Pancreatic endocrine tumor, also known as pancreatic neuroendocrine tumor (PNET), describes a group of endocrine tumors originating in the pancreas that are usually indolent and benign, but may have the potential to be malignant. They can be functional, exhibiting a hormonal hypersecretion syndrome, but can be non-functional presenting with non-specific symptoms and include insulinoma, glucagonoma, VIPoma, somatostatinoma (SSoma), PPoma and Zollinger-Ellison syndrome (ZES, or gastrinoma) and other ectopic hormone producing tumors (such as GRFoma) (see these terms).

Summary:
Epidemiology
Prevalence in the U.S. is estimated at 1/4,000-1/3,300 and 1/37,000 in Japan, but this is likely an underestimate due to a low detection rate.
Clinical description
PNETs, when functional, usually present in the 5th decade of life as various hypersecretion syndromes. These include insulinoma presenting with hyperinsulinemic hypoglycemia; glucagonoma with necrolytic migratory erythema, diabetes mellitus, and thomboembolisms; VIPoma with watery diarrhea, hypokalemia and or hypo/achlorhydia; SSoma with diabetes mellitus, cholelithiasis, steatorrhea and hypochlorhydria; and ZES with severe peptic ulcer disease. Rarely PNETs secrete ectopic hormones (i.e. growth regulatory hormone). Non-functioning PNETs are not associated with distinct hormonal features but may still secrete hormones (i.e. PPoma). They are usually discovered incidentally in the 4-5th decade of life, due to non-specific symptoms, and in many cases have already metastasized to the liver. Malignant behavior is seen in >50% of PNETs (except insulinoma, ~10%). PNETs can also be associated with familial endocrine tumor syndromes (10% of cases) such as multiple endocrine neoplasia type 1, neurofibromatosis type 1, and Von Hippel-Lindau disease (see these terms).
Etiology
Etiology is unknown. They are thought to be derived from pluripotential epithelial cells in pancreatic ductules or Langerhans islet cells and are most commonly located in the pancreas. SSoma and gastrinoma can also be found in the upper small intestine. Inactivation of tumor suppressor genes or activation of oncogenes may be causative as seen in familial endocrine tumor syndromes.
Diagnostic methods
Diagnosis requires clinical examination, endocrine testing, imaging studies and histopathology examination (HPE) of the tumor. Computed tomography, MRI, endoscopic ultrasound and somatostatin receptor scintigraphy allows for the visualization of a PNET (>0.5) as well as liver, lymph node and peritoneal metastases. HPE and immunohistochemistry help to identify and grade the tumor. Chromogranin A, neuron-specific enolase and pancreastatin are often elevated. Elevated hormone levels may help to identify functional PNETs.
Differential diagnosis
Differential diagnosis is tumor specific and includes endocrine tumor and carcinoid syndrome (see this term).
Genetic counseling
Most PNETs are sporadic but about 10% are associated with autosomal dominantly inherited endocrine tumor syndromes.
Management and treatment
Management involves resolving the hormone-excess state and treating the tumor itself. Removal of as much of the primary and (if present) metastatic tumors is the current approach. Systemic therapy, with somatostatin analogues (octreotide and lanreotide), effectively treats most functional tumors. If ineffective, systemic interferon-alpha can be given. Complications caused by specific functional tumors should equally be addressed. Surgical procedures involve enucleation and pancreatectomies (with regional lymphadenectomy in most cases). In those with liver metastases, locoregional therapy (i.e. chemoembolization as well as radiofrequency, alcohol and microwave ablation) is recommended to treat liver metastases. Chemotherapy is considered only in those with an intermediate-high grade PNET.
Prognosis
Prognosis is variable. A less favorable prognosis is associated with higher tumor grade and liver and lymph node metastasis. The 5-year survival rate is 30% for nonfunctional PNETs and up to 97% for functional resectable PNETs. Hormonal complications can be life threatening.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Run YU


A rare subtype of neuroendocrine neoplasm, arising from enterochromaffin-like cells in the stomach, with a variable clinical presentation, disease course and prognosis, depending on the disease type and histological grade. Most patients are asymptomatic, with diagnosis usually occurring incidentally during gastroscopy, however, symptoms of dyspepsia, anemia, pain, weight loss and gastrointestinal bleeding can be observed. Association with Zollinger-Ellison syndrome and multiple endocrine neoplasia type I has been reported.


A rare epithelial tumor of the large intestine, arising from enterochromaffin cells, most commonly in the cecum or ascending colon. The tumor is usually slow-growing and can be diagnosed as an incidental finding in an asymptomatic patient, while in the later stages patients can present with abdominal pain, palpable abdominal mass, changes in bowel habits, signs of bowel obstruction, gastrointestinal bleeding, anorexia, weight loss or, rarely, carcinoid syndrome (facial flushing, diarrhea, tachycardia, hypo- and hypertension, cardiac abnormalities).


Neuroendocrine tumor of the rectum is a rare epithelial tumor of rectum arising from enterochromaffin cells, most often in the mid-rectum. The tumors are slow growing, in early stages majority are asymptomatic and are diagnosed incidentally. Later in the course, the tumor may present with rectal bleeding, abdominal or rectal pain, tenesmus, changes in bowel habits, or weight loss. In some cases it may present with carcinoid symptoms of flushing and increased gut motility.


Neurofaciodigitorenal syndrome is a rare multiple developmental anomalies syndrome characterized by neurological abnormalities (including megalencephaly, hypotonia, intellectual disability, abnormal EEG), dysmorphic facial features (high prominent forehead, grooved nasal tip, ptosis, ear anomalies) and acrorenal defects (such as triphalangism, broad halluces, unilateral renal agenesis). Additionally, intrauterine growth restriction, short stature and congenital heart defects may be associated. There have been no further descriptions in the literature since 1997.


Neuroferritinopathy is a late-onset type of neurodegeneration with brain iron accumulation (NBIA; see this term) characterized by progressive chorea or dystonia and subtle cognitive deficits.

Summary:
Epidemiology
Prevalence of neuroferritinopathy is unknown. To date fewer than 50 cases have been reported.
Clinical description
The disease presents typically in the fourth to sixth decades, although cases with symptoms in their late teens have been observed. Symptoms are restricted to the nervous system and include chorea, dystonia, bradykinesia, dystonic dysarthria, and Parkinsonian features. Choreiform movements tend to occur in the face, orolingual musculature and upper limbs and onset is usually asymmetrical. Dystonia can affect the face, tongue, arms and legs and onset is also usually asymmetrical. The majority of individuals develop a characteristic orofacial action-specific dystonia related to speech that leads to dysarthrophonia. Frontalis overactivity is common, as is orolingual dyskinesia. Cognitive deficits, behavioral issues and dysphagia can be a late feature.
Etiology
Neuroferritinopathy is caused by mutations in the ferritin light chain (FTL) gene (19q13.3-q13.4) and is inherited in an autosomal dominant manner with high penetrance.
Diagnostic methods
Diagnosis is based on clinical findings including adult-onset chorea or dystonia, low serum ferritin (typically 20 micrograms/L or less) and iron deposition in the basal ganglia shown on brain MRI. Molecular genetic testing is available on a limited basis.
Differential diagnosis
Differential diagnoses include Huntington disease and spinocerebellar ataxia type 17 (see these terms), although neither has the characteristic findings on neuroimaging; choreoacanthocytosis and McLeod neuroacanthocytosis syndrome (see these terms), although, unlike in these two diseases, the reflexes are preserved in neuroferritinopathy, and juvenile-onset Parkinson disease, aceruloplasminemia and Neimann-Pick type C (see these terms), although these disorders do not show the characteristic neuroimaging of neuroferritinopathy. The MRI findings are similar to those found in pantothenate kinase-associated neurodegeneration (PKAN; see this term). Individuals with neuroferritinopathy also show the 'eye of the tiger'' sign.
Antenatal diagnosis
Prenatal testing for pregnancies at increased risk may be available through laboratories offering prenatal testing if the disease-causing mutation in the family is known.
Management and treatment
Treatment is of the manifestations of the disease and includes levodopa, tetrabenazine, benzhexol, sulpiride, diazepam, clonezepam and deanol for the movement disorder and botulinum toxin for painful focal dystonia. Treatment also includes ensuring adequate caloric intake and physiotheraphy to maintain mobility. Iron supplements are not recommended.
Prognosis
The movement disorder is progressive, involving additional limbs in five to ten years and becoming more generalized within 20 years.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Pr Patrick CHINNERY


A rare benign peripheral nerve sheath tumor characterized by a well-demarcated intraneural or diffusely infiltrative extraneural space-occupying lesion consisting of Schwann cells, perineurial-like cells, and fibroblasts. It presents as a cutaneous nodule, a circumscribed mass in a peripheral nerve, a plexiform enlargement of a major nerve trunk, or with diffuse but localized involvement of skin and subcutaneous tissue. Multiple neurofibromas are typically associated with neurofibromatosis 1. Malignant transformation occurs almost exclusively in plexiform neurofibromas and neurofibromas of major nerves.


Neurofibromatosis type 1 (NF1) is a clinically heterogeneous, neurocutaneous genetic disorder characterized by café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, and multiple neurofibromas.

