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Noonan syndrome

Noonan Syndrome (NS) is a relatively common congenital genetic condition which affects both males and females. 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. NS is one of the most common conditions associated with congenital heart anomalies, especially those of the right heart. The syndrome is named after Dr Jacqueline Noonan, a paediatric cardiologist based in Kentucky. more...

Necrotizing fasciitis
Neisseria meningitidis
Nemaline myopathy
Neonatal hemochromatosis
Nephrogenic diabetes...
Nephrotic syndrome
Neuraminidase deficiency
Neurofibrillary tangles
Neurofibromatosis type 2
Neuroleptic malignant...
Niemann-Pick Disease
Nijmegen Breakage Syndrome
Non-Hodgkin lymphoma
Noonan syndrome
Norrie disease

It is believed that 1 in 1,000 to 1 in 2,500 children worldwide are born with Noonan syndrome. It is one of the most common genetic syndromes associated with congenital heart malformations, similar in frequency to Down syndrome. However, the features can vary greatly in patients with NS, thus diagnosis can often be delayed.


Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. A clearly affected person had up to a 50% chance of transmitting it to a child. The fact that affected parents cannot be identified for many children with Noonan syndrome suggests that (1) a parent could carry the gene without being affected, (2) that manifestations were variably expressed and could be so subtle as to go unrecognized, (3) that a high proportion of cases represented new, sporadic mutations, or (4) that Noonan syndrome is heterogeneous, comprised of more than one similar condition of differing cause, some not inherited.

In most of the families with multiple affected members, Noonan syndrome mapped to chromosome 12q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2 (Tartaglia M, et al. Nature Genetics 2001;29:465-468). The protein SHP-2 is a component of several intracellular signal transduction systems involved in embryonic development that modulate cell division,differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves.

Noonan syndrome has been assigned OMIM number 163950 .

Manifestations by organ system

The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.

HEART(2/3 of patients have a heart defect)

Pulmonary Valvular Stenosis(50%)
Septal defects: atrial —(10%) or ventricular —(less common)
Heart murmur


Failure to thrive as an infant
Decreased appetite
Faddy eater
Digestive/Intestinal problems
Frequent or forceful vomiting
Swallowing difficulties


Cryptorchidism (undescended testicles)(almost all males)


Posterior cervical Hygroma (webbed neck)
Lymphedema (build-up of body fluid due to poor functioning of the lymphatic system)



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Childhood primary parotid non-Hodgkin's lymphoma with direct intracranial extension: a case report
From Ear, Nose & Throat Journal, 12/1/04 by Jonathan W. Hafner


Childhood primary parotid non-Hodgkin's lymphoma (NHL) is a rare but well-recognized entity in the literature. Perineural extension of masses between the head and neck and cranium, although rare, has also been well documented. We report the first documented case, to our knowledge, of a left-sided primary parotid NHL in a child with direct intraeranial extension through the foramen rotundum. The mass arose in a 1 1/2-month period. Following evaluation by computed tomography and magnetic resonance imaging, diagnostic procedures (first, fine-needle aspiration and, subsequently, an open biopsy) were undertaken. We discuss the case report and briefly review childhood NHL and perineural metastasis.


The differential diagnosis for a neck mass in the pediatric population is vast and includes infectious, neoplastic, and congenital causes. Primary lymphoma of the parotid gland, although rare, is a well-recognized cause of a neck mass. We present a case of primary parotid non-Hodgkin's lymphoma (NHL) with direct extension into the middle cranial fossa.

Case report

A 17-month-old girl was referred to the University of Tennessee Department of Pediatric Otolaryngology for evaluation of a 1 1/2-month history of a left parotid mass. The patient's past medical history was notable only for repair of an atrial septal defect and supravalvar pulmonary stenosis at 11 months of age. She displayed features of Noonan's syndrome (short stature, small face, protuberant abdomen with no mass, and developmental delay), for which her mother was also diagnosed.

Initially, the left parotid mass had appeared with subjective fever. The patient had received amoxicillin/clavulanate from her pediatrician for 1 week with no change. An infectious disease workup at an outlying hospital for tuberculosis (TB), mumps, Bartonella (cat scratch fever), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) had been negative. Computed tomography (CT) of the head and neck had demonstrated a benign-appearing, well-circumscribed left parotid mass (3.75 x 2.5 x 3.0 cm) with no surrounding inflammatory changes. After no significant change on 5 days of intravenous ceftriaxone/vancomycin, the patient had been discharged home on 7 days of oral azithromycin. Two weeks later, a repeat CT showed no appreciable growth of the mass.

Approximately 1 1/2 months after the patient's initial symptoms, the mass rapidly expanded, with the addition of lesions on her head, back, and eyelid. She was admitted 2 days later, and Otolaryngology was consulted.

