Noonan Syndrome (NS) is a relatively common congenital genetic condition which affects both males and females equally[1]:550 . It used to be referred to as the male version of Turner’s syndrome[2]; 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.

Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. 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:

In most of the families with multiple affected members, NS maps 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.[3] The SHP2 protein is a component of several intracellular signal transduction pathways 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. It has recently been shown that activating mutations in SOS1 also give rise to NS.[4] Shp2 and SOS1 both have roles as positive regulators of the Ras/MAP kinase pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome.[5] Additional mutations in KRAS [6] and RAF1[7] genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. Chromosomal abnormalities, such as a duplication of chromosome region 12q24 encompassing gene PTPN11 can result in an apparent Noonan syndrome[8].

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

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Neutropenia (adjective neutropenic), from Latin prefix neutro- and Greek suffix -pe??a (deficiency) is a hematological disorder characterized by an abnormally low number of a type of white blood cell called a neutrophil. Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections by destroying bacteria in the blood. Hence, patients with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening (neutropenic sepsis).

Neutropenia can be acute or chronic depending on the duration of the illness. A patient has chronic neutropenia if the condition lasts for longer than 3 months. It is sometimes used interchangeably with the term leukopenia (“deficit in the number of white blood cells”), as neutrophils are the most abundant leukocytes, but neutropenia is more properly considered a subset of leukopenia as a whole.

There are numerous causes of neutropenia that can roughly be divided between either problems in the production of the cells by the bone marrow and destruction of the cells elsewhere in the body. Treatment depends on the nature of the cause, and emphasis is placed on the prevention and treatment of infection.

There are three general guidelines used to classify the severity of neutropenia based on the absolute neutrophil count (ANC) measured in cells per microliter of blood:[1]

The above mentioned ranges were developed in Caucasians. In blacks, mild neutropenia is a normal phenomenon, and neutropenia in this population is more properly defined as ANC < 1200. Higher cutoffs may lead to overdiagnosis of neutropenia in the black population.[1]

Neutropenia can go undetected, but is generally discovered when a patient has developed severe infections or sepsis. Some common infections can take an unexpected course in neutropenic patients; formation of pus, for example, can be notably absent, as this requires circulating neutrophil granulocytes.

Some common symptoms of neutropenia include fevers and frequent infections. These infections can result in conditions such as mouth ulcers, diarrhea, a burning sensation when urinating, unusual redness, pain, or swelling around a wound, or a sore throat.

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Neurofibromatosis is a genetically-inherited disease in which nerve tissue grows tumors (e.g. neurofibromas) that may be harmless or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells (Schwann cells, melanocytes, endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body forming tumors and the melanocytes function abnormally resulting in disordered skin pigmentation.The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems. [1]

Neurofibromatosis is autosomal dominant, which means that it affects males and females equally and is dominant (only one copy of the affected gene is needed to get the disorder). Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. Disease severity in affected individuals, however, can vary (this is called variable expressivity). Moreover, in around half of cases there is no other affected family member because a new mutation has occurred.

Neurofibromatosis type 1 – mutation of neurofibromin chromosome 17q11.2. The diagnosis of NF1 is made if any two of the following seven criteria are met:

Neurofibromatosis type 2 – mutation of merlin chromosome 22q12

Schwannomatosis – gene involved has yet to be identified

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A neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. Usually found in individuals with Neurofibromatosis Type 1 (NF1), a genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability. Neurofibromas arise from Schwann cells that exhibit biallelic inactivation of the NF1 gene that codes for the protein neurofibromin.[1] This protein is responsible for regulating the RAS-mediated cell growth pathway. In contrast to schwannomas, another type of tumor arising from Schwann cells, neurofibromas incorporate many additional types of cells and structural elements in addition to Schwann cells, making it difficult to identify and understand all the mechanisms through which they originate and develop.[2]

Neurofibromas arise from Schwann cells that are homozygous for the inactive version of the NF1 gene, which leads to a complete loss of expression of neurofibromin. The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17qll.2.[3] This gene codes for neurofibromin which is a large 220-250 KDa cytoplasmic protein that is composed of 2,818 amino acids with three alternatively spliced exons (9a, 23a and 48a). The functional part of neurofibromin is a GAP, or GTPase-activating protein. GAP accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form, inactivating RAS and reducing RAS-mediated growth signaling. Loss of RAS control leads to increased activity of other signaling pathways including RAF, ERK1/2, PI3K, PAK and mTOR-S6 kinase. It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival.[4] Genes that code for proteins that regulate cell growth, such as NF1 and TP53, are referred to as tumor suppressor genes. Neurofibromin has other growth-regulatory properties besides its ability to regulate RAS activity, but these other functions are poorly understood at this time. [5] While one defective allele may be inherited, loss of heterozygosity (LOH) must occur before a neurofibroma can form; this is called the ‘two-hit hypothesis’. This LOH happens by the same mechanisms, such as oxidative DNA damage, that causes mutations in other cells.