Summary:
Epidemiology
Prevalence is reported to be 1/3,000 live births. NF1 is reported in many ethnic groups and affects males and females equally.
Clinical description
The clinical features are highly variable, even within the same family. Multiple café-au-lait macules are found in almost all patients (some at birth and most before the first year). Intertriginous freckling develops starting at 5 years of age. Multiple cutaneous and subcutaneous neurofibromas develop in adults. In older patients, they continue to increase in number and size. Cutaneous neurofibromas do not become malignant. Plexiform neurofibromas (growing along the nerve and its branches) may cause disfigurement, pain, and functional problems and are usually present at birth and may become malignant later in life. Ocular manifestations include optic pathway gliomas and iris hamartomas (Lisch nodules). Optic pathway gliomas usually develop before age 6 years, and rarely progress thereafter. Osteopenia, osteoporosis, bone overgrowth, short stature, macrocephaly, scoliosis, skeletal dysplasia (sphenoid wing, vertebral), and pseudoarthrosis may be present. Other features include hypertension, vasculopathy, intracranial tumors, malignant peripheral nerve sheath tumor (MPNST; see this term), and occasionally seizures or hydrocephalus. Intellectual development is usually not severely affected but cognitive deficits and learning difficulties are frequent (50%-75%). The overall cancer risk is higher than the general population (lifetime risk of 10-12% for MPNST, mostly between 20-40 years; increased risk of breast cancer before age 50). Familial spinal and segmental forms of NF1 have been described. Watson syndrome forms part of the NF1 spectrum. Neurofibromatosis-Noonan syndrome is a variant of NF1 in 99% of cases (see these terms).
Etiology
NF1 is caused by mutations in the tumor suppressor neurofibromin 1 NF1 gene (17q11.2) and rarely by 17q11 microdeletion (only 5%).
Diagnostic methods
Formal diagnostic criteria have been established. 2 or more of the following are diagnostic: more than 5 café-au-lait macules, 2 or more neurofibromas or one plexiform neurofibroma, optic glioma, freckling, 2 or more Lisch nodules, specific bone dysplasias, first-degree relative. Magnetic resonance imaging can determine the extent of plexiform neurofibromas. Molecular genetic testing can be requested but is mostly not needed.
Differential diagnosis
Legius syndrome (see this term) is often clinically indistinguishable from NF1 and is seen in about 2% of people fulfilling NF1 diagnostic criteria. There are however a small number of individuals with NF1 who like Legius syndrome patients do not develop non-pigmentary manifestations. Constitutional mismatch repair deficiency syndrome should be considered. Other differential diagnoses include McCune-Albright syndrome, Noonan syndrome with lentigines and Proteus syndrome. Most cases of multiple non-ossifying fibromatosis are cases of NF1 (see these terms).
Antenatal diagnosis
Prenatal and preimplantation genetic testing for at-risk pregnancies is possible
Genetic counseling
The mode of inheritance is autosomal dominant. 1 in 2 cases is caused by de novo NF1 mutations. Penetrance is 100% but disease manifestations vary widely, complicating genetic counseling.
Management and treatment
Specific cardiovascular, ocular, neurological and orthopedic manifestations should be treated by corresponding specialists. Cutaneous or subcutaneous neurofibromas can be removed surgically. Plexiform neurofibromas are far more difficult to treat.
Prognosis
Overall prognosis is good but significant morbidity is common. MPNST generally has a poor prognosis. Malignancy and vascular disease are the most common causes of early demise.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Eric LEGIUS


Neurofibromatosis-Noonan syndrome (NFNS) is a RASopathy and a variant of neurofibromatosis type 1 (NF1) characterized by the combination of features of NF1, such as café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, optic nerve glioma and multiple neurofibromas, and Noonan syndrome (NS), such as short stature, typical facial features (hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly rotated ears with a thickened helix, and a broad forehead), congenital heart defects and unusual pectus deformity. As these three entities have significant phenotypic overlap, molecular genetic testing is often necessary for a correct diagnosis (such as when café-au-lait spots are present in patients diagnosed with NS).


Neurogenic arthrogryposis multiplex congenita

A form of arthrogryposis multiplex congenita characterized by congenital immobility of the limbs with fixation of multiple joints and muscle wasting. This condition is secondary to neurogenic muscular atrophy.


Neurogenic scapuloperoneal syndrome, Kaeser type

A rare, genetic, neuromuscular disease characterized by adult-onset muscle weakness and atrophy in a scapuloperoneal distribution, mild involvement of the facial muscles, dysphagia, and gynecomastia. Elevated serum CK levels and mixed myopathic and neurogenic abnormalities are associated clinical findings.


Neurogenic thoracic outlet syndrome (NTOS) is a form of thoracic outlet syndrome (TOS; see this term) that presents with pain, paresthesias and weakness in an upper extremity and is divided into true NTOS and disputed NTOS.

Summary:
Epidemiology
The incidence of NTOS is unknown. It affects women more than men. Disputed NTOS is the most controversial form and accounts for approximately 95% of all cases of TOS and 99% of cases with neurologic symptoms
Clinical description
NTOS presents with upper extremity paresthesias, pain and weakness. True NTOS manifests slowly with the progressive unilateral atrophic weakness of the intrinsic hand muscles and sensory abnormalities in a T1 distribution due to a lower trunk brachial plexopathy. Disputed NTOS does not cause muscle atrophy, but there is scalene muscle tenderness and symptoms worsen with arm use and provocative maneuvers.
Etiology
True NTOS is caused by lower trunk brachial plexus compression in the thoracic outlet at the interscalene triangle, costoclavicular space, or subcoracoid space deep to the pectoralis minor tendon. Disputed NTOS may be due to scarring of scalene muscles, poor posture or a congenital anomaly.
Diagnostic methods
Radiographs may identify compressive sources including an elongated C7 transverse process or anomalous first rib. Electrodiagnostic (EDX) findings demonstrate a lower trunk brachial plexopathy. MRI identifies compressive sources and rules out other causes such as a Pancoast tumor. Disputed NTOS is a clinical diagnosis that depends on scalene muscle tenderness and provocative maneuvers eliciting pain and paresthesias in the affected extremity as it lacks objective EDX evidence. It is most often a diagnosis of exclusion.
Differential diagnosis
Differential diagnoses include arterial and venous TOS (see these terms), cervical radiculopathy, carpal tunnel syndrome or any disorder involving nerve fibers derived from C8 or T1 nerve roots such as cubital tunnel syndrome. EDX testing differentiates the lower trunk brachial plexopathy of NTOS from other neurologic diagnoses. Arterial TOS presents with ischemia and venous TOS presents with venous congestion.
Management and treatment
Disputed NTOS is treated with physical therapy, medication and use of orthoses and neck collars. Refractory cases may undergo surgical decompression. For true NTOS surgical decompression is considered based on the degree of nerve injury and is indicated if there is acute or sub-acute progressive weakness or disabling pain and paresthesias.
Prognosis
In cases of true NTOS, decompression relieves pain, but full neurologic recovery requires time for remyelination or axonal regeneration. If there is axonal loss, recovery may be incomplete. Success rates for surgical decompression of disputed NTOS are 91%-93% immediately after treatment, but drop to 64% to 71% after 10 years due to a high rate of recurrence.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Dr Joseph FEINBERG  - Dr Paul SCHOLTEN


A rare neuropsychiatric syndrome associated with administration of antipsychotic or other central dopamine (D2) receptor antagonists, and characterized by hyperthermia, muscular rigidity, autonomic dysfunction and altered consciousness.

Summary:
Epidemiology
Neuroleptic malignant syndrome (NMS) occurs in 1/5,000 to 10,000 patients treated with antipsychotics or other central dopamine (D2) receptor antagonists (all age groups; male:female ratio 2:1 in some studies; higher incidence rates have been reported in the past). The incidence may be lower with newer less potent antipsychotics and with reduced severity of symptoms, particularly for clozapine.
Clinical description
In about 16% of patients, the syndrome occurs within 24 hours after the initiation of the antipsychotic treatment, 66% within the first week, and less commonly within or after 30 days on stable medication regimens. Manifestations include hyperthermia, muscular rigidity and tremor, mental status alteration and autonomic dysfunction. Other signs may include profuse diaphoresis, tachycardia, tachypnea, labile blood pressure, acidosis, incontinence, and elevated serum creatine kinase (CK) and transaminases from rhabdomyolysis with risk of subsequent renal failure. Once symptoms develop, they last on average 7-10 days after discontinuation of oral triggering drugs, with peak intensity within the first 72 hours. Risk factors include prior NMS episodes, physical exhaustion, agitation, dehydration, pre-existing catatonia, use of restraints, use of high doses, high potency drugs, acute parenteral forms of antipsychotics, and rapid antipsychotic dosage increase.
Etiology
The syndrome is thought to result from acute central dopamine receptor blockade. All antipsychotic agents, typical or atypical, may trigger the syndrome, although potent antipsychotics (haloperidol, fluphenazine) are more frequently associated. Dopamine blocking agents used in non-psychiatric settings (metoclopramide, prochlorperazine, droperidol) and dopamine depleting agents (tetrabenazine) have also been implicated.
Diagnostic methods
Diagnosis is based on clinical signs of the syndrome in the context of treatment with dopamine blocking agents, and the exclusion of alternative etiologies via thorough investigation with laboratory and imaging tests. Although elevated CK is a frequent correlate of muscle dysfunction in NMS, it is nonspecific. The likelihood of an NMS diagnosis can be assessed using the International Expert Consensus (IEC) criteria which are based on priority scores assigned to major clinical features (antipsychotic exposure, hyperthermia, rigidity, mental status changes, CK elevation, etc.). A total cut-off threshold score of ≥74 on the IEC criteria offers 69.6% sensitivity and 90.7% specificity in diagnosing NMS.
Differential diagnosis
The differential diagnosis is of prime importance. It includes malignant hyperthermia of anesthesia, serotonin syndrome, parkinsonism hyperpyrexia syndrome, heat stroke, idiopathic malignant catatonia, infections (sepsis, meningitis, encephalitis), autoimmune disorders (limbic encephalitis with NMDA receptor antibodies, lupus cerebritis) delirium tremens, status epilepticus, salicylate poisoning, endocrinopathies, stroke, and brain trauma.
Management and treatment
Immediate cessation of the antipsychotic medication and supportive measures (volume resuscitation, physical cooling) are essential in management. Specific treatments are unproven. Benefits in cases treated empirically based on phenomenology, severity and duration of symptoms with benzodiazepines, dopaminergic agents (bromocriptine, amantadine), dantrolene (in cases with extreme hyperthermia, rigidity and rhabdomyolysis) and electroconvulsive therapy have been reported. Careful monitoring for cardiorespiratory failure, renal failure, aspiration pneumonia and coagulopathies is required. Ventilatory assistance and dialysis may be required.
Prognosis
After discontinuation of oral psychotropic agents, resolution usually occurs within 1-2 weeks in most uncomplicated cases. However, the syndrome is still potentially lethal. Death may result from sudden cardiorespiratory arrest, aspiration pneumonia, pulmonary emboli, myoglobinuric renal failure, or disseminated intravascular coagulation. Mortality rate is estimated at 5-10% with adverse outcomes more likely with potent antipsychotics, older age and pre-existing cardiorespiratory disease. Most patients recover completely but amnestic syndromes, extrapyramidal and cerebellar disorders, peripheral neuropathy, myopathy and contractures have been reported in rare cases.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Pr STANLEY CAROFF  - Dr Henry ROSENBERG


Neurolymphomatosis is a rare syndrome of peripheral and cranial nerve dysfunction in patients with hematologic malignancies, mostly non-Hodgkin's lymphoma or acute leukemia, characterized by painful or painless involvement of peripheral or cranial nerves or nerve roots. The clinical presentation is diverse depending on the site involved and includes plexopathy, mononeuritis multiplex, peripheral neuropathy, radiculopathy and cranial nerve palsies.