On examination, the patient had a 1.5-cm, solid, non-tender, well-circumscribed, and nonmobile nodule of the left parotid gland. She had two 1- to 2-cm flat, violaceous, hard, oval lesions on her back, two on her face, and one on her neck. She had three palpable occipital lymph nodes, cervical lymphadenopathy, III/VI systolic murmur, two well-healed abdominal scars, a palpable liver 2 cm below the costal margin, and a palpable spleen.

Imaging studies of the head and neck demonstrated a 5.0-cm mass expanding and occupying the left parotid gland (figure 1). The mass extended along the path of the maxillary branch of the trigeminal nerve into the middle cranial fossa through the left foramen rotundum (figure 2), which was enlarged and had increased in size since 3 weeks earlier. The mass measured 3.5 cm intracranially (figure 3). It had displaced the adjacent temporal lobe laterally and had displaced the left internal carotid artery in its cavernous portion medially. The mass displayed sharp borders that did not invade the cavernous sinus. There was diffuse marrow involvement of the skull base from extension of the tumor with no evidence of bony metastasis.


CT of the abdomen and pelvis revealed multiple round, hypodense nodules within the cortex of the kidney, the largest measuring 2.5 x 1.8 cm within the anterior portion of the lower pole of the right kidney. Subsequent to a dose of steroids, the parotid mass decreased in size, and the skin lesions resolved.

The patient underwent fine-needle aspiration (FNA) of the left parotid mass. Gross inspection of the FNA demonstrated a nonmobile, nonsolid, left parotid mass. Pathology of the FNA demonstrated benign lymphoid tissue. An open biopsy of the left parotid mass 5 days after admission demonstrated a firm and fixed mass, superficial to the left parotid gland and lateral to the facial nerve. Pathology of the mass demonstrated parotid parenchyma and local muscle diffusely infiltrated by malignant lymphoid neoplasm of small to medium-sized lymphocytes with a focal "starry sky" pattern to some nuclei. The lymphocytes were positive on B-cell staining (figure 4).


The patient was diagnosed with advanced-stage (Murphy III), precursor B-cell non-Hodgkin's lymphoblastic lymphoma/leukemia by World Health Organization classification. She was further classified as central nervous system (CNS) II status because of 46% blasts seen in the cerebrospinal fluid on cytocentrifuge. The patient was referred to a local children's research hospital where she began a chemotherapy protocol.

Restaging imaging status post-chemotherapy, post-induction, and post-high-risk consolidation demonstrated an enlarged, lobulated, enhancing left parotid gland. Repeat open biopsy of the left parotid gland and inclusive lymph nodes later demonstrated benign parotid parenchyma with no evidence of malignant processes. CT of the abdomen demonstrated resolution of the left renal hypodensities. The right renal intrapolar hypodensity initially decreased in size post-chemotherapy but appeared slightly enlarged post-consolidation.


Head and neck masses are more likely to be benign in children than in adults, in whom head and neck masses tend to be malignant. Congenital sources of neck masses in children include cystic hygroma, branchial cleft cysts, and thyroglossal duct cysts. Infectious sources of neck masses in children include Staphylococcus and Streptococcus species, which cause cervical lymphadenopathy, retropharyngeal abscesses, cat scratch fever, and TB.

The traditional approach to evaluating head and neck masses in children includes initiation of treatment for infectious causes with simultaneous hematologic testing (TB, mumps, CMV, EBV, syphilis, and Bartonella) and imaging studies. As in our case, open biopsy is an appropriate procedure following nondiagnostic FNA in a unilateral parotid mass with an otherwise negative workup.

Primary noninfectious head and neck tumors in children are rare but include malignancy of the salivary glands, hemangiomas, and lymphoma. Salivary neoplasms account for less than 10% of all pediatric head and neck tumors. (1) They usually present as painless, enlarging masses without signs or symptoms of infection. Most occur in the parotid gland, with mucoepidermoid carcinomas accounting for 50% and adenoid cystic carcinoma accounting for 5 to 10%. (1)

Common malignant tumors involving the region of the skull base arise primarily in the skin, parotid gland, naso- and oropharynx, and orbit. A frequent mechanism of intracranial spread is through the neural foramina, resulting in frequent cranial nerve symptoms, such as blindness, diploplia, facial numbness, and anosmia from nasal carcinomas. (2) Hearing loss and tinnitus normally accompany facial nerve or vestibular schwannomas. The seventh (peripheral facial paresis) or fifth (decreased corneal reflex, facial numbness) cranial nerve is usually involved. (2) Clinical evidence of perineural tumor infiltration is often missing or not specific. (3)

No cases of unilateral NHL of the parotid gland with direct extension into the CNS have been reported in the English-language literature to our knowledge. Although rare, the tendency for perineural and endoneural tumor spread is a recognized form of metastatic disease. (1,4) The most common parotid malignant neoplasm with perineural invasion and intracranial extension is adenoid cystic carcinoma. (1,4) A case of well -differentiated, non-Hodgkin's lymphocytic lymphoma extending from the orbit through the foramen ovale and cavernous sinus into the infratemporal region, as well as a case of an intracranial malignant lymphoma with perineural extension through the foramen ovale along the path of the mandibular trigeminal nerve into the intraorbital fossa, have been documented. (3,5)

