced a paper entitled “Hypertelorism with Turner Phenotype”, and in 1971 at the Symposium of Cardiovascular defects, the name ‘Noonan Syndrome’ became officially recognized. ^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul

Them most studied mutation leading to Noonan syndrome involves the N-SH2 domain of the SHP-2 protein involved in signal transduction as part of the RAS-MAP Kinase pathway. This mutation allows SHP-2 to become constitutively activated leading to an increase in downstream signaling and disruption of embryogenesis.

The functional pathogenesis of Noonan syndrome has been mostly elaborated in the context of PTPN11 mutations. The PTPN11 gene codes for the SHP-2 protein, a cytoplasmic SH2 domain-containing protein tyrosine phosphatase that is ubiquitous in adult and embryonic tissues. Functionally, the SHP-2 protein acts as an intracellular signal transducer that has a particularily important role during development. It is mainly involved in mesodermal patterning and gastrulation during early embryogenesis but also plays a role in the formation of terminal and skeletal structures, semilunar valvulogenesis, and hematopoiesis. It has been shown that SHP-2 positively controls the activation of the RAS/MAPK cascade, the SRC family kinase, and IL-1/TNF-dependent NF-κB activation.^[1]

Structurally, the SHP-2 protein has 2 important domains an SH2 and a catalytically active PTP domain whose interaction is defective in patients with PTPN11 mutations. The SH2 domain acts as a chaperon that covers the active site of PTP basally. Because of this interaction, SHP-2 is maintained auto-inhibited except when it is required to be functional. Most of the mutations in PTPN11 affect amino acid residues close to this interaction surface between those 2 domains. This suggests that the pathophysiology of Noonan syndrome involves a shift in the equilibrium between active and inactive SHP-2 toward the active form without any effect on the function of the protein itself.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul

Most cases of Noonan syndrome have an autosomal dominant inheritance pattern and have been associated with either one of eight genes all involved in the RAS/MAP kinase pathway. In order of prevalence, the causative mutations involve the following genes: PTPN11, SOS1, RAF1, SHOC2, KRAS, BRAF, NRAS, and CBL.

Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominantinheritance and variable expression. Mutations in the Ras/MAPK signaling pathways are known to be responsible for ~70% of NS cases.^[1]

A person with NS has up to a 50% chance of transmitting it to a child. The fact that an affected parent is not always identified for children with NS suggests several possibilities:

1. Manifestations are variably expressed and could be so subtle as to go unrecognized (variable xpressivity)
2. A high proportion of cases represent new, sporadic mutations
3. Noonan syndrome is heterogeneous, comprising more than one similar condition of differing cause, some not inherited.

A number of inheritable mutations can be responsible for Noonan syndrome, most notably mutations of the PTPN11 gene on chromosome 12 seen in more than half of the patients. Almost all causative mutations seen in the PTPN11 gene are missense changes. The single most common mutation in PTPN11 accounting for 25% of cases of Noonan sydrome is an A-to-G transition at nucleotide 922. In order of prevalence, the causative mutations involve the following genes: PTPN11, SOS1, RAF1, SHOC2, KRAS, BRAF, NRAS, and CBL. Below is a table that details some common genetic loci involved. ^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul

Noonan syndrome can be considered in any patient with congenital cardiac anomalies although 3 important syndromes can resemble the Noonan phenotype particularly LEOPARD syndrome, Costello syndrome, and Turner syndrome in girls.

LEOPARD syndrome, also known as multiple lentigines syndrome, is a rare congenital condition characterized by skin, facial and cardiac anomalies. LEOPARD is an acronym that summarizes the most important features of this disease which includes Lentigines, ECG findings (conduction abnormalities), Ocular problems (hypertelorism), Pulmonic stenosis, Abnormal genitalia, growth Retardation, and Deafness.^[1] Phenotypically and genotypically, LEOPARD syndrome closely resembles Noonan syndrome although around 200 cases have only been reported worldwide. The disorder also involves mutations in the PTPN11 gene responsible for the NSH-2 domain on SHP-2. Several common loci of missense mutations are shared between these 2 syndromes, and genetic analysis alone can sometimes be hard to differentiate the two. Clinically, LS is a combination of neurofibromatosis type 1 and Noonan syndrome. The lentigines are important to make the diagnosis, although some do not appear before 4 to 5 years of age. Other signs more prominent in LS compared to Noonan are the very high prevalence of hypertrophic cardiomyopathy and deafness.^[2]

Costello syndrome is an autosomal dominant disorder that occurs secondary to germline mutations in the HRAS proto-oncogene^[3] that is characterized by growth retardation, coarse facial features, loose skin, cardiomyopathy, developmental delay and friendly behavior. Patients with Costello syndrome usually develop oral papillomata and are at a higher predisposition for malignancy especially rhabdomyosarcoma. The pathophysiology is unclear, but recent studies suggest defects in elastogenesis.^[4]

Turner syndrome is a congenital disorder that occurs in 1 of every 2000 to 5000 live female births. It does not affect male patients as it is characterized by an XO karyotype. Clinically, Turner syndrome can have variable phenotypes with features usually including congenital lymphedema, short stature, congentical cardiac abnormalities, and gonadal dysgenesis.^[5] Although Turner syndrome has been genetically and clinically delineated and can be differentiated from Noonan’s syndrome, initially, Noonan’s was considered a form of Turner syndrome that can affect males due to the marked overlap between the 2 disorders. In 1968, Dr. Jacqueline Noonan published a paper entitled “Hypertelorism With Turner Phenotype: A New Syndrome With Associated Congenital Heart Disease” describing the syndrome as “the male Turner syndrome”.^[6] In females with any difficulty in differentiating the syndromes clinically due to the variable expression, karyotype and genetic analysis are helpful.