Schwann cells are the neoplastic element in neurofibromas. There are two kinds of Schwann cells, myelinating and nonmyelinating. While myelinating Schwann cells cover large diameter (>1 micrometer) peripheral nervous system (PNS) axons with myelin, nonmyelinating Schwann cells encapsulate small diameter PNS axons with their cytoplasmic processes. This conglomeration of nonmyelinating Schwann cells and axons is called a Remak bundle. While nonmyelinating Schwann cells are the origin of neurofibromas, the mutations that make them susceptible to this transformation occur in Schwann cell precursors during early nerve development. Mutated nonmyelinating Schwann cells do not form normal Remak bundles. Instead, they fail to properly surround and segregate target axons. It is unknown at this time why, if both types of Schwann cells exhibit bilallelic inactivation of the NF1 gene, only the nonmyelinating variety give rise to neurofibromas. According to Zheng et al. in the paper Induction of Abnormal Proliferation by Nonmyelinating Schwann Cells Triggers Neurofibroma Formation, “Taken together, our data suggest that the initially expanded nonmyelinating Schwann cells are early-stage tumor cells, which are responsible for both the initiation and progression of plexiform neurofibromas.”[6]

Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, through genetic mutation and DNA damage caused by environmental factors, it begins to proliferate rapidly. This condition is called hyperplasia, which is cell growth beyond what is normally seen. However, despite increased numbers of nonmyelinating Schwann cells, there is no neurofibroma yet. In order for the neurofibroma to develop, cells that are heterozygous for the NF1 gene must be recruited to the site. It has been hypothesized that the proliferating nonmyelinating Schwann cells secrete chemoattractants such as the KIT ligand, and angiogenic factors such as the heparin-binding growth factor midkine. These chemicals promote the migration of different kinds of cells that are heterozygous for the NF1 gene into the hyperplastic lesions created by the nonmyelinating Schwann cells. These cell types include fibroblasts, perineurial cells, endothelial cells, and mast cells. The mast cells then secrete mitogens or survival factors that alter the developing tumor microenvironment and result in neurofibroma formation. Dermal and plexiform neurofibromas do differ in later development stages, but the details are unclear at this point.[4]

Once a plexiform neurofibroma has formed, there is a chance that it will undergo transformation into a malignant peripheral nerve sheath tumor (MPNST). The formation of malignant cancers from neurofibromas is associated with the loss of expression of the CDKN2A or TP53 gene in non-myelinating Schwann cells that also exhibit biallelic inactivation of the NF1 gene.

Neurofibromas have been subdivided into two broad categories: dermal and plexiform. Dermal neurofibromas are associated with a single peripheral nerve, while plexiform neurofibromas are associated with multiple nerve bundles. According to the World Health Organization classification system, dermal and plexiform neurofibromas are grade I tumors.

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Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 new cases per year in the US.[1] Close to 50 percent of neuroblastoma cases occur in children younger than two years old.[2] It is a neuroendocrine tumor, arising from any neural crest element of the sympathetic nervous system or SNS. A branch of the autonomic nervous system, the SNS is a nerve network that carries messages from the brain throughout the body and is responsible for the fight-or-flight response and production of adrenaline or epinephrine. Its solid tumors, which take the form of a lump or mass, commonly begin in one of the adrenal glands, though they can also develop in nerve tissues in the neck, chest, abdomen, or pelvis. Esthesioneuroblastoma, also known as olfactory neuroblastoma, is believed to arise from the olfactory epithelium and classification remains controversial. Since it is not a sympathetic nervous system malignancy it is a distinct clinical entity not to be confused with neuroblastoma.[3][4]

The cause of neuroblastoma is unknown, though most physicians believe that it is an accidental cell growth that occurs during normal development of the adrenal glands.

Neuroblastoma is one of the rare human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular appearance.

