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Noonan’s Syndrome

Noonan Syndrome

A familial condition similar to both Turner Syndrome. It is different however, in that here is no chromosomal defect as is involved with Turner and unlike Noonan's, this condition can affect both sexes.

As with Turner Syndrome and Klinefelter Syndrome, lymphedema is listed as a complication. Generally, it is transient, but if it remains constant or progresses, treatment and care of the patient will need to include management of the lymphedema.

Though an early description of the syndrome is credited to a Russian medical student, Koblinsky, at the Russian/Estonian University at Dorpat, the condition is named after an American cardiologist, Jacquline A. Noonan. She and pediatrician Dorothy Ehmke conducted an extensive clinical study of 833 children with congenital heart disease. Their findings were published and reported to the Midwest Society of Pediatric Research held in Cincinnati in 1962.

Cardiac abnormalities occur in 50% of patients: these include pulmonary valve stenosis, thick and dysplastic pulmonary valves, right heart anomalies and left ventricular cardiomyopathy.

Symptoms of the disorder include not only heart indications but valvular pulmonary stenosis, short stature, hypertelorism and skeletal anomalies, and, in boys, retentio testis.

Other symptoms include visual problems are common and include squint, short sightedness (myopia) and prominence of the eyes (proptosis).

Abnormalities of blood clotting may occur, with easy bruising. There is a characteristic breastbone (sternum) deformity with a funnel chest (pectus excavatum) below and a pigeon chest (pectus carinatum) above. Most males are born with undescended testicles, which may require surgery.

Skin manifestations present as transient lymphedema, in the dorsal hands during infancy and progresses to stasis in adulthood. Scalp findings include low posterior neck hairline and coarse curly hair. Scanty pubic, axillary, and beard hair growth has been noted. Nails show short and wide dystrophic changes.

Diagnosis is based on the combination of symptoms, but as the genetic abnormalities in Noonan become identified, genetic tests may be possible. Until then there's no foolproof method of prenatal diagnosis. High-resolution ultrasound in pregnant women with a family history of Noonan's may detect features suggestive of the syndrome.

There's no cure for Noonan syndrome, but medical and surgical treatments are important for complications such as the congenital heart defects, and supportive therapy, such as educational support or speech therapy, can help individuals reach their potential.

Pat

Noonan Syndrome

National Organizations for Rare Disorders

Synonyms of Noonan Syndrome

  • Female Pseudo-Turner Syndrome
  • Male Turner Syndrome
  • NS
  • Turner Phenotype with Normal Chromosomes (Karyotype)

Disorder Subdivisions

General Discussion

Noonan syndrome is a rare genetic disorder that is typically evident at birth (congenital). The disorder may be characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity.

In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low hairline in the back of the head; and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); vertical skin folds that may cover the eyes' inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a low nasal bridge; and low-set, prominent, abnormally rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, mild mental retardation, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings.

In some affected individuals, Noonan syndrome appears to result from spontaneous (sporadic) genetic changes (mutations). In others, the disorder may be transmitted as an autosomal dominant trait. Genetic analysis of one affected multigenerational family (kindred) suggests that the disorder may result from mutations of a gene located on the long arm (q) of chromosome 12 (12q24). However, many investigators indicate that Noonan syndrome may be caused by mutations of different genes (genetic heterogeneity).

Rare Diseases.org

Noonan syndrome Medline

Alternative names

Turner-like syndrome of males; Noonan's Syndrome

Definition

Noonan syndrome is a genetic disorder that causes abnormal development of multiple parts of the body. In particular there is webbing of the neck and different shapes to the chest that are reminiscent of Turner syndrome, hence the former name Turner-like syndrome.

