A rare neurologic disease characterized by excessive daytime sleepiness associated with uncontrollable sleep urges and sometimes sleep paralysis, and hypnagogic/hypnopompic hallucinations.

Summary:
Epidemiology
No clear epidemiological data are available. Narcolepsy type 2 prevalence numbers are controversial, sometimes higher and sometimes lower than those of narcolepsy type 1, depending on reports.
Clinical description
Narcolepsy type 2 manifests generally between the age of 10 and 30 years old, although onset in childhood is rare. Narcolepsy type 2 has a variable phenotype and evolution, with sometimes improvement or even disappearance of the symptoms, rarely the development of cataplexy (conversion to narcolepsy type 1), or a change in the phenotype to idiopathic hypersomnia. It can also be a lifelong disease, with stable symptomatology.
Etiology
The etiology is still unknown, probably because this disorder is heterogeneous. Reduction of hypocretin-1 levels is found in the cerebrospinal fluid in 10-20% of cases, and in which case the disorder is reclassified narcolepsy type 1. The presence of the HLA DQB1*0602 allele is reported in 40% of cases (more than in the general population but less than in cases of narcolepsy type 1, 98%).
Diagnostic methods
Definitive diagnosis requires the presence of clinical symptoms and characteristics polysomnography findings. Nocturnal and daytime polysomnography demonstrates an average sleep latency of under eight minutes with at least two sleep onset rapid eye movement periods (SOREMP) on multiple sleep latency tests. A pure clinical diagnosis is not possible due to the absence of pathognomonic symptom such as cataplexy, and daytime sleepiness being a non-specific symptom.
Differential diagnosis
Other causes of sleepiness, including narcolepsy type 1, chronic insufficient sleep and idiopathic hypersomnia (especially the form without long sleep time), must be systematically taken into account.
Genetic counseling
Rare familial cases have been reported; however, the mode of inheritance is unclear.
Management and treatment
Treatment is only symptomatic, based on stimulant drugs and a good sleep hygiene (sufficient sleep duration at night is required, with scheduled short naps during the day). Modafinil or pitolisant are the first line treatments with the best benefit/risk ratio. Second-line treatments include methylphenidate, sodium oxybate, solriamfetol or amphetamines.
Prognosis
The disease has a negative impact on scholarly and professional performances. Spontaneous evolution of the disease has not been much studied, but the phenotype and evolution seems variable : stability, disappearance of the symptoms, development of cataplexy (conversion to narcolepsy type 1) , or change to idiopathic hypersomnia.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Lucie BARATEAU  - Pr Yves DAUVILLIERS


A clinically heterogeneous progressive condition characterized by a combination of proximal neurogenic muscle weakness, sensory-motor neuropathy, ataxia, and pigmentary retinopathy.

Summary:
Epidemiology
Wordwide prevalence is unknown but may be estimated at 0.8-1/100,000.
Clinical description
NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa) syndrome is characterized by a great phenotypic variability and habitually clearly manifests in young adulthood. Early childhood manifestations often describe learning difficulties, developmental delay and ataxia, whereas ocular signs, proximal neurogenic muscle weakness with sensory neuropathy usually develop in the second decade of life. Ocular manifestations are variable and range from early salt and pepper retinopathy to retinitis pigmentosa, sluggish pupils, nystagmus, ophthalmoplegia, night blindness and loss of visual field. Other features may include short stature, seizures, corticospinal tract atrophy, depression, dementia, sleep apnea, hearing loss or cardiac arrhythmias.
Etiology
NARP syndrome is caused in the large majority of patients by a m.8993T>C/G in the subunit 6 of mitochondrial H(+)-ATPase gene (MTATP6). Most NARP patients have 70-90% mutated mitochondrial DNA. The m.8993T>G mutation is also present in 8-10% of patients with Leigh syndrome when mutated mitochondrial DNA is > 90%. Less common ATP6 heteroplasmic mutations include m.8839G>C, m.8989G>C, m.8618-8619insT, m.9032T>C, and m.9127-9128 delAT microdeletion, all identified in single families.
Diagnostic methods
Diagnosis is based on clinical manifestations, electroretinogram, and genetic testing. Peripheral neuropathy may be demonstrated by electromyography, whereas an MRI may pick up cerebral and cerebellar atrophy in later stages. Serum lactate may be normal or elevated. At muscle biopsy, histochemical or biochemical signs of oxidative phosphorylation may be absent.
Differential diagnosis
Differential diagnosis includes maternally inherited Leigh syndrome (MILS, like NARP syndrome part of the same group of disorders of mitochondrial oxidative phosphorylation), Refsum disease, Cockayne syndrome, abetalipoproteinemia, Usher syndrome (see these terms), neurological complication of lipidosis or rare cases of spinocerebellar disorder/ataxia.
Antenatal diagnosis
Prenatal diagnosis by amniocentesis or chorionic villus sampling and cytogenetic analysis if the mutation has been identified in an affected family member. Preimplantation genetic diagnosis is available for affected couples in few centers.
Genetic counseling
NARP syndrome is a maternally inherited syndrome and women can transmit to all their offspring. Clinical severity usually depends on the mutation load. There must be extreme caution in predictive counseling because of the genetic shift between mother and offspring.
Management and treatment
Management and treatment is only supportive and may include sodium bicarbonate or sodium citrate for acute aggravation of acidosis; antioxidant treatment, treatment of epileptic seizures by appropriate anticonvulsants; treatment of dystonia (e.g., benzhexol, baclofen, tetrabenazine, and gabapentin); and anticongestive therapy in case of cardiomyopathy. Patients require psychological support and should be followed up periodically by neurologists, ophthalmologists and cardiologists to monitor disease progression. Agents to avoid include Sodium Valproate, barbiturates and anesthesia (in general) as well as dichloroacetate.
Prognosis
As NARP syndrome is progressive, patients may become increasingly dependent of others. The quality of life is severely reduced. Patients may go blind and deaf and may experience depression and dementia. Due to the progressive neurogenic muscle weakness patients may become wheelchair bound.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Claudia NESTI  - Pr Filippo SANTORELLI