Neurometabolic disorder due to serine deficiency

Serine-deficiency syndrome is a very rare infantile-onset potentially treatable neurometabolic disorder characterized clinically by microcephaly, neurodevelopmental disorders and seizures. Three serine-deficiency syndromes have been described: 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, 3-phosphoserine phosphatase (3-PSP) deficiency, and phosphoserine aminotransferase deficiency (see these terms).


A rare inflammatory disease of the central nervous system characterized mainly by attacks of uni- or bilateral optic neuritis (ON) and acute myelitis.

Summary:
Epidemiology
Neuromyelitis optica spectrum disorder (NMOSD) has a worldwide distribution and estimated prevalence of 1-5/100,000. The average annual incidence is 1/770,000 worldwide. Nearly 90% of affected individuals are female.
Clinical description
Patients are predominantly female with onset typically in late middle-age. Presentation is with acute, often severe, attacks of blindness and paraparesis or quadriparesis, accompanied by sensory and sphincter impairments. Most patients have relapsing attacks (more frequent in women), separated by months or years with partial recovery, typically with sequential episodes of ON and myelitis. More rarely, the disease course is monophasic, with nearly simultaneous episodes of ON and myelitis. This form may occur in younger individuals with no sex predilection. Rarely, patients experience other neurological manifestations, including intractable vomiting and nausea due to inflammation in the medulla, endocrine and sleep disorders due to involvement of the hypothalamus, and attacks of cerebral edema that may cause confusion or coma. Patients frequently have other systemic autoimmune disorders, such as systemic lupus erythematosus (SLE), Sjögren's syndrome or myasthenia gravis.
Etiology
Etiology is unknown but NMO is believed to be an autoimmune disease associated with autoantibodies to aquaporin-4 (AQP4) in 70% and autoantibodies to myelin oligodendrocyte glycoprotein (MOG) in 15% of patients. 15% of patients are double seronegative for these antibodies. Patients with autoantibodies to MOG have overlapping clinical features, but have demographic and clinical differences from patients with autoantibodies to AQP4 and patients with these antibodies are diagnosed with MOG associated disorders (MOGAD).
Diagnostic methods
Diagnosis is primarily clinical, but MRI evidence of long spinal cord lesions extending over three or more vertebral segments during an acute attack of myelitis is helpful in differentiating this disorder from multiple sclerosis (MS), as are normal brain MRI findings in the early stages of NMOSD. When aquaporin-4 antibodies are detected, their specificity permits diagnosis in circumstances when the clinical diagnosis is less straightforward, such as in patients with a first event of transverse myelitis or in patients with atypical brain lesions. Detection of MOG antibodies is generally reliable in diagnosis of MOG associated disorders, as distinct from MS and NMOSD, but the serology is less specific when antibodies are detected in low titer and a combination of clinical, radiologic and serologic data is necessary to achieve a specific diagnosis in patients with low titer MOG antibodies.
Differential diagnosis
Differential diagnoses include MS; idiopathic, viral, paraneoplastic and connective tissue disease (e.g. SLE)-associated myelitis; ischemic and connective tissue associated optic neuropathies.
Genetic counseling
Fewer than 5% of individuals report relatives with NMOSD; polygenic inheritance is thought to be responsible for the small excess of familial cases relative to expected.
Management and treatment
Acute attacks are treated with high dose intravenous corticosteroids and if this fails, with plasma exchange. For patients with AQP4 antibodies, three agents are approved (in the USA and Europe) eculizumab, inebilizumab and satralizumab, and which reduce clinical attacks by 75-95%. Alternative maintenance treatments for patients with AQP4 antibodies or MOG antibodies are immunosuppressive drugs (e.g. azathioprine or mycophenolate mofetil), often combined with corticosteroids, or rituximab.
Prognosis
The prognosis is variable: patients may recover completely from individual attacks, but residual neurological deficits are common and sometimes severe. Unrecognized or untreated, up to 30% of patients may die in the first 5 years of their illness due to an attack of severe myelitis leading to respiratory failure. A high proportion of patients will become legally blind in one or both eyes and/or have substantial residual paraparesis. The prognosis for good recovery from attacks is much better for those with MOG antibodies compared to those with AQP4 antibodies.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Pr Brian WEINSHENKER


Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited progressive degenerative brain diseases characterized clinically by a decline of mental and other capacities, epilepsy, and vision loss through retinal degeneration, and histopathologically by intracellular accumulation of an autofluorescent material, ceroid lipofuscin, in the neuronal cells in the brain and in the retina.

Summary:
Epidemiology
The exact prevalence and incidence of this group of disorders are unknown.
Clinical description
The clinical presentation varies widely between forms but the clinical hallmark is a combination of dementia, visual loss, and epilepsy. Manifestations may begin between the neonatal period and young adult age depending on the form, leading to the original classification of NCLs by age at onset into congenital, infantile, late infantile, juvenile and adult NCL subgroups (see these terms). A Northern epilepsy variant (progressive epilepsy-intellectual deficit, Finnish type; see this term), in which the visual problems may be absent or be mild and go unrecognized, has also been described.
Etiology
To date, at least 10 genetic NCL disorders have been reported and are designated as CLN1 to CLN10. The majority of NCLs are inherited in an autosomal recessive manner, however, autosomal dominant inheritance has been reported in one adult-onset form designated as a CLN4 disease.
Diagnostic methods
Diagnosis is based on clinical findings, electron microscopy studies revealing storage material with autofluorescent ceroid lipopigments, and enzymatic testing for deficiencies in palmitoyl-protein thioesterase 1, tripeptidyl-peptidase 1 and cathepsin D, present in patients with the CLN1, CLN2 and CLN10 diseases, respectively. With the exception of the CLN4 and CLN9 diseases (for which the causative genes have not yet been identified), the diagnosis can be confirmed by molecular testing.
Differential diagnosis
The differential diagnoses should include other causes of vision loss, dementia and seizures with an appropriate age of onset (typically mitochondrial disorders, inborn errors of metabolism and other lysosomal storage disorders).
Antenatal diagnosis
Prenatal diagnosis is feasible through molecular testing if the disease-causing mutation in the family has already been identified or through enzymatic analysis in some cases.
Management and treatment
There is no curative treatment for NCLs and management is supportive only.
Prognosis
Although all NCLs lead to severe disability, the prognosis is variable with life expectancy ranging from a few hours or days after birth for the congenital form to survival into the fifth decade for patients with the adult-onset form.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Pr Alfried KOHLSCHÜTTER


Neuronal intestinal pseudoobstruction is a form of chronic intestinal pseudoobstruction caused by a developmental failure of the enteric neurons to differentiate or migrate properly and manifests as a bowel obstruction.


Neuronal intranuclear inclusion disease (NIID) is a very rare multisystem neurodegenerative disorder characterized by the presence of eosinophilic intranuclear inclusions in neuronal and glial cells, and neuronal loss.

Summary:
Epidemiology
Infantile, juvenile, and adult-onset cases have been described in approximately 30 patients word-wide.
Clinical description
As any part of the nervous system can be affected (central, peripheral, and autonomic nervous systems), the clinical manifestations depend on the sites involved, and widely vary. The most common neurological signs include ataxia, extra-pyramidal signs (tremor and oculogyral crises), lower motor neuron findings (absent deep tendon reflexes, weakness, muscle wasting, foot deformities), and less apparent behavioural or cognitive difficulties. Dementia is reported as a predominant neurological symptom in adult patients, while infantile/juvenile cases show disproportionate ataxia and other movement symptoms. Occasionally, gastrointestinal dysmotility with severe weight loss may be present, if the enteric nervous system is involved.
Diagnostic methods
NIID may be diagnosed by a full thickness rectal biopsy.
Differential diagnosis
The differential diagnosis should consider spinocerebellar ataxias, progressive juvenile parkinsonism and dystonia.
Genetic counseling
Most cases are sporadic. Despite reports of several familial cases (including a pair of identical twins), no causative gene has been identified. Autosomal dominant transmission has been suggested in these families.
Management and treatment
There is no cure or treatment that slows the progression of the disease. Symptomatic treatments may improve the quality of life.
Prognosis
NIID is slowly progressive (within 10 to 20 years) and fatal.

                            Last update:
                            April 2007

                            - Expert reviewer(s):
                            Pr Bertrand FONTAINE


This syndrome is characterized by the association of sensorineural hearing impairment and peripheral neuropathy.

Summary:
Epidemiology
It has been described in members from four generations of a Spanish family.
Clinical description
The hearing impairment was mild and often asymmetrical. The neuropathy was demyelinating with predominantly sensory involvement but severity was variable ranging from asymptomatic individuals to patients with skin ulcers and osteomyelitis requiring amputation.
Etiology
Neuropathy with hearing impairment is caused by mutations in the GJB3 gene (1p34).
Genetic counseling
The syndrome is transmitted in an autosomal dominant manner.

                            Last update:
                            January 2009


Neurotrophic keratopathy is a rare degenerative disease of the cornea characterized by reduction or loss of corneal sensitivity that can be asymptomatic or present with red-eye and, during the early stages of the disease, a minor decrease in visual acuity. It eventually leads to loss of vision.