Neuroblastoma comprises 6-10% of all childhood cancers, and 15% of cancer deaths in children. The annual mortality rate is 10 per million children in the 0- to 4-year-old age group, and 4 per million in the 4- to 9-year old age group.[5]

The highest incidence is in the first year of life, and some cases are congenital. The age range is broad, including older children and adults,[6] but only 10% of cases occur in people older than 5 years of age.[7]

The etiology of neuroblastoma is not well understood. Several risk factors have been proposed and are the subject of ongoing research. Due to characteristic early onset many studies have focused on parental factors around conception and during gestation. Factors investigated have included occupation (i.e. exposure to chemicals in specific industries), smoking, alcohol consumption, use of medicinal drugs during pregnancy and birth factors, however results have been inconsistent.[8]

Other studies have examined possible links with atopy and exposure to infection early in life,[9] use of hormones and fertility drugs,[10] and maternal use of hair dye.[11]

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Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein[1] (proteinuria at least 3.5 grams per day per 1.73m2 body surface area)[2] from the blood into the urine.

Nephrotic syndrome has small pores in the podocytes, large enough to permit proteinuria (and subsequently hypoalbuminemia, because some of the protein albumin has gone from the blood to the urine) but not large enough to allow cells through (hence no hematuria). By contrast, in nephritic syndrome, RBCs pass through the pores, causing hematuria.

It is characterized by proteinuria (>3.5g/day), hypoalbuminemia, hyperlipidemia and edema. A few other characteristics are:

The following are baseline, essential investigations

Further investigations are indicated if the cause is not clear

Nephrotic syndrome has many causes and may either be the result of a disease limited to the kidney, called primary nephrotic syndrome, or a condition that affects the kidney and other parts of the body, called secondary nephrotic syndrome.

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Necrotizing fasciitis (NF) or fasciitis necroticans, commonly known as flesh-eating disease or flesh-eating bacteria, is a rare infection of the deeper layers of skin and subcutaneous tissues, easily spreading across the fascial plane within the subcutaneous tissue. Type I describes a polymicrobial infection, whereas Type II describes a monomicrobial infection. Many types of bacteria can cause necrotizing fasciitis (eg. Group A streptococcus (Streptococcus pyogenes), Staphylococcus aureus, Vibrio vulnificus, Clostridium perfringens, Bacteroides fragilis).

Historically, Group A streptococcus made up most cases of Type II infections. However, since at least 2001, another serious form of monomicrobial necrotizing fasciitis has been observed with increasing frequency.[1] In these cases, the bacterium causing it is methicillin resistant Staphylococcus aureus (MRSA), a strain of S. aureus which is resistant to methicillin, the antibiotic used in the laboratory that determines the bacterium’s sensitivity to flucloxacillin that would be used for treatment clinically.

The infection begins locally, at a site of trauma, which may be severe (such as the result of surgery), minor, or even non-apparent. Patients usually complain of intense pain that may seem in excess given the external appearance of the skin. With progression of the disease, tissue becomes swollen, often within hours. Diarrhea and vomiting are common symptoms as well. Inflammation does not show signs right away if the bacteria are deep within the tissue. If they are not deep, signs of inflammation such as redness and swollen or hot skin show very quickly. Skin color may progress to violet and blisters may form, with subsequent necrosis (death) of the subcutaneous tissues. Patients with necrotizing fasciitis typically have a fever and appear very ill. Mortality rates have been noted as high as 73 percent.[2] Without surgery and medical assistance, such as antibiotics, the infection will rapidly progress.[3]

“Flesh-eating bacteria” is a misnomer as the bacteria do not actually eat the tissue. They cause the destruction of skin and muscle by releasing toxins (virulence factors), which include streptococcal pyogenic exotoxins. S. pyogenes produces an exotoxin known as a superantigen. This toxin is capable of activating T-cells non-specifically, which causes the overproduction of cytokines.

Patients are typically taken to surgery based on a high index of suspicion, determined by the patient’s signs and symptoms. In necrotizing fasciitis, aggressive surgical debridement (removal of infected tissue) is always necessary to keep it from spreading and is the only treatment available. Diagnosis is confirmed by visual examination of the tissues, and by tissue samples sent for microscopic evaluation. Early medical treatment is often presumptive; thus, antibiotics should be started as soon as this condition is suspected. Initial treatment often includes a combination of intravenous antibiotics including penicillin, vancomycin and clindamycin. Cultures are taken to determine appropriate antibiotic coverage, and antibiotics may be changed when culture results are obtained. As in other maladies characterized by massive wounds or tissue destruction, hyperbaric oxygen treatment can be a valuable adjunctive therapy, but is not widely available.[4] A recent study demonstrated excellent clinical outcomes from the use of topical negative pressure, a technology which is portable and readily available.[5] Amputation of the affected organ(s) may be necessary. Repeat explorations usually need to be done to remove additional necrotic tissue. Typically, this leaves a large open wound which often requires skin grafting. The associated systemic inflammatory response is usually profound, and most patients will require monitoring in an intensive care unit.