Causes, incidence, and risk factors

Noonan syndrome can be inherited in an autosomal dominant manner. It affects at least 1 in 2,500 children. The fact that some children do not have a parent with Noonan syndrome likely reflects sporadic inheritance, that is, presumably the occurrence of a new mutation. The first specific gene that causes Noonan syndrome, called PTPN11, was discovered in 2001. It is expected that other genes will be discovered that cause Noonan syndrome. Frequently seen abnormalities include webbing of the neck, changes in the sternum (usually a sunken chest called pectus excavatum), facial abnormalities, and congenital heart disease (especially pulmonic stenosis). Because these abnormalities resemble those of Turner syndrome (which only affects females), Noonan syndrome used to be called “male Turner syndrome,” this term is no longer used because Noonan syndrome can affect females also.

Facial abnormalities may include low-set or abnormally shaped ears, sagging eyelids (ptosis), wide-set eyes (hypertelorism), epicanthal folds, and a small jaw (micrognathia). Mild mental retardation is present in about 25% of cases. Hearing loss varies. Puberty is usually delayed, and males may have undescended testicles and a small penis. Adult height is usually decreased.

Symptoms

  • webbed and short appearing neck
  • sternum abnormalities (pectus excavatum, occasionally pectus carinatum)
  • sagging eyelids (ptosis)
  • wide-set (hypertelorism) or down-slanting eyes
  • low-set or abnormally shaped ears
  • undescended testicles
  • delayed puberty
  • mental retardation in only a quarter of patients
  • short stature
  • small penis

Signs and tests

Examination may show an extra fold of skin above the eyes (epicanthal folds). The eyes may also appear down-slanted (antimongoloid palpebral slant). The arms may be held at an unusual angle (cubitus valgus). There may be signs of congenital heart disease (often pulmonic stenosis, occasionally ASD). There may be a bleeding tendency revealed by low platelet count or coagulation tests and measuring the levels of specific coagulation factors in the blood (factors XI-XIII).

Testing will depend on the symptoms present. For example, if there are signs of heart disease, an ECG, chest X-ray or echocardiogram may be recommended. Hearing tests are indicated if there is any sign of decreased hearing. Genetic testing has two purposes. First, a karyotype analysis can make sure that no easily detected abnormality of chromosomes can be mistaken for Noonan syndrome. Second, research genetic testing for mutations in the PTPN11 gene may be available.

Treatment

There is no single treatment for Noonan syndrome. Treatment focuses on the problems that occur. Growth hormone has been used successfully in Noonan syndrome to treat short stature.

Support Groups

The Noonan Syndrome Support Group, Inc. 888-686-2224; www.noonansyndrome.org Expectations (prognosis)

The expected outcome depends on the extent and severity of symptoms that are present. Patients can lead normal lives. Mental retardation, if present, is usually mild.

Complications

  • low self-esteem
  • social difficulties related to physical abnormalities
  • male infertility in those with both testes undescended
  • abnormal heart structure
  • accumulation of fluid in tissues of body (lymphedema, cystic hygroma)
  • failure to thrive in infants
  • short stature

Calling your health care provider

This condition may be detected on early infant examinations. Evaluation by an experienced geneticist is often needed to determine a diagnosis of Noonan syndrome. If there are any signs of Noonan or Turner syndrome ask your health care provider for the name of a geneticist to see. Genetic counseling is recommended if you have a family history of Noonan syndrome.

Prevention

People with a family history of Noonan syndrome may want to consult with their health care provider before having children, although at this time there are no tests to detect the tendency for this disorder. Prevention of complications, such as heart disease, depends on early detection and continuing care of a cardiologist.

Update Date: 8/6/2003

MedLine Plus

Noonan syndrome: A case report

Year : 2007 Asokan S, Muthu MS, Rathna Prabhu V Dept. of Pediatric Dentistry, Meenakshi Ammal Dental College, Chennai, Tamil Nadu, India Correspondence Address: Asokan S - Dept of Pediatric Dentistry, Meenakshi Ammal Dental College, Alapakkam Main Road, Chennai – 600 095, Tamil Nadu India

Source of Support: None, Conflict of Interest: None

Abstract

Noonan syndrome is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects and skeletal malformations. It may be sporadic or inherited as an autosomal dominant or recessive trait and occurs, one in 1000-2500 children. This is a case report of a 13 year-old girl who was referred by a general dental practitioner to a pediatric dentist for management. Full mouth dental rehabilitation was done and the child was brought to a dental institution for correction of orofacial and occlusal defects. Multidisciplinary treatment is the key to success in managing children with Noonan syndrome and the pediatric dentists play an important position to lead the health team.