Summary:
Epidemiology
No epidemiological data are available. However, prevalence can be estimated at around 1/2,380 in Europe.
Clinical description
Neurotrophic keratopathy (NK) most commonly occurs in adults, and rarely presents in children. It is often asymptomatic, but early signs can include red-eye, blurred vision, and decreased visual acuity. As the disease progresses, epithelial defects and corneal ulcers may develop; corneal scarring and astigmatism can lead to further reduction of visual function. Eventually, progression towards corneal melting and perforation can result in vision loss.
Etiology
NK results from an impairment of trigeminal innervation that provides trophic support to the cornea. The most common causes are viral infection (e.g. herpes simplex) and surgery that damages the trigeminal nerve. Other causes of corneal nerve impairment include: chronic use of topical medications (e.g. timolol, betaxolol), iatrogenic injury (e.g. long-term use of contact lenses), systemic diseases (e.g. diabetes mellitus, multiple sclerosis), chemical burns, and intracranial masses (e.g. schwannoma, aneurysms). Congenital causes (e.g. HSAN4) are extremely rare and most often reported in children.
Diagnostic methods
Diagnosis is based on clinical findings of impaired corneal sensitivity, associated with corneal epithelial changes and medical history. Corneal sensitivity is commonly evaluated using the wisp of a cotton-tipped applicator (although the quantitative method is Cochet-Bonnet aesthesiometry). Slit-lamp and dilated fundus oculi examinations should be carried out and Schirmer and tear ﬁlm break-up time tests prove useful. Corneal and conjunctival vital staining (with fluorescein, rose Bengal or lissamine green) highlight epithelial defects. Corneal nerve morphology is evaluated by in vivo corneal confocal microscopy. Microbiological examination excludes infections. NK staging uses the Mackie classification system: stage 1) punctate keratopathy, epithelial irregularities, stromal scarring, and superficial neovascularization; stage 2) persistent corneal epithelial defect (PED), possible stromal swelling; stage 3) involvement of the corneal stroma, with corneal ulcer progressing to perforation and/or stromal lysis.
Differential diagnosis
Differential diagnoses include all ocular surface and corneal diseases involving the epithelium or causing stromal ulceration: dry-eye, exposure keratitis, corneal limbal stem-cell deficiency, topical drug toxicity, contact-lens abuse, infectious keratitis, corneal dystrophies, and endothelial decompensation.
Management and treatment
Management depends on stage of the disease. In stage 1, artificial tears every 2-4 hours and lubricant ointment at night is prescribed to prevent epithelial breakdown. In addition to artificial tears and lubricant ointment, patients with stage-2 NK, are managed with corneal/scleral contact lenses and topical antibiotic eye drops. Surgery is generally reserved for refractory cases, with partial or total tarsorrhaphy being the most common procedure. For refractory neurotrophic corneal ulcers and severe cases with impending perforation, amniotic membrane transplantation and conjunctival flap surgery is performed, respectively. Small perforations are repaired with cyanoacrylate glue, and a soft-bandage contact lens. Frequent monitoring, ranging from every 1-2 weeks for stage 1 NK to daily for stage 3 disease, is necessary. New treatment methods (e.g. neuropeptides and nerve growth factors), aiming to restore corneal nerves and sensitivity, are currently under investigation.
Prognosis
The prognosis of NK is variable and depends on many factors. A longer duration of the disease, together with severe comorbidities, results in a poorer prognosis.

                            Last update:
                            March 2017

                            - Expert reviewer(s):
                            Dr Paolo RAMA  - Dr Marta SACCHETTI


Neutral lipid storage disease with ichthyosis

A form of autosomal recessive neutral lipid storage disease characterized by the accumulation of lipid vacuoles in granulocytes (so-called Jordan's anomaly) and a variety of other cell types. Clinically, the skin symptoms with ichthyosiform erythroderma and scaling are initially in the foreground. Later, steatosis hepatis, hepatomegaly and muscle weakness develop. Other manifestations include growth delay, cataracts, sensorineural hearing loss, intellectual disability and bowel disease.

Summary:
Epidemiology
The disease is very rare and the prevalence is unknown. Approximately 150 cases have been described in the literature.
Clinical description
The infants are often born with a collodion membrane and develop a pronounced generalized ichthyosiform erythroderma with mostly fine white scaling. In more than half of the cases, moderate myopathy and moderate hepatomegaly (or functional impairment of the liver) occur in adulthood. Other symptoms include intellectual deficits, eye abnormalities (cataracts, retinopathy) and hearing impairment, as well as neuropathy and short stature.
Etiology
Neutral lipid storage disease with ichthyiosis (NLSD-I) is caused by biallelic mutations in the gene ABHD5 which is located on chromosome 3p21. ABHD5 codes for an enzyme involved in the breakdown of triglycerides in the cell. The disruption of this process leads to an accumulation of lipid vacuoles in many cell types.
Diagnostic methods
A simple diagnostic method is a blood smear which reveals lipid droplets in peripheral leucocytes (Jordan's anomaly). The accumulation of lipid vacuoles can also be detected histologically, in biopsies from skin or muscle. Elevated liver and muscle enzyme levels can be detected in a blood test. The current standard procedure is next generation sequencing test of the ABDH5 gene to detect biallelic variants.
Differential diagnosis
Differential diagnoses include : congenital ichthyosiform erythroderma, other syndromic ichthyoses, neutral lipid storage disease with myopathy (mutations in ATGL/PNPLA2) and different mitochondrial diseases with accumulation of cytoplasmic triglycerides (e.g. deficiencies in carnitine, cartinine palmitoyl transferase or fatty acid oxidation enzymes).
Antenatal diagnosis
Prenatal diagnosis based on molecular genetic testing (after amniocentesis or chorionic villus sampling) is possible if the pathogenic variants in ABDH5 has previously been identified in a family member.
Genetic counseling
NLSD-I belongs to the syndromic ichthyoses spectrum and is inherited in an autosomal recessive manner. Couples at risk (both persons are carriers of a disease-causing mutation) should receive genetic counseling in which they are informed that there is a 25% risk of having an affected child with each pregnancy.
Management and treatment
A diet with high medium chain triglycerides/long chain triglycerides ratio can be beneficial. Retinoids (standard treatment for ichthyosis) should be used with caution due to the risk of liver toxicity.
Prognosis
In NLSD-I, the severity of the disease depends primarily on the severity of liver involvement and myopathy. Cases in which a liver transplant was necessary have been described. The development of the disease varies from patient to patient but is relatively slow; most patients do not have a significantly reduced life expectancy.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                            Pr Judith FISCHER | ERN-Skin*

                                * European Reference Network


Neutral lipid storage disease with myopathy

A form of neutral lipid storage disease characterized by adult onset of slowly progressive muscular weakness of the limbs and axial muscles, and accumulation of lipid droplets in the muscles and leukocytes.

Summary:
Epidemiology
Prevalence and incidence of Neutral Lipid Storage Disease with Myopathy (NLSD-M) are unknown. About 100 cases have been described in the literature, with about 30 different gene mutations. The disease is diffuse worldwide, with more reported cases in Italy, China and Japan. It is thought that the disease, due to lack of knowledge, may be underdiagnosed.
Clinical description
The expression of phenotype is highly variable, from very mild to severe disease. Generally, the disease starts in young-adult age with an asymmetrical weakness and atrophy of proximal muscle of a limb which frequently involves cervical and lumbar muscles, and finally, the distal muscles of limbs. Generally, bulbar and respiratory muscles are spared. Some patients are wheelchair confined. Cardiomyopathy is developed by a little less than 50% of patients in the later disease course. Additional, less frequent, variable manifestations include triglycerides infiltration of liver, thyroid, pancreas and kidney. Serum creatine kinase is always elevated.
Etiology
The pathophysiology of the disease is largely unclear and phenotype-genotype correlations remain incomplete. The disease is associated with mutations of the PNPLA2 gene. PNPLA2 gene encode for ATGL, a lipase that is a lipid droplet-associated protein and catalyzes the first step in the hydrolysis of triacylglycerols. The mutations in both alleles of the PNPLA2 gene cause the production of a defective protein. The detachment of fatty acids from triglycerides is compromised, therefore triglycerides accumulate in lipid droplets within the cytoplasm of cells. There is evidence of altered mitochondrial metabolism, likely a consequence of the low availability of fatty acids. However, many unresolved issues remain, such as muscle fiber damage resulting in muscle atrophy.
Diagnostic methods
The diagnosis is suspected when a patient presents hyperckemia and limb weakness. Peripheral blood smear reveals triacylglycerol-containing lipid droplets in leukocytes (Jordan's anomaly), a very sensitive diagnostic marker present in 100% of patients. Muscle biopsy reveals a massive accumulation of lipid droplets. The diagnosis is then confirmed by genetic testing.
Differential diagnosis
Based on the clinical phenotype, many hereditary and acquired myopathies can be differentially diagnosed with NLSD-M. Furthermore, from a histological point of view, all myopathies with lipid accumulation, such as multiple acyl-CoA dehydrogenase deficiency or primary carnitine deficiency, can constitute a diagnostic alternative.
Antenatal diagnosis
The disease is very rare and the mode of transmission is recessive, so prenatal screening is not required except in the cases of consanguinity of parents with a family history of NLSD-M.
Genetic counseling
Genetic counseling could be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. There is no genotype-phenotype correlation; therefore, it is impossible to predict the expression of the genetic mutation in a child of a carrier couple.
Management and treatment
There is no specific therapy. Supportive therapies can improve cardiomyopathy and generally the consequences of damage to internal organs. Some cases required implantation of cardiac devices. Strength training or aerobic exercise programs, or both, might optimize muscle and cardiorespiratory function and prevent additional disuse atrophy and deconditioning.
Prognosis
Quality of life is mainly influenced by motor disability. There are no studies on the life expectancy of people affected by this disease.

                            Last update:
                            January 2024

                            - Expert reviewer(s):
                            Pr Enrico BERTINI | EURO-NMD* - Dr Elena PENNISI

                                * European Reference Network


Neutral lipid storage disease (NLSD) refers to a group of diseases characterized by a deficit in the degradation of cytoplasmic triglycerides and their accumulation in cytoplasmic lipid vacuoles in most tissues of the body. The group is heterogeneous: currently cases of NLSD with icthyosis (NLSDI/Dorfman-Chanarin disease; see this term) and NLSD with myopathy (NLSDM/neutral lipid storage myopathy; see this term) can be distinguished.