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Nasopharyngeal carcinoma (NPC) is a cancer originating in the nasopharynx, the uppermost region of the pharynx or “throat”, where the nasal passages and auditory tubes join the remainder of the upper respiratory tract. NPC differs significantly from other cancers of the head and neck in its occurrence, causes, clinical behavior, and treatment. It is vastly more common in certain regions of East Asia and Africa than elsewhere, with viral, dietary, and genetic factors implicated in its causation.

Nasopharyngeal carcinoma, commonly known as nasopharyngeal cancer, is classified as a malignant neoplasm, or cancer, arising from the mucosal epithelium of the nasopharynx, most often within the lateral nasopharyngeal recess or fossa of Rosenmüller. There are three microscopic subtypes of NPC: a well-differentiated keratinizing type, a moderately-differentiated nonkeratinizing type, and an undifferentiated type, which typically contains large numbers of non-cancerous lymphocytes (chronic inflammatory cells), thus giving rise to the name lymphoepithelioma. The undifferentiated form is most common, and is most strongly associated with Epstein-Barr virus infection of the cancerous cells. [1]Babe Ruth is the most famous sufferer of this type of cancer.

Nasopharyngeal carcinoma produces few symptoms early in its course, with the result that most cases are quite advanced when detected. Once the tumor has expanded from its site of origin in the lateral wall of the nasopharynx, it may obstruct the nasal passages and cause nasal discharge or nosebleed. Obstruction of the auditory tubes may cause chronic ear infections, and patients may experience referred pain to the ear. Metastasis of cancer to the lymph nodes of the neck may also be the first noticeable sign of the disease.[1]

Numerous studies have linked common subtypes of NPC to infection with the Epstein-Barr virus (EBV),[2] which has also been implicated in the development of other cancers such as Hodgkin’s disease, Burkitt’s lymphoma, and HIV-associated lymphomas.

There is some evidence that genetic factors, such as HLA type may play a role in the susceptibility of certain ethnic groups to NPC. [3]

Finally, dietary risk factors, such as the consumption of salt-cured fish high in nitrosamines, may play a role in the Asian endemic regions. Well-differentiated NPC, with a microscopic appearance most similar to other squamous cell cancers of the head and neck may be more closely associated with the standard risk factors for that disease, such as cigarette smoking.[1][4]

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Nail-patella syndrome (NPS) (also known as “Fong syndrome,” and “Hereditary osteoonychodysplasia”[1]) is a genetic disorder that is also referred to as Iliac Horn Syndrome, Hereditary Onychoostedysplasia, Fong Disease or Turner-Kiser Syndrome.

The Nail-Patella syndrome is inherited via autosomal dominancy (see autosomal dominant) linked to aberrancy on human chromosome 9′s q arm (q stands for longer arm), 9q34. This autosomal dominancy means that only a single copy, instead of both, is sufficient for disorder to be expressed in the offspring, meaning that the chance of getting the disorder from an affected parent is 50%. The frequency of the occurrence is 1/50,000. The disorder is linked to the ABO blood group locus.

The hallmark features of this syndrome are poorly developed fingernails, toenails, and patellae (kneecaps). Sometimes, this disease causes the affected person to have either no thumbnails or a small piece of a thumbnail on the edge of the thumb. Other common abnormalities include elbow deformities, abnormally shaped pelvis bone (hip bone), and kidney (renal) disease. Also, some research shows that people with NPS are more prone to glaucoma and scoliosis, due to poorly developed spines.

People with nail-patella syndrome may display only a few or many of the recognized signs of this disease. Symptoms vary widely from person to person. Signs even vary within a single family with multiple affected members.

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Naegeli-Franceschetti-Jadassohn syndrome (also known as “Chromatophore nevus of Naegeli”[1]:548 )[2] is a rare autosomal dominant[3] form of ectodermal dysplasia, characterized by reticular skin pigmentation, diminished function of the sweat glands, the absence of teeth and hyperkeratosis of the palms and soles. One of the most striking features is the absence of fingerprint lines on the fingers.

Naegeli syndrome is similar to Dermatopathia pigmentosa reticularis,[4] both of which are caused by a specific defect in the keratin 14 protein.

It was named after Oskar Naegeli.[5]

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