Keywords Noonan syndrome, oral rehabilitation, orofacial defects

Introduction

Ullrich (1930) and Turner (1938) described females with a syndrome of short stature, sexual infantilism and a pattern of characteristic minor anomalies like pterygium colli. This syndrome originally named as Ullrich-Turner syndrome More Details was later called as Noonan syndrome. It was first reported by Kobylinski (1883), but it was first recognized as a unique entity in 1963 when Pediatrician and Heart specialist Jacqueline Noonan and Ehmke described a series of patients with unusual facies and multiple malformations, including congenital heart defects. The characteristic abnormalities resemble those in Turner syndrome, which only affects females and so Noonan syndrome was used to be called as ” Male Turner syndrome More Details”. This term is no longer used because Noonan syndrome can affect females also. Noonan syndrome is also called as Webbed neck syndrome, Pseudo-Ullrich Turner syndrome, Female Pseudo-Turner syndrome or Turner-like syndrome More Details. [1],[2],[3],[4] These patients were previously thought to have a form of Turner syndrome, with which Noonan syndrome shares a number of clinical features. The observation that patients with Noonan syndrome have normal karyotypes (46XY) was important in allowing the distinction to be made between the Turner and Noonan syndromes.

Noonan syndrome can be inherited as an autosomal dominant trait. It affects 1 in 1000 to 2500 children. [5] The fact that some children do not have a parent with Noonan syndrome likely reflects sporadic inheritance, that is, the presumed occurrence of a new mutation. In 2001, the gene mutation responsible for Noonan syndrome, PTPN11 was identified on chromosome number 12. Now there is evidence of autosomal recessive forms of Noonan syndrome also. Offspring of an affected individual have a 50% chance of developing Noonan syndrome.

Major Features of Noonan Syndrome

Nirmal et al reported a case of a 4-year-old male child with Noonan syndrome. [8] A case of multiple giant cell lesions of the mandible that occurred in a nine year old female child with phenotypic features of Noonan syndrome [9] was reported by Lee and Cooper (2005).

Case Report Noonan’s Syndrome

A 13-year-old girl reported with her mother, referred by a general dental practitioner. The child had pain in her right lower back tooth region (85) since 10 days. History revealed that the child had delayed milestones and had undergone cardiac surgery and a surgery in her anal region three years back. General examination revealed that the child had a short stature, facial asymmetry, hypertelorism, down slanting palpebral fissures, depressed nasal bridge, low set ears with auricular tags, broad philtrum, short neck and clubbed fingers [Figure - 1],[Figure - 2]. Oral manifestations included incompetent lips, high arch palate, anterior openbite [Figure - 3], hypoplastic jaws (left), retrognathic maxilla and prognathic mandible. Intraoral examination revealed dental caries in the retained primary teeth (55, 65, 75, 85) and 16,26,36,47.

Pain on percussion was elicited in relation to 85. OPG showed complete resorption of the distal roots and partial resorption of the mesial roots in the over retained primary teeth. Extraction of all over retained teeth was planned after consent from the general physician and the mother was asked to bring the reports of the child's medical history at the next visit. The child's medical reports indicated that the child had Noonan syndrome with severe pulmonary stenosis, moderate right ventricular hypertrophy and large ostium secundum atrial septal defect (ASD). Summary of a pericardial patch closure of ASD and pulmonary valvotomy was documented in the reports. The child was also operated for an anovestibular fistula. Oral prophylaxis, extraction of all four retained primary teeth and restoration of decayed permanent teeth were done. The child was then referred to Meenakshi Ammal Dental College and Hospital, Chennai, India.