Summary:
Epidemiology
The group of diseases is very rare and the prevalence is unknown (around 50 cases have been reported in medical literature, of which 3 had NLSDM) because of the vagueness of the descriptions.
Clinical description
In NLSDI, generalized ichthyosis occurs in 95% of cases, moderate myopathic syndrome (or abnormal serum muscle enzyme levels), intellectual deficit and moderate hepatomegaly (or functional impairment of the liver) occur in 60% of cases, ocular (cataract, retinopathy) and hearing abnormalities (deafness) occur in 40% of cases, and neuropathy and short stature occur in 20% of cases.
Etiology
NLSDI/Dorfman-Chanarin disease is caused by mutations in the ABHD5 gene (3p21), NLSDM by mutations in the PNPLA2/ATGL gene (localized to 11p15.5).
Diagnostic methods
Biological diagnosis is based on evidence of leukocytes in the vacuoles of neutral lipids and a deficiency in the degradation of cytoplasmic triglycerides in cultured cells (lymphoblasts or fibroblasts), while mitochondrial function (in particular the transport and b-oxidation of fatty acids) is normal. Genetic diagnosis is also possible.
Differential diagnosis
Differential diagnoses include mitochondrial diseases with accumulation of cytoplasmic triglycerides (deficiencies in carnitine, cartinine palmitoly transferase or fatty acid oxidation enzymes; see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible by genetic testing (for mutations in chorionic or amniotic cells) when parental mutations have been identified.
Genetic counseling
Transmission of the disorder is autosomal recessive.
Management and treatment
There is no treatment to correct the metabolic deficiency.
Prognosis
For NLSDI/Dorfman-Chanarin disease, the severity of the disease is linked to the myopathy and any associated disorders (which may include ocular and cerebral involvement). The evolution of the disease varies between patients, but is relatively slow because some patients reach late adulthood.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Pr Judith FISCHER  - Dr Anne NEGRE-SALVAYRE  - Pr Robert SALVAYRE


Neutropenia-monocytopenia-deafness syndrome is characterised by neutropenia with myeloid marrow hypoplasia, monocytopenia, and congenital deafness. It has been described in three siblings who suffered recurrent bacterial infections.


A rare, life-threatening, cutaneous disease characterized by a keratinocytic epidermal nevus presenting thick, hystrix-like, white or brownish hyperkeratosis associated with multiple extracutaneous vascular malformations, including angiodysplasia that involves large-vessel arteriovenous shunts that may be fatal during the neonatal period.


A rare, syndromic nevus characterized by the association of typically unilateral, closely arranged, linear, slightly elevated, multiple, nevus comedonicus lesions located usually on the face, neck, trunk or limbs (with or without a central, dark, firm, hyperkeratotic plug and secondary acneiform lesions) with extracutaneous ocular, skeletal, and/or central nervous system abnormalities, such as ipsilateral cataract, corneal erosion, poly-/syndactyly, absent fifth finger, scoliosis, vertebral defects, corpus callosum agenesis, seizures, interhemispheric cyst, intellectual deficiency, and/or developmental delay.


Nevus of Ito is a benign dermal melanocytosis occurring most frequently in the Asian populations and characterized by unilateral, asymptomatic, blue, gray or brown skin pigmentation within the acromioclavicular and upper chest area (involving the side of the neck, the supraclavicular and scapular areas, and the shoulder region). It is usually diagnosed in early infancy and in early adolescence. Nevus of Ito may progressively enlarge and darken in color (particularly with puberty) and its appearance usually remains stable once adulthood is reached. Spontaneous regression does not occur. Malignant melanoma has rarely been reported within a nevus of Ito. It shares the clinical features of nevus of Ota, except its anatomic location and in rare occasions, mayoccur together with the latter.


Nevus of Ota is an oculodermal melanocytosis more commonly found in Asian and African populations, usually present at birth and characterized by a usually unilateral, bluish gray, patchy, speckled pigmentation (that may progressively enlarge and darken) affecting the skin of the face along the distribution of the ophthalmic and maxillary divisions of the trigeminal nerve (periorbital region, temple, forehead, malar area, nose). In 2/3 cases the ipsilateral sclera is affected. Nevus of Ota usually remains stable once adulthood is reached but an increased risk of glaucoma and uveal melanoma may be observed. Extracutaneous lesions may also occur in cornea, retina, tympanum, nasal mucosa, pharynx, palate. Nevus of Ota occurs as solitary conditions but seldom may occur together with the nevus of Ito or nevus spilus.


New-onset refractory status epilepticus is an acute encephalopathy with inflammation-mediated status epilepticus characterized by an acute refractory status epilepticus, typically of the tonic-clonic type, following prodromal symptoms of confusion, fever, fatigue, headache, symptoms of gastrointestinal or upper respiratory tract infection, behavioral changes or hallucinations. Brain MRI abnormalities and abnormal findings in CSF, including pleocytosis and/or elevated protein levels, are frequently found during acute episode. Treatment-resistant epilepsy, cognitive and psychiatric impairments are usual consequences.


A rare, genetic, syndromic intellectual disability characterized by short stature, sparse hair, characteristic coarse face, brachydactyly with prominent interphalangeal joints, seizures and intellectual disability. Facial characteristics include triangular shaped face, dense and prominent eyelashes, rounded premaxilla, broad nasal base, thick alae nasi, upturned nasal tip, broad philtrum, thin upper vermilion, thick and everted lower vermilion and wide mouth.

Summary:
Epidemiology
Although the prevalence of the disorder is unknown, it is thought to be less than 1/1,000,000. To date, there are fewer than 100 molecularly confirmed, affected individuals reported in the literature. No significant difference in male-to-female ratio or geographical distribution has been reported.
Clinical description
At birth, patients may be small for gestational age (one-third of cases), have facial hypertrichosis, a low anterior-lateral hairline, and microcephaly (one-quarter). Postnatally, microcephaly and proportional short stature is present in over half of the patients. Sparse scalp hair is present in almost all patients and may be evident in the first months of life. Prominent inter-phalangeal joints due to decreased subcutaneous fat, are the most characteristic sign, and may be accompanied by fetal pads (half of patients). Radiological findings of the hands include short metacarpals, short phalanges, cone-shaped epiphyses, and ivory epiphyses in a few cases. Patients can show mild shortening of the toes, sandal gap and some thickening of the distal phalanx of the hallux. Most of these characteristics, particularly limbs and facial features, tend to be more evident with time. Hypotonia is reported in one third of patients, but major motor milestones such as sitting and walking independently are usually not very delayed. Intellectual disability (ID) is severe in nearly half, moderate in a third, and mild in the remainder of cases. Nearly a third never develop speech or language skills. Epilepsy occurs in two-thirds of patients, with onset between 18 to 24 months, and may correlate with regression. Seizure type is variable, even within the same individual and can be difficult to manage. Disposition is generally happy and very friendly, but temper outbursts and bouts of aggression are possible. Other congenital anomalies are variably observed.
Etiology
The disorder is due to missense variants (80% of case) or intragenic deletions in SMARCA2 (9p24.3). This gene encodes a protein belonging to the ATP-dependent chromatin remodeling enzymes, implicated in the regulation of gene expression and cell cycle control. In almost 17% of patients, no variant has been identified.
Diagnostic methods
Diagnosis is suspected on peculiar combination of facial features with sparse hair, intellectual disability, brachydactyly with prominent interphalangeal joints and seizures. Molecular diagnosis is based on identification of variants in SMARCA2.
Differential diagnosis
Differential diagnosis includes Coffin-Siris syndrome, Williams syndrome and Cornelia de Lange syndrome.
Antenatal diagnosis
If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at theoretic increased risk is possible.
Genetic counseling
Transmission is autosomal dominant. To date, all affected individuals have had a de novo SMARCA2 pathogenic variant, suggesting a low risk to siblings. However, because of the theoretic possibility of parental germline mosaicism, the empiric recurrence risk to siblings is approximately 1%.
Management and treatment
Clinical management requires periodical evaluation by a child neurologist/neuropsychiatrist in order to monitor the evolution of the intellectual development or onset of seizures. Enabling and supporting therapies (including non-verbal communication) and special school program are required. Anti-epileptic drugs appear necessary for controlling seizures, sometimes unsuccessfully and with consequent need for hospitalization. Regular follow up of ophthalmologic and/or audiologic abnormalities is recommended.
Prognosis
Prognosis is variable and is predominantly influenced by the age of onset of seizures and the difficulty in managing it. Independent living depends on the degree of intellectual disability, and is likely never totally achieved.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Gianluca CONTRO | ITHACA* - Dr Livia GARAVELLI | ITHACA*

                                * European Reference Network


A rare lysosomal lipid storage disease characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSPG), dysarthria, dysphagia, dystonia, seizures, gelastic cataplexy, and psychiatric disorders.

Summary:
Epidemiology
Prevalence at birth of Niemann-Pick disease type C (NPDC) ranges between 1/45,000-286,000 worldwide.
Clinical description
The clinical onset and presentation is heterogeneous. NPDC is classically a neurovisceral condition with hepatosplenomegaly usually preceding the neurological symptoms, occurring in infancy or childhood but possibly occurring much later. Some patients exhibit lung disease early on and a small subset of patients can develop rapidly deteriorating hepatic or respiratory failure in early infancy. Neurological onset varies between early infancy to adulthood. Typically, neurologic involvement is progressive and consists mainly of dystonia, cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. VSGP and cataplexy (with or without narcolepsy) are characteristic. Psychiatric disturbances are frequent in late-onset patients.
Etiology
Most patients (95%) have mutations in the NPC1 gene (localized to 18q11.2), which encodes a membrane glycoprotein. The remainder have mutations in the NPC2 gene (localized to 14q24.3 ), which encodes a soluble lysosomal protein that binds cholesterol. The loss of function of those proteins blocks cholesterol egress from lysosomes leading to accumulation of lipid membrane components (unesterified cholesterol, glucosylceramide, and gangliosides) in the late endosomal/lysosomal compartment of the cell.
Diagnostic methods
The diagnosis of NPDC must be confirmed by mutation analysis and, if necessary, filipin test (based on the reaction of unesterified cholesterol with fluorescent antibiotic filipin). Several biomarkers are used alone or in combination as a first-line test to screen for NPDC: oxysterols (cholestane-3β, 5α, 6β-triol); lyso-SM-509 and lyso-sphingomyelin. Foam cells and sea-blue histiocytes are usually present in the bone marrow.
Differential diagnosis
In the first 2 years of life, NPDC must be differentiated from Niemann-Pick types A and B, Wolman disease, Gaucher disease type II/III, idiopathic neonatal hepatitis, and other causes of cholestatic jaundice. In older children and adults, neurodegenerative disorders such as mitochondrial diseases, Wilson disease, late-onset lysosomal storage diseases, Friedreich Ataxia, progressive supranuclear palsy, Huntington disease, Alzheimer disease, Pick disease, frontotemporal dementias, amyotrophic lateral sclerosis, primary psychiatric illnesses must be ruled out. Acquired conditions such as pineal region or midbrain tumors, attention-deficit disorder, learning disabilities, absence seizures, other dementia illnesses, HIV encephalopathy, sleep disorders, and syncope also should also be included in the differential diagnosis.
Antenatal diagnosis
Prenatal diagnosis of NPDC should be offered to couples at risk. Molecular genetic analysis is the preferred strategy.
Genetic counseling
NPDC is an autosomal recessive disease. Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management of NPDC remains largely symptomatic. Treatment with an iminosugar inhibitor of glucosylceramide synthase (miglustat) was approved for the management of neurologic manifestations of NPDC in several countries. There are presently some therapies under investigation, including 2-hydroxypropyl-beta-cyclodextrin and arimoclomol.
Prognosis
Lifespan varies from a few days (in case of fetal hydrops) to a few decades. Death in early infancy can be due to either liver failure or severe pulmonary insufficiency (usually before 3-6 months). Early infantile, severe, neurological onset is often fatal between 3-5 years of age, late-infantile neurologic onset typically between 7-12, and juvenile neurologic onset between adolescence and 30 years of age.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Ekaterina ZAKHAROVA