A rare otorhinolaryngological malformation characterized by a dermoid cyst along the nasal dorsum or glabella, lined by keratinized squamous epithelium and containing intraluminal keratin and mature adnexal structures, such as hair follicles, sebaceous and sweat glands. The majority of nasal dermoid cysts are superficial, rarely they extend intracranially. The cysts are typically benign but are susceptible to recurrent infections that may progress to osteomyelitis, meningitis or an intracranial abscess.


A rare otorhinolaryngological malformation characterized by the presence of a dermoid cyst, located on the dorsum of the nose, which presents a fistula, often extending to the intracranial region. Patients present a firm, slow-growing mass, which contains skin and dermal elements (including hair follicles and sebaceous glands), that do not transilluminate or compress, and may be associated with intermittent or chronic discharge of sebaceous material, soft tissue and skeletal deformity, and local infection. Meningitis, convulsions and cerebral abscess may be observed if intracranial extension exists.


Nasal encephalocele is an extracranial herniation of intracranial contents (that maintain a connection to the subarachnoid space) into the fonticulus frontalis, presenting with nasal broadening and/or as a compressible, blue, pulsatile mass near the nasal bridge (that enlarges on crying or with jugular vein compression) or as an intranasal mass originating in the cribiform plate and that can cause nasal obstruction or respiratory distress. Hydrocephalus and increased intracranial pressure are also reported in some cases.


Nasal ganglioglioma is a rare tumor, presenting in newborns, containing both neuronal and astrocytic components and that can be endonasal, extranasal or both. It is usually identified as a nasal mass that may cause feeding difficulties and nasal obstruction.


Nasal glial heterotopia is a rare developmental abnormality presenting usually at birth or in early childhood (rarely in adulthood) as a benign, non-pulsatile mass that can lead to nasal obstruction, deformation of the septum and nasal bone, and respiratory distress if untreated. Nasal glial heterotopias have no communication with the central nervous system; however an associated defect in the cribriform plate is sometimes reported.


Nasolacrimal duct cyst describes a unilateral or bilateral congenital cyst of the nasolacrimal duct, which is almost always associated with dacryocystocele, presenting most commonly at birth or a few weeks of age (but rarely presenting in adulthood) as a benign, grayish blue mass in the inferomedial canthus or in the nasal cavity, that can cause epiphora, dacryocystitis (inflammation of the lacrimal sac) and nasal obstruction. It is more commonly reported in females.


A rare multiple congenital anomalies syndrome characterized by nasopalpebral lipomas, bilateral lid coloboma, and telecanthus.