The child reported to the Department of Pediatric Dentistry after one month, intra oral examination showed erupting second premolars. OPG and lateral cephalometric radiographs were taken. Opinion was obtained from the department of orthodontics and oral and maxillofacial surgery. Orthodontic treatment with chin cap and headgear, to prevent further mandibular advancement was started [Figure - 4]. Follow up was done on monthly basis. After 6 months, a considerable change in her profile and a reduction in the anterior openbite with competent lips were seen [Figure - 5],[Figure - 6]. The mother was satisfied with the treatment provided and the results obtained. Transposition of left upper permanent canine was seen [Figure - 5] and orthodontic alignment of teeth would be done in association with the Department of Orthodontics. Surgical intervention with maxillary advancement was the treatment option for the hypoplastic jaws. But orthognathic surgery has been deferred for 2-3 years considering the child's age and nutritional (health) status.

Discussion Noonan’s Syndrome

Noonan syndrome is a developmental disorder characterised by facial dysmorphia, short stature, cardiac defects and skeletal malformations. Recently, PTPN11 which encodes the non-receptor protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2) was identified as the defective gene. The locus was mapped on chromosome 12 (12g 24.1). SHP-2 is a member of a small family of cytosolic protein tyrophosphatases (PTP). These proteins exhibit high degree of homology in amino acid sequence and are essential during development. SHP-2 is the key molecule in the cellular response to growth factors, hormones, cytokines and cell adhesion molecules. It is required for activation of the mitogen activated protein (MAP) kinase cascade induced by epidermal, fibroblast and hepatocyte growth factors. It is involved in mesodermal patterning, limb development, hematopoetic cell differentiation and semilunar valvulogenesis. Missense mutations in PTPN11 accounted for more than 50% of cases of Noonan syndrome. [10] The failure to identify a PTPN11 mutation does not rule out Noonan syndrome.

As the syndrome has a wide spectrum of disorders, patients with Noonan syndrome have to undergo the following lab studies and investigations:

  • Hematological investigations (Total blood count, coagulation profile and measurement of factor XI level at the minimum)
  • Karyotyping and mutation analysis
  • Cardiac investigations (ECG, echocardiogram and consultation with a pediatric cardiologist)
  • Assessment of development (IQ, Identify any delays, mental retardation)
  • Audiologic evaluation

Treatment focuses on the problems that occur and is usually multidisciplinary as in most other syndromes. The expected outcome depends on the extent and severity of symptoms that are present. Activities of the child may be limited depending on cardiac status and the presence of hematologic abnormalities. Certain types of congenital heart lesions are amenable to surgical correction. No specific pharmacologic therapy or special dietary restrictions is necessary. Patients with bleeding disorders must be advised against the use of aspirin and aspirin containing products or other medications that may interfere with coagulation or platelet function. Growth hormone has been used to accelerate growth in some patients with this syndrome. All patients require continuous developmental, audiologic and ophthalmologic follow-up.

In the present case, the child's biochemical and hematological investigations showed no abnormalities. The child had a normal karyotype (46XY). Cardiac investigations showed S1 S2 wide, fixed, split; ejection systolic murmur; severe stenotic pulmonary valve 14 mm at annulus with moderate right ventricular hypertrophy and large ostium secundum ASD with bi-directional shunt. The child was below average in school and had a hearing difficulty, which increased over the months. The cardiac and anal defects were surgically corrected. Extraction of over retained primary teeth and restoration of decayed permanent teeth was done. Orthodontic treatment with chin cap and headgear considerably reduced the anterior openbite. Orthognathic surgery has been planned to correct the orofacial and occlusal defects. The child has now been referred to an Ear Nose Throat surgeon for the management of hearing impairment.

The children with Noonan syndrome usually have a wide array of health problems, making it important for all practitioners to be aware of the child's special care needs. Multidisciplinary treatment is the key to success in managing children with syndromes. The pediatric dentist can be the first health personnel to identify such a child and may lead the multidisciplinary health team in treating their problems.