Night blindness-skeletal anomalies-dysmorphism syndrome

A rare, genetic, multiple congenital anomalies/dysmorphyc syndrome characterized by slowly progressive night blindness, skeletal abnormalities (sloping shoulders, joint hyperextensibility, minor radiological anomalies) and characteristic facial features (periorbital anomalies, malar flatness, retrognathia). Additional manifestations include myopia and extinguished electroretinograms. There have been no further descriptions in the literature since 1979.


Nijmegen breakage syndrome-like disorder is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by growth retardation, short stature, developmental delay, intellectual disability, craniofacial dysmorphism (i.e. severe microcephaly, sloping forehead, prominent eyes, broad nasal ridge, hypoplastic nasal septum, epicanthal folds), spontaneous chromosomal instability, cellular hypersensitivity to ionizing radiation and radioresistant DNA synthesis, without severe infections, immunodeficiency or cancer predisposition. Additional reported features include mild spasticity, slight and nonprogressive ataxia, hyperopia, multiple pigmented nevi, widely spaced nipples, and clinodactyly.


A rare, genetic chromosomal instability syndrome presenting at birth with microcephaly, dysmorphic facial features which become more noticeable with age, growth delay, recurring sinopulmonary infections and extremely high frequency of malignancies.

Summary:
Epidemiology
Whilst global prevalence is unknown, the disease seems to occur worldwide, but has a much higher prevalence among Central and Eastern European Slavic populations due to a founder mutation. Average prevalence of NBS in patients with Eastern Slavic origin (Belarus, Ukraine, Russia, and Latvia) was recently estimated as 1/1,000,000 and, based on carrier frequency, the prevalence in the Western Slavic region (Poland, Slovakia and Czech Republic) is estimated at 1/330,000.
Clinical description
Clinical manifestations are not pathognomonic and may vary in severity. The main signs are microcephaly, present at birth and progressing with age, dysmorphic facial features (prominent midface emphasized by a sloping forehead and receding mandible), mild growth retardation and, in females, premature ovarian insufficiency are common. Various congenital anomalies have been reported, including central nervous system (hydrocephaly, schizencephaly, arachnoid cysts), respiratory tract (cleft lip/palate, choanal atresia), urogenital system (horseshoe kidney, ectopic/dystopic kidneys, hypospadias, cryptorchidism, ovary hypoplasia), mild skeletal anomalies (pre- and postaxial polydactyly, hypoplastic or duplicated thumb, clinodactyly of 5th fingers). Café au lait and/or vitiligo spots are frequently observed and, in some patients, multiple pigmented nevi occur. Other principal manifestations include immune deficiency with recurrent respiratory tract infections, a strong predisposition to malignancies (predominantly lymphoid, but solid tumors also occur), and radiosensitivity. By age 20, over 40% of patients develop a malignant disease and are prone to develop secondary malignancies. Cognitive development is close to the average (normal/borderline) in infancy and preschool age, but intellectual skills gradually decline with age (from mild to moderate).
Etiology
Nijmegen breakage syndrome (NBS) is caused by mutations in the NBN gene (8q21-q24), specifically within exons 6-10, which lead to partially functional truncated fragments of nibrin, the gene product involved in repairing DNA double strand breaks. Over 90% of patients are homozygous for the founder mutation of Slavic origin (c.657_661del5).
Diagnostic methods
Diagnosis is based on the clinical manifestations and confirmed by either single gene sequencing (typically for Slavic populations) or multigene next generation sequencing panels. Where genetic testing is unavailable, diagnosis can be supported by evidence of chromosomal instability (spontaneous and induced), increased cellular sensitivity to ionizing radiation in vitro, combined immunodeficiency, and complete absence of full-length nibrin. A family history (malignancies, microcephaly or hydrocephaly, early death of a sibling) can also support diagnosis.
Differential diagnosis
Differential diagnosis includes Fanconi anemia, LIG4 syndrome, Cernunnos-XLF deficiency, NBS-like disorder, ataxia-telangiectasia-like disorder, Bloom syndrome.
Antenatal diagnosis
Affected families may be offered prenatal diagnosis by molecular analysis if both disease-causing gene mutations are known.
Genetic counseling
The pattern of inheritance is autosomal recessive. Parents of an affected child are obligate carriers of NBN mutations and thus, for each pregnancy, there is a 25% risk that offspring inherit the disease. Carriers of a Slavic founder mutation should be offered monitoring for cancer, in particular breast in women and prostate in men.
Management and treatment
There is no specific therapy. Early diagnosis is important to avoid severe recurrent infections, unnecessary radiation exposure for diagnostic purposes and adverse effects of radiotherapy of tumors. Patients require multidisciplinary management and long-term follow-up (malignancy, immunodeficiency, growth, hypergonadotropic hypogonadism in females). Monitoring of the immune system is extremely important throughout life; specific modes and types of immunization are necessary (acellular vaccines are recommended). In case of lymphoid malignancy, hematopoietic stem cell transplantation (HSCT) is recommended after the first complete remission. Females should be monitored for puberty progress from the age of 12 (endocrinologist/ gynecologist) and hormonal replacement therapy should be offered at appropriate age.
Prognosis
Prognosis is poor, with malignancy as the major cause of death. Patients who developed lymphoma or leukemia died from disease progression, relapses and secondary malignancies. A beneficial effect of HSCT on the long-term survival has been confirmed in recent studies.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Pr Krystyna CHRZANOWSKA | ITHACA*

                                * European Reference Network


A rare, genetic, primary combined T and B cell immunodeficiency characterized by recurrent, severe viral and bacterial infections. Immunologic findings include decreased immunoglobulin levels, decreased numbers of B and NK cells, reduced relative CD19+ B cells in peripheral blood, impaired memory responses to viral infections and defective antigen-specific T-cell proliferation.


Nipah virus disease, caused by the Nipah virus, is a recently discovered zoonotic disease characterized by fever, constitutional symptoms and encephalitis, sometimes accompanied by respiratory illness.

Summary:
Epidemiology
Nipah virus disease is endemic to south Asia, where sporadic outbreaks have been noted in Malaysia, Singapore, India, and Bangladesh since the virus was first isolated in 1999. Less than 20 cases are typically reported per year worldwide, although systematic surveillance is lacking.
Clinical description
The incubation period is typically 4-20 days. Patients usually present with fever, malaise, headache, myalgia, sore throat, nausea and vomiting, sometimes accompanied by vertigo and disorientation. Severe cases progress to encephalitis, which may be complicated by seizures and coma. Atypical pneumonia, sometimes leading to the acute respiratory distress syndrome, may be seen. Asymptomatic infections have been documented. Cases of relapse occurring weeks or even months after recovery have also been described. Neurologic sequelae occur in up to 20% of survivors of Nipah encephalitis and include persistent seizures and personality or mood changes.
Etiology
Nipah virus is a member of the Paramyxoviridae family, genus Henipavirus. The virus appears to be maintained in fruit bats (Pteropus genus), which may infect humans through direct exposure to their saliva or excreta, including through contaminated food, especially palm tree sap. Bats may also transmit the virus to intermediate hosts, especially pigs, which develop respiratory disease and may pass the virus on to humans. Serologic evidence of infection has also been noted in cats, dogs and horses. Swine farmers and abattoir workers are at increased risk. Human-to-human transmission has been occasionally noted through exposure to bodily fluids.
Diagnostic methods
Common diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.
Differential diagnosis
Nipah virus disease is difficult to distinguish from a host of other febrile illnesses, at least during its onset. More common causes of viral pneumonia, including adenovirus and influenza, and viral encephalitis, in particular Japanese encephalitis (see this term), which is also transmitted by swine, need to be excluded.
Management and treatment
Patients should be isolated and precautions (face shields, surgical masks, double gloves, surgical gowns and aprons) should be used to prevent nosocomial transmission. As there is presently no antiviral drug available for Nipah virus disease, treatment is supportive. Ribavirin has been used on a few patients but its efficacy for Nipah virus disease has not yet been determined.
Prognosis
The case-fatality varies from 40-70% depending on whether encephalitic or severe manifestations are noted and whether adequate healthcare facilities are available. Advanced age, underlying diabetes, and neurological symptoms confer a poor prognosis.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Daniel BAUSCH  -  Andrew BENNETT


Natural killer (NK)-cell enteropathy is a benign NK-cell lymphoproliferative disease characterized by minor abdominal symptoms (abdominal pain, diverticulosis, constipation and reflux) due to NK cell-derived lesions in the mucosal layer of the gastrointestinal tract and often mistaken for NK or T-cell lymphoma (see these terms).


NKX6-2-related autosomal recessive hypomyelinating leukodystrophy

A rare leukodystrophy characterized by a spectrum of progressive neurologic manifestations comprising rapidly progressive early-onset nystagmus, spastic tetraplegia, and visual and hearing impairment, resulting in death in early childhood, as well as later onset of slowly progressive complex spastic ataxia with pyramidal and cerebellar symptoms and loss of developmental milestones. Brain imaging shows diffuse hypomyelination of the subcortical and deep white matter, cerebellar atrophy, and diffuse spinal cord volume loss.