Although extranodal sites are rarely involved at presentation of the disease in adults, extranodal disease is more common in childhood NHL. (6,7) It is usually diffuse in histologic pattern, often presents as a palpable mass involving the cervical or abdominal area, is commonly widespread, and tends to disseminate early. (8) The most common organ involved in NHL in children is the parotid gland. (9) Asymptomatic lymphadenopathy is the most frequent presenting complaint in NHL of the parotid gland. (10) Children present clinically with a slowly enlarging, painless mass. They often present with widespread disease associated with fever, malaise, weight loss, pain, and neurologic manifestations. (11) One study noted 29.4% CNS involvement in children diagnosed with NHL. There was a male predominance (2.4: 1), a high frequency of a palpable mass in the neck and abdomen (85.3%), and a classification of diffuse undifferentiated or poorly differentiated lymphoma. (4) Intermediate and high-grade lymphoma classification is a risk factor for CNS involvement in NHL. (12) Lymphoblastic histology, stage IV disease, and B symptoms are also associated with increased risk of CNS disease. (12,13)

In conclusion, appropriate workup for infectious, congenital, and other neoplastic causes of a head and neck mass should be addressed first. However, although rare, it is important to recognize perineural tumor extension along the trigeminal nerve into the cranial vault in the differential diagnosis of a unilateral head and neck mass. MRI is an invaluable tool in demonstrating both tumor infiltration of the intracranial fossa and perineural tumor spread.


(1.) Callender DL, Frankenthaler RA, Luna MA, et al. Salivary gland neoplasms in children. Arch Otolaryngol Head Neck Surg 1992;118: 472-6.

(2.) Lee KJ. Essential Otolaryngology: Head and Neck Surgery. 8th ed. Chicago: McGraw-Hill, 2003.

(3.) Laine FJ, Braun IF, Jensen ME, et al. Perineural tumor extension through the foramen ovale: Evaluation with MR imaging. Radiology 1990;174:65-71.

(4.) Kumar PP, Patel AA, Ogren FP, et al. Intracranial skip metastasis from parotid and facial skin tumors: Mechanism, diagnosis, and treatment. J Natl Med Assoc 1993;85:369-74.

(5.) Wakamoto H, Miyazaki H, Tomita H, Ishiyama N. [Perineural spreading along the trigeminal nerve in a patient with primary intracranial malignant lymphoma: A case report]. No Shinkei Geka 2000;28:471-6.

(6.) Economopoulos T, Asprou N, Stathakis N, et al. Primary extranodal non-Hodgkin's lymphoma of the head and neck. Oncology 1992;49: 484-8.

(7.) Mehle ME, Kraus DH, Wood BG, et al. Lymphoma of the parotid gland. Laryngoscope 1993;103:17-21.

(8.) Wang JH, Chang TK, Hsieh YL, Hwang BT. Non-Hodgkin's lymphoma in childhood--Five years survey in VGH-Taipei. Zhonghua Yi Xue Za Zhi (Taipei) 1989;44:249-55.

(9.) Akata D, Akhan O, Akyuz C, et al. Involvement of the thyroid and the salivary glands in childhood non-Hodgkin's lymphomas at initial diagnosis. Eur J Radiol 2002;44:228-31.

(10.) Wright D, McKeever P, Carter R. Childhood non-Hodgkin lymphomas in the United Kingdom: Findings from the UK Children's Cancer Study Group. J Clin Pathol 1997;50:128-34.

(11.) McGill TJ, Wu CL. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 19-2002. A 13-year-old girl with a mass in the left parotid gland and regional lymph nodes. N Engl J Med 2002;346:1989-96.

(12.) Liang R, Chiu E, Loke SL. Secondary central nervous system involvement by non-Hodgkin's lymphoma: The risk factors. Hematol Oncol 1990;8:141-5.

(13.) Keldsen N, Michalski W, Bentzen SM, et al. Risk factors for central nervous system involvement in non-Hodgkin lymphoma--A multivariate analysis. Acta Oncol 1996;35:703-8.

From the Department of Otolaryngology-Head and Neck Surgery (Mr. Hafner, Dr. Costello, Dr. Stocks, and Dr. Thompson) and the Department of Pathology (Dr. Ibrahim), University of Tennessee-Health Science Center, Memphis.

Reprint requests: Rose Mary S. Stocks, MD, PharmD, Department of Otolaryngology-Head and Neck Surgery, University of Tennessee-Health Science Center, 956 Court Ave., Coleman Building, Room B216, Memphis, TN 38163. Phone: (901) 448-5885; fax: (901) 448-5120; e-mail:

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