Acknowledgements

The authors would like to thank the parents of the child for their kind permission in allowing us to present a case report of their child with her photographs. Thanks to Dr. Nandakumar and Dr. Manikandan, Professors from the Department of Orthodontics and Oral and Maxillofacial Surgery for their valuable opinions and help. Thanks to Mr. Sam for helping us with the photographs. Special thanks to our institution Meenakshi Ammal Dental College and Hospital, Chennai for making all the charges free for the child's investigations and treatment.

References

Allanson JE. Noonan syndrome. J Med Genet 1987;24:9-13 2. Gorlin RG, Cohen MM Jr, Hennekam RC. Syndromes of the head and neck. 2 nd ed. Oxford University Press: New York; 2001. p. 469 3. Cohen MM Jr, Gorlin RJ. Noonan-like/multiple giant cell lesion syndrome. Am J Med Genet 1991;40:159-66 4. Yazdizadeh M, Tapia JL, Baharvand M, Radfar L. A case of neurofibromatosis-Noonan syndrome with a central giant cell granuloma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98:316-20 5. Nora JJ, Nora AH, Sinha AK, Spangler RD, Lubs HA. The Ullrich-Noonan syndrome (Turner phenotype). Am J Dis Child 1974;127:48-55 6. Noonan JA. Noonan syndrome: An update and review for the primary pediatrician. Clin Pediatr (Phila) 1994;33:548-55 7. Tullu MS, Muranjan MN, Kantharia VC, Parmar RC, Sahu DR, Bavdekar SB, et al. Neurofibromatosis-Noonan syndrome or LEOPARD Syndrome? A clinical dilemma. J Postgrad Med 2000;46:98-100 8. Nirmal T, Muthu MS, Arranganal P. Noonan syndrome: A case report. J Indian Soc Pedodont Prevent Dentist 2001;19:77-9 9. Lee SM, Cooper JC. Noonan syndrome with giant cell lesions. Int J Pediatr Dentist 2005;15:140-5 10.Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, et al. PTPN11 mutations in Noonan syndrome: Molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002;70:1555-63

Journal of Indian Society of Pedodontics and Preventative Dentistry

Usefulness of lymphoscintigraphy in demonstrating lymphedema in patients with noonan syndrome

Clin Nucl Med. 2008 Mar

Cheng MF, Wu YW, Tzen KY, Yen RF. From the Department of Nuclear Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Lymphatic dysplasia/hypoplasia is found in 15% to 20% of patients with Noonan syndrome. We report a 16-year-old boy with a classic phenotype of Noonan syndrome but a normal karyotype in chromosomal study. During the last 5 years, he had progressive bilateral lower limb edema. The microfilaria study, duplex sonography, and MRI of the lower extremities were all unremarkable. But lymphoscintigraphy showed stocking-like dermal backflow in both legs, delayed lymphatic flow to the inguinal nodes, and dilated lymphatic channels in the abdomen and thorax. These findings suggest that lymphoscintigraphy may be useful in providing vital information on the lymphatic drainage for patients with Noonan syndrome.

PMID: 18287856 PubMed - in process

Clinical Genetics of Noonan Syndrome

2007 RA SteinaaDepartment of Pathology, New York University Medical Center, New York, NY 10016, USA e-mail: steinr01@med.nyu.edu aDepartment of Pathology, New York University Medical Center, New York, NY 10016, USA e-mail: steinr01@med.nyu.edu

Germline gain-of-function mutations in SOS1 cause Noonan syndrome Roberts et al. (2007) Nature Genetics 39: 70–74 Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome Tartaglia et al. (2007) Nature Genetics 39: 75–79

Blackwell Synergy

Diagnostic Codes Noonan's Syndrome

ICD-9 - 759.89

ICD-10 - Q87.1

Congenital malformation syndromes predominantly associated with short stature Syndrome:

· Aarskog · Cockayne · De Lange · Dubowitz · Noonan · Prader-Willi · Robinow-Silverman-Smith · Russell-Silver · Seckel · Smith-Lemli-Opitz

Bleeding disorders in Noonan syndrome. Feb 2012

Wiley

The benefits of growth hormone therapy in patients with Turner syndrome,Noonan syndrome and children born small for gestational age. Dec 2011 ScienceDirect

Rosette forming glioneuronal tumor in association with Noonan syndrome: pathobiological implications. Nov-Dec 2011 Dustri.com

Two cases of Noonan syndrome: aortic coarctation causing a giant aneurysm of the descending aorta. Oct 2011 PubMed


Anesthetic considerations and difficult airway management in a case of Noonan syndrome. Jul 2011

PubMed


Bleeding from the small intestine and aortic regurgitation in Noonan syndrome. 2011

Jstage

Short stature and its treatment in Turner and Noonan syndromes. Feb. 2010 PubMed

Organizations related to Noonan Syndrome

American Heart Association

National Center Dallas TX 75231-4596 Phone #: 214-373-6300 800 #: 800-242-8721 e-mail: inquire@heart.org Home page: http://www.americanheart.org

Big Hearts for Little Hearts

365 Willis Avenue Mineola NY 11501 Phone #: 516-741-5522 800 #: – e-mail: N/A Home page: http://www.bigheartstolittlehearts.org/

Children's Cardiomyopathy Foundation

PO Box 547 Tenafly NJ 07670 Phone #: 201-227-8852 800 #: – e-mail: info@childrenscardiomyopathy.org Home page: http://www.childrenscardiomyopathy.org

Congenital Heart Anomalies, Support, Education, & Resource

2112 North Wilkins Road Swanton OH 43558 Phone #: 419-825-5575 800 #: – e-mail: chaser@compuserve.com Home page: http://www.csun.edu/~hcmth011/chaser/chaser-news.html

Human Growth Foundation

997 Glen Cove Avenue Glen Head NY 11545 Phone #: 516-671-4041 800 #: 800-451-6434 e-mail: hgf1@hgfound.org Home page: http://www.hgfound.org/

MAGIC Foundation for Children's Growth

6645 W. North Avenue Oak Park IL 60302 Phone #: 708-383-0808 800 #: 800-362-4423 e-mail: mary@magicfoundation.org Home page: http://www.magicfoundation.org

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue White Plains NY 10605 Phone #: 914-428-7100 800 #: 888-663-4637 e-mail: Askus@marchofdimes.com Home page: http://www.marchofdimes.com

NIH/National Heart, Lung and Blood Institute Information Center

P.O. Box 30105 Bethesda MD 20824-0105 Phone #: 301-592-8573 800 #: – e-mail: nhlbiinfo@rover.nhlbi.nih.gov Home page: http://www.nhlbi.nih.gov/

Noonan Syndrome Support Group, Inc

P.O. Box 145 Upperco MD 21155 Phone #: 410-374-5245 800 #: 888-686-2224 e-mail: wanda@noonansyndrome.org Home page: http://www.noonansyndrome.org

Restricted Growth Association

P.O. Box 4744 Dorset Intl DT2 9FA Phone #: 013-08 -898445 800 #: – e-mail: rga1@talk21.com Home page: http://www.rgaonline.org.uk

The Arc (a national organization on mental retardation)

1010 Wayne Ave Silver Spring MD 20910 Phone #: 301-565-3842 800 #: 800-433-5255 e-mail: info@thearc.org Home page: http://www.thearc.org/

Additional External Links

Noonan Syndrome

Noonan's Syndrome

Noonan Syndrome e Medicine

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.

SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome.

Germline gain-of-function mutations in RAF1 cause Noonan syndrome

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity

Lymphedema People Internal Links

Lymphedema People Resources

noonan_s_syndrome.txt · Last modified: 2012/10/16 14:40 (external edit)