NLRC4-related familial cold autoinflammatory syndrome

A rare hereditary periodic fever syndrome characterized by infantile or childhood onset of episodes of fever and cold-induced urticaria-like rash and arthralgias. Ocular features such as conjunctivitis and uveitis may also be present. Presentation is typically mild, and symptoms resolve without treatment in most cases.


NLRP12-associated hereditary periodic fever syndrome

A rare autoinflammatory syndrome characterized by episodic and recurrent periods of fever combined with various systemic manifestations such as myalgia, arthralgia, joint swelling, urticaria, headache and skin rash. Common trigger of these episodes is cold.


Cryopyrin associated periodic syndrome (CAPS) defines a group of autoinflammatory diseases, characterized by recurrent episodes of systemic inflammatory attacks in the absence of infection or autoimmune disease. CAPS comprises 3 disorders on a continuum of severity: severe CINCA syndrome, intermediate Muckle-Wells syndrome (MWS) and milder familial cold urticaria (FCAS) (see these terms).

Summary:
Epidemiology
The prevalence in France is estimated to be 1/360,000. Males and females are equally affected.
Clinical description
CAPS comprises 3 disorders on a continuum of severity: FCAS which usually has an early-onset after birth (< 20 years), and is characterized by recurrent episodes of urticarial rash triggered by exposure to cold, low-grade fever (malaise), conjunctivitis, abdominal discomfort, and arthromyalgia; MWS which usually presents at birth or later in childhood, with recurrent urticarial rash, fever, abdominal pain, arthralgia/arthritis, myalgias, secondary amyloidosis (see this term) and/or premature deafness; and CINCA syndrome characterized by the triad of arthropathy, chronic urticarial rash (neonatal onset), and central nervous system (CNS) involvement (ranging from hearing loss to chronic aseptic meningitis and intellectual disability). Non-pruriginous urticarial rash (diffuse, erythematous, edematous plaques on a background of generalized, faintly erythematous patches) is a key feature of CAPS and is generally present with marked intensification during acute episodes. These disorders were previously thought to be distinct conditions but represent now three grades of severity in which FCAS and CINCA syndrome are the extremes in a single spectrum of clinical manifestations.
Etiology
CAPS is due to mutations in the  NLRP3 (1q44; gene encoding cryopyrin), which result in a gain of function of cryopyrin, leading to increased secretion of interleukin (IL)-1 beta and and dysregulated inflammation. Patients with identical amino acid substitution may present distinct clinical subtypes, suggesting the role of additional genetic and/or environmental factors in disease expression. Somatic NLRP3 mosaicism could explain 30-60% of these patients. Some patients with MWS, FCAS or CINCA syndrome may not have mutations in NLRP3.
Diagnostic methods
Diagnosis is based on clinical manifestations and on laboratory findings revealing generalized leukocytosis and neurophilia along with others elevated acute phase reactants (C reactive protein and serum amyloid A). Progressive secondary amyloidosis manifests as proteinuria and is observed in the most severe cases (25% of cases). In CINCA syndrome, an increase in cytokine or neopterin levels in the cerebrospinal fluid may be detected. Histologic examination of affected skin shows a characteristic neutrophilic dermal infiltration in the reticular dermis. Diagnosis is confirmed by genetic screening of the NLRP3 gene.
Differential diagnosis
Differential diagnosis includes systemic-onset juvenile idiopathic arthritis, rheumatoid arthritis, systemic lupus erythematosus, familial mediterranean fever, Schnitzler syndrome, PLCG2-associated antibody deficiency and immune dysregulation, mevalonate kinase deficiency, TRAPS syndrome (see these terms), acquired cold and common allergic urticaria and serum sickness-like reaction.
Genetic counseling
CAPS can occur sporadically or be inherited as an autosomal dominant trait. In the latter case, genetic counseling may be proposed.
Management and treatment
The only effective treatment for CAPS is IL-1 blockade using anakinra, riloncept, or canakinumab. Supportive treatment is essential to manage the global burden of the disease including learning and cognitive impairment, growth and pubertal retardation, psychological /psychiatric distress, consequences of visual and hearing impairments.
Prognosis
CAPS is a life-long disease, and early diagnosis and early treatment may improve prognosis. With optimal treatment adjustments, progression of hearing loss and vision loss can be halted in most patients.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Isabelle KONE-PAUT


A rare limbic encephalitis characterized by the presence of autoantibodies against NMDA receptors in serum and cerebrospinal fluid. It may be of paraneoplastic (most commonly associated with ovarian teratoma) or non-paraneoplastic origin and is life-threatening but potentially treatable. Patients present with acute behavioral change, psychosis, and catatonia, rapidly progressing to seizures, memory deficit, dyskinesias, speech problems, and autonomic and breathing dysregulation.


Nocardiosis is a local (skin, lung, brain) or disseminated (whole body) acute, subacute, or chronic bacterial infection.

Summary:
Epidemiology
Annual incidence in the United States is estimated at around 1/250,000 inhabitants, but may be underestimated. The exact incidence in Europe is unknown. Men are more frequently affected than women (sex ratio: 3:1).
Clinical description
Nocardiosis may occur in any age group, but it is more common in middle-aged adults. Clinical manifestations depend on the site of infection. Most patients present with pulmonary disease. Frequent signs are fatigue, fever, chills, coughing (similar to the cough in pneumonia or tuberculosis), dyspnea, pleural chest pain, and weight loss. Primary cutaneous nocardiosis may present as cutaneous, lymphocutaneous or subcutaneous infection. Cutaneous infection manifests as cellulitis, pustules, pyoderma, paronychia, ulcerations or localized abscesses. Similar lesions are present with lymphocutaneous infection but are associated with ascending regional lymphadenopathy. Subcutaneous infection manifests as the apparition of mycetoma (see this term), predominantly affecting the extremities. Disseminated nocardiosis typically affects immunocompromised hosts. Lesions in the brain or meninges are frequent.
Etiology
The disease is caused by Nocardia infections. Nocardia is an aerobic, Gram-positive branching filamentous bacteria found in soil, decaying vegetable matter, and aquatic environments. Infection may occur through direct inhalation or inoculation. At least 13 species of Nocardia are reported to cause human disease, with the most frequently identified causes being N. asteroids complex and N. brasiliensis. Nocardiosis is often associated with a patient history of trauma (puncture wounds or cat scratches), immunodeficiency, resistance to previous antibiotic therapy, or fever.
Diagnostic methods
The diagnosis is based on analysis of cultures of the causative organism from the infection site and on identification of Nocardia throughmolecular techniques (RFLP or PCR assays). Chest radiography may also be required.
Differential diagnosis
The differential diagnosis should include tuberculosis, aspergillosis, histoplasmosis, Kaposi sarcoma, sporotrichosis, non-Hodgkin lymphoma (see these terms), lung abscess and pneumonia.
Management and treatment
Management includes antibiotic therapy, in particular with trimethoprim-sulfamethoxazole (TMP-SMX). The duration of therapy (1 to 12 months) depends on the type of Nocardia infection. Surgical resection may be feasible for localized abscesses.
Prognosis
Prognosis is generally favorable, except in cases of disseminated nocardiosis in immunocompromised patients.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr François TREMOLIERES


Nodal marginal zone B-cell lymphoma is a rare, indolent B-cell non-Hodgkin lymphoma, characterized by abnormal clonal proliferation of mature B-lymphocytes with involvement of the lymph nodes, sometimes the bone marrow, and rarely the blood. Clinically it presents with disseminated peripheral, abdominal and/or thoracic lymphadenopathy. Cytopenia and bulky tumors (greater than 5 cm) are rare. Association with Hepatitis C virus and chronic inflammation has been reported.


Primary localized cutaneous nodular amyloidosis (PLCNA) is the most rare form of primary cutaneous amyloidosis (see this term), a skin disease characterized by the accumulation of amyloid deposits in the dermis, characterized clinically by yellowish waxy crusted nodules and papules on the face, lower extremities, trunk, scalp, and genitalia and histologically by the localized deposition of immunoglobulin-derived amyloid in the papillary dermis and subcutis. PLCNA can be associated with connective tissue disorders such as Sjögrens syndrome and CREST syndrome (see these terms).


A rare soft tissue tumor characterized by a solitary mass-forming fibrous proliferation that usually occurs in the subcutaneous tissue, composed of uniform fibroblastic/myofibroblastic cells displaying a loose growth pattern. Upper extremities, trunk, and head and neck are most frequently affected. The lesion typically grows rapidly and almost always measures less than five centimeters in diameter. Macroscopically, it may appear circumscribed or infiltrative but is not encapsulated. Recurrence after excision is very rare, and metastasis does not occur.


Nodular lichen myxedematosus is a rare form of localized lichen myxedematosus (see this term) characterized by the development of skin-coloured mucinous nodules on the limbs and trunk, with mild or absent papular eruption.


Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL; see this term) characterized histologically by malignant lymphocyte predominant (LP) cells and the absence of typical Hodgkin and Reed-Sternberg (HRS) cells.