It is absolute that delayed puberty is the result of any disturbances in hypothalamus–pituitary–gonadal (HPG) axis. Delayed puberty has found to be on a genetic basis, most of the times. It is assumed that the main factor in determining the puberty timing is genetic elements. In case of constitutional delay of growth and puberty (CDGP), researchers suggested 50-75% of positive family history of delayed puberty. About 25 various genes, in 3 different group of Kallman syndrome related genes, hypothalamus–pituitary–gonadal (HPG) axis related genes, and obesity related genes, play roles in delayed puberty. Boys are more commonly affected by delayed puberty (constitutional delay of puberty) than girls. The most potent risk factor in the development of delayed puberty is hypothalamus–pituitary–gonadal (HPG) axis disturbance. Other risk factors are including genetic, endocrinologic, and environmental; which may disturb the HPG axis. Patients with delayed puberty usually appear normal, not ill or toxic. Physical examination of patients with delayed puberty is usually remarkable for delayed growth spurt along with small testicular size (less than 4 mL or 2.5 cm) in more than 14 years old boys and thelarche stage 0-1 in more than 13 years old girls.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul

The estimated prevalence of Noonan Syndrome in the general population is 1 in 1000 to 2500 individuals with equal male to female ratio.

Noonan syndrome is inherited in an autosomal dominant pattern, and despite the disease being congenital, it can manifest at different ages due to its variable expression. In general, males and females have the same incidence of the disease which can be explained by the inheritance pattern. The estimated prevalence in the general population is 1 in 1000 to 2500 individuals.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul

Patients with Noonan syndrome have a constellation of complications associated with the disorder. Significant cardiac complications may arise secondary to pulmonary valve stenosis or HCM the two most common cardiac manifestations. Other complications include increased risk for developing malignancy, bleeding, short stature, hearing loss, poor feeding, and some form of developmental or intellectual insufficiency.

What is known about the natural history of Noonan syndrome is based on limited long-term follow-up studies. The most important study on the clinical course of Noonan sydrome comes from Shaw et al. who studied 112 patients with clinical or genetic diagnosis of Noonan syndrome with a mean follow-up of 12 years.^[1] Patients with documented feeding difficulties during infancy were found to have poorer outcomes. Those with feeding problems had a mean age of speaking in two-word phrases of 39 months, compared with 26 months in patients with no feeding difficulties. Furthermore, whereas only 12.5% of patients with no problems feeding required attendance at a school for children with special needs, 58% of patients with feeding problems required the same care. In general, special academic assistance was needed in 44% of patients, although academic achievement was comparable to the general population. The average adult height was 167.4 cm in males and 152.7 cm in females.^[1]

During the study interval, 10 patients died, three of which were secondary to hypertrophic cardiomyopathy. In total, 19% of patients had hypertrophic cardiomyopathy. Other cardiac anomalies included pulmonary stenosis in 65% of patients half of which required intervention. No patients died secondary to arrhythmias. The overall mortality rate was approximately 9%, with age of death ranging from a 4 months to 61 years.^[1] In general, adults with Noonan syndrome required close cardiac follow-up as on third of them had an ongoing cardiac problem requiring either medical treatment, defibrillation, or pacemaker placement. Markers of good prognosis included normal cardiac output at rest, peak right ventricular pressure of <100 mm Hg, normal pulmonary artery pressure, and absence of symptoms.^[2][1]

Below is a list of the most common cardiac complications of Noonan syndrome:^[3]

• Right ventricular outflow tract obstruction
• Hypertrophic cardiomyopathy
• Dilated cardiomyopathy evolving from hypertrophic cardiomyopathy
• Restrictive cardiomyopathy
• Aortic insufficiency
• Aortic root dilation
• Aortic dissection
• Giant aneurysm of the sinuses of Valsalva
• Constrictive pericarditis
• Idiopathic pulmonary hypertension

Patients with Noonan syndrome are at an increased risk for the development of hematologic and solid malignancies:^[3]

• Juvenile myelomonocytic leukemia
• Acute myelogenous leukemia
• B-cell acute lymphoblastic leukemia
• Embryonal rhabdomyosarcoma
• Granular cell tumors
• Pilocytic astrocytoma
• Sertoli cell tumor
• Malignant mastocytosis
• Malignant epithelioid angiosarcoma

Although most patients with Noonan syndrome have normal intelligence compared to the general population, studies have reported that the prevalence of intellectual impairment is slightly more elevated in this group. Studies have suggested that patients may require some form of special learning aid. Other reported developmental complications include mood disturbances, social and communication problems, reading and spelling difficulties, and short-term memory impairment. ^[3]

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