Summary:
Epidemiology
NLPHL accounts for only 5-10% of HL cases and has an annual incidence of approximately 1/ 830,000.
Clinical description
Disease onset usually occurs before the age of 40 and there is a 3:1 male predominance for the disease. Unlike classical Hodgkin lymphoma (CHL; see this term) NLPHL has a greater tendency to be restricted to peripheral lymph nodes (neck, axilla or inguino-femoral). Mediastinal involvement is rare and nodal spread is discontiguous. More than 80% of cases present with stage 1 or 2 disease. B-symptoms (fever, drenching night sweats and unexplained weight loss) are also less commonly observed and there is usually no impaired immunity in NLPHL patients. Extranodal disease is extremely uncommon in NLPHL but it can occur in the spleen (10-15% of cases), the liver (<5% of cases) and bone marrow or lungs (<5% of cases). Long-term complications include secondary malignancies (diffuse large B-cell lymphoma (25% risk by 20 years; see this term) or epithelial cancers (lung, breast, GI), which often arise from within a prior irradiated area).
Etiology
The exact cause is unknown. Unlike the Hodgkin cells and multinucleated Reed-Sternberg (HRS) cells seen in CHL, LP cells are usually negative for all EBV markers. Genetics may play a role as LP cells frequently contain rearranged immunoglobulin genes and chromosomal abnormalities are observed in two thirds of cases.
Diagnostic methods
A biopsy (usually of a lymph node) is first performed in order to diagnose NLPHL. Diagnosis is based on the presence of CD20 positive, CD15 negative and CD30 negative LP cells. LP cells are monoclonal B cells of germinal center origin. Staging (based on the Cotswold staging system) is then performed in order to determine the severity and spread of NLPHL and decide on the best course of therapy.
Differential diagnosis
Differential diagnosis includes lymphocyte-rich classical HL (see this term), progressive transformation of germinal centers and T-cell rich large B-cell lymphoma.
Management and treatment
Previously the usual treatment for limited stage 1 or 2 disease was involved-field radiation therapy (IFRT) at 30-36Gy; however; many authorities now recommend that NLPHL be treated the same as CHL. Chemotherapy or combined modality therapy is necessary in advanced disease stages. Relapses are common (seen in 10-15%) and can occur multiple times. In cases where salvage therapies used in CHL are unsuccessful, rituximab shows promise for the treatment of recurrent NLPHL as it attacks LP cells via surface CD20. Patients need to be monitored for secondary malignancies and cardiopulmonary disease as these long-term complications can arise due to therapy-related toxicity.
Prognosis
Prognosis is good with usually a 90-100% remission rate with primary therapy. Relapse is common (seen in 10-15% of patients) and occurs on average 3-6 years after diagnosis. Overall 10 year survival rates are >90% in limited stage disease.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Joseph CONNORS


A rare non-syndromic cerebral malformation due to abnormal neuronal migration characterized by clusters of disorganized neurons in abnormal locations such as periventricular and subcortical. The extent of the lesions ranges from isolated single to bilateral confluent nodules. Pediatric patients typically show variable degrees of developmental delay, intellectual disability, and intractable epilepsy, and concomitant cerebral and/or systemic malformations are frequent. Milder forms may present with onset of seizures in adulthood.


A rare skin disorder characterized by recurring inflammation in the subcutaneous layer of fat.

Summary:
Epidemiology
Nodular non-suppurative panniculitis, known as Weber-Christian disease (WCD) prevalence is unknown. It occurs more often in adult women (approximately 75% of reported cases).
Clinical description
WCD is characterized by single or multiple, tender or painful edematous and often erythematous subcutaneous nodules (1-2 cm large, most often affecting the lower extremities) healing with a depressed scar. The upper extremities, buttocks, abdominal wall, breasts, and face can also be involved. In most cases WCD is associated with fever, malaise, myalgia, arthralgia, and abdominal pain. Nausea, vomiting, weight loss, and hepatomegaly may occur. The disease tends to recur at intervals of weeks or months. WCD can present as a severe systemic illness. Unusual nodule locations include the abdomen (as an abscess), mesentery of the small or large bowel (with bowel obstruction), lungs, heart, liver, spleen, adrenal glands, kidneys, scrotum, and cranium. In patients with systemic disease, morbidity and mortality are significant.
Etiology
Etiology remains unknown.
Diagnostic methods
Histological examination of a subcutaneous nodule is necessary to confirm the diagnosis (the fat lobules are replaced by neutrophils, lymphocytes, and histiocytes in the early stages, and by macrophages and fibrotic tissue later).
Differential diagnosis
Differential diagnosis includes erythema nodosum and erythema induratum of Bazin, which represent the commonest forms of predominantly septal panniculitis and predominantly lobular panniculitis with vasculitis, respectively, as well as a variety of distinctive disease entities associated with panniculitis. The latter comprise bacterial, viral and fungal infections, connective tissue disorders, disturbances of lipid metabolism, pancreatic and renal diseases, gout, lymphoproliferative neoplasia, trauma, alpha1-antitrypsin deficiency (see this term).
Management and treatment
Treatment is symptomatic and supportive and may include systemic steroids and nonsteroidal anti-inflammatory drugs. Responses to fibrinolytic agents, hydroxychloroquine, azathioprine, thalidomide, cyclophosphamide, tetracycline, and cyclosporin A have been reported in some patients.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


Nodular regenerative hyperplasia of the liver

A form of portosinusoidal vascular disease characterized histologically by the absence of cirrhosis and diffuse benign transformation of the hepatic parenchyma into multiple small nodules (typically 1-3 mm).


Noma is a gangrenous disease that causes severe destruction of the soft and osseous tissues of the face.

Summary:
Epidemiology
Its exact prevalence is unknown. The disease was present in the Western world up until the start of the 20th century, but it now mainly affects children between 2 and 6 years of age living in the poorest regions of the world. Rare cases of noma have been described in adults with severe immunodeficiency (individuals with AIDS or myelopathy, or those being treated with immunosuppressants) in Africa and in the Western world.
Clinical description
In addition to the severe facial destruction, children with noma often present with rhinolalia aperta, uncontrollable drooling, and socially handicapping halitosis. The most debilitating sequela is permanent jaw constriction. Spontaneous resolution of the disease is associated with the formation of extremely dense and fibrous scars that may lead to osseous ankylosis between the mandible and maxilla or the mandible and the malar bone. The buccal opening in these children is limited to between 0 and 10 mm making intake of solid foods problematic or impossible. The risk factors associated with noma are malnutrition, intercurrent disease such as rubella or malaria, poor oral hygiene, and the presence of a lesion of the gingival mucosa (an early sign of necrotising gingivitis).
Etiology
The aetiology remains unknown. A bacterial aetiology has long since been suggested but carrying out extensive studies in the regions most affected by the disease is problematic. The few studies reported have indicated that bacteria from the Prevotella and Fusobacteria groups may play a role in the disease.
Management and treatment
The management of acute noma is aimed at improving the health status (introduction of a balanced diet and vitamin supplements, and sufficient hydration) of affected individuals and providing topical care. Antibiotics are recommended to prevent the often lethal complications associated with infection and to help limit extension of the lesion. If the lesion is still intrabuccal and limited, antibiotics may also prevent progression of the disease in some cases. Once the cicatrisation stage is complete, stepwise reconstructive surgery (aimed at relieving the stricture of the mouth and then reconstruction of the mandible and maxilla, cheek, lips and nose) can be considered. In addition to reconstruction of the face of affected children, reconstructive surgery can be used to allow improvement of impaired function (elocution, salivary continence, buccal opening).
Prognosis
Noma is associated with significant morbidity and mortality, often due to complications such as generalised sepsis, intracerebral septic emboli, bronchial aspiration or inanition. The disease develops very rapidly and in isolated regions medical care is often only sought after the lesions are well established. Delayed treatment will not allow a return to status quo ante. The disease leads to social exclusion of affected children: they are rarely admitted into schools for fear of contamination (which in reality does not occur) and are often rejected by their families and village, who continue to view noma as a malediction.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Dr Denise BARATTI-MAYER


A rare neurological disease which is a circadian rhythm sleep disorder characterized by non-synchronization to a 24-hour day leading to insomnia and daytime sleepiness with sometimes severe associated manifestations.

Summary:
Epidemiology
Approximately half of all people with complete blindness are thought to be affected by non-24 hour disorder. Rare cases are found in partially blind subjects. The disorder may be largely underdiagnosed in blind individuals. Sighted individuals with the disorder are far less numerous and about 100 cases have been reported in the medical literature to date.
Clinical description
Non-24 hour sleep-wake syndrome can occur at any age in sighted individuals but often develops in childhood. In blind people, it can occur at any age. In affected patients, the circadian system does not synchronize with the 24-hour day. Patients have gradual delays in sleep onset time from one day to the next. Sleep onset therefore occurs later and later during the night and then eventually during the daytime. In rare cases, sleep onset time moves backward from one day to the next. Constant and changing misalignment between the patient's circadian rhythm and standard times can result in fragmented sleep and signs of sleepiness when the patient attempts to maintain a regular 24h sleep-wake cycle. These manifestations include diurnal sleepiness, nocturnal insomnia, and fatigue. Other repercussions may include headaches, depression, difficulty concentrating, confusion, memory disorders, decreased appetite, ataxia, and psychological difficulties (loneliness, isolation). At certain times, the sleep pattern coincides with standard times providing temporary remission of symptoms.
Etiology
Defective functioning of the suprachiasmatic nucleus (SCN) located in the hypothalamus, which controls circadian rhythms, is thought to underlie the disorder, especially in sighted patients. The circadian clock has a slight deviation from 24h (generally 24.2h) which is corrected in healthy people by environmental time cues (including the solar light-dark cycle). Core body temperature cycle and production of melatonin are also affected. Absence of perception of light in completely blind subjects is thought to lead to failed sleep training. Abnormal development of the brain, trauma, and iatrogenic factors may play a role in sighted patients with non-24 disorder.
Diagnostic methods
The diagnosis is based on recurrent or relapsing insomnia and daytime drowsiness. The disorder should be suspected in blind individuals with recurrent insomnia and daytime sleepiness. At certain times, the sleep pattern coincides with standard times due to misalignment between the 24-hour light-dark cycle and the undeveloped endogeneous circadian rhythm. Symptoms persist for at least 3 months. Daily sleep logs and actigraphy, for at least 14 days, demonstrates a pattern of sleep and wake times that delay each day with a circadian period that is usually longer than 24 hours. A non-24-hour pattern of cortisol or melatonin secretion may assist diagnosis.
Differential diagnosis
Differential diagnoses include delayed sleep phase disorder, irregular sleep-wake disorder, sleep apnea syndrome, Kleine Levin syndrome, and idiopathic hypersomnia.
Management and treatment
Some patients may find relief by following their own changing sleep-wake cycle. This is however generally not compatible with regular occupational and social constraints. Phototherapy in the morning and scototherapy late in the day has been found to successfully improve sleep cycles in some sighted patients. Melatonin can also be used to this end in both sighted and blind patients. Hypnotics and/or stimulants may also play a role in the management. Tasimelteon, a melatonin-receptor agonist, is used for treatment of non-24 hour disorder in blind patients without light perception.
Prognosis
Without treatment, this disorder disrupts social, emotional and occupational functioning and may be severely debilitating.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Yves DAUVILLIERS


Non-acquired combined pituitary hormone deficiency-sensorineural hearing loss-spine abnormalities syndrome is a rare, genetic, non-acquired, combined pituitary hormone deficiency disorder characterized by panhypopituitarism (with or without ACTH deficiency) associated with spine abnormalities, including frequent rigid cervical spine and short neck with limited rotation, and variable degrees of sensorineural hearing loss. The anterior pituitary gland is usually abnormal (typically hypoplastic) and rarely a mild developmental delay or intellectual disability may be associated.