Summary:
Epidemiology
Nasopalpebral lipoma-coloboma-telecanthus syndrome (NPLCS) is a very rare syndrome. About 20 patients from 5 families were reported in the literature.
Clinical description
NPLCS is characterized by a congenital facial malformation associating bilateral upper eyelid and nasopalpebral lipomas, colobomas of upper and lower eyelids, telecanthus, and maxillary hypoplasia. Additional features may include displaced or aplastic lacrimal punctae, epiphora, aberrant eyelashes, conjunctival hyperemia, corneal and lens opacities, strabismus, nanophtalmos, limbal dermoid, dysplastic ears and nasopalpebral hamartomas. No extra-facial abnormalities are described.
Etiology
A heterozygous frameshift variant in the zinc finger transcription factor, encoded by ZDBF2 (2q33.3) has been identified in one sporadic patient. However, no functional studies were published to support the pathogenicity of this variant and no further patients have been reported since.
Diagnostic methods
The diagnostic is based on clinical examination.
Differential diagnosis
The main differential diagnoses include congenital infiltrating lipomatosis of the face, oculocerebrocutaneous syndrome, and conditions with eyelid coloboma and hypertelorism such as frontonasal dysplasia, craniofrontonasal syndrome, and oculoauriculofrontonasal syndrome.
Antenatal diagnosis
Genetic prenatal diagnosis is not available since the molecular basis is unknown.
Genetic counseling
Vertical, male-to-male transmission in 3 and 4 generations suggests autosomal dominant mode of inheritance with complete penetrance. Genetic counseling should be offered to affected families.
Management and treatment
Plastic and reconstructive surgery can be performed, notably excision of the lipomas and eyelid coloboma repair.
Prognosis
There are limited data in the literature regarding the prognosis of the affected individuals. Cognitive development seems to be normal.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Laurence OLIVIER-FAIVRE | ITHACA*

                                * European Reference Network


Nasopharyngeal carcinoma (NPC) is a tumor arising from the epithelial cells that cover the surface and line the nasopharynx.

Summary:
Epidemiology
The annual incidence is around 1/100 000 in Western countries. Incidence is higher in the Chinese and Tunisian populations. Although rare, NPC accounts for about one third of childhood nasopharyngeal neoplasms.
Clinical description
Three subtypes of NPC are recognized in the World Health Organization (WHO) classification: 1) squamous cell carcinoma, typically found in the older adult population; 2) non-keratinizing carcinoma; 3) undifferentiated carcinoma. The tumor can extend within or out of the nasopharynx to the other lateral wall and/or posterosuperiorly to the base of the skull or the palate, nasal cavity or oropharynx. It then typically metastases to cervical lymph nodes. Cervical lymphadenopathy is the initial presentation in many patients, and the diagnosis of NPC is often made by lymph node biopsy. Symptoms related to the primary tumor include trismus, pain, otitis media, nasal regurgitation due to paresis of the soft palate, hearing loss and cranial nerve palsies. Larger growths may produce nasal obstruction or bleeding and a 'nasal twang'.
Etiology
Etiological factors include Epstein-Barr virus (EBV), genetic susceptibility and consumption of food with possible carcinogens - volatile nitrosamines.
Diagnostic methods
Diagnostic methods include indirect nasopharyngoscopy to assess the primary tumor, clinical evaluation of the size of cervical lymph nodes and biopsy of either the lymph nodes or primary tumor for histological examination. Other potential sites of metastasis are further investigated by neurological examination of cranial nerves, computed tomography (CT)/magnetic resonance imaging (MRI) scan of the head and neck, chest radiotherapy and bone scintigraphy. EBV viral capsid antigen and EBV DNA can be detected by serum analysis.
Management and treatment
The recommended treatment schedule consists of three courses of neoadjuvant chemotherapy, irradiation, and adjuvant interferon (IFN)-beta therapy.
Prognosis
Presentation with lymphadenopathy implies that the disease has spread beyond the primary site. However, in childhood, the presence of metastatic disease in cervical lymph nodes at diagnosis does not adversely affect prognosis. Factors associated with a poor prognosis are skull base involvement, extent of the primary tumor and cranial nerve involvement.

                            Last update:
                            July 2006

                            - Expert reviewer(s):
                            Pr Bernadette BRENNAN


Nasu-Hakola disease (NHD), also referred to as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare inherited leukodystrophy characterized by progressive presenile dementia associated with recurrent bone fractures due to polycystic osseous lesions of the lower and upper extremities.

Summary:
Epidemiology
Over 200 cases have been reported worldwide in the literature, the majority of them being in the Japanese and Finnish population. The prevalence in Finland is estimated between 1/500,000 and 1/1,000,000.
Clinical description
The disease course is generally divided into four stages: latent, osseous, early neurologic, and late neurologic. After a normal development during childhood (latent stage), the disease starts manifesting during adolescence or young adulthood (typical age of onset 20-30 years) with pain in the hands, wrists, ankles, and feet. Patients then start suffering from recurrent bone fractures due to polycystic osseous and osteoporotic lesions in the limb bones (osseous stage). During the third or fourth decade of life (early neurologic stage), patients present with pronounced personality changes (e.g. euphoria, lack of concentration, loss of judgment and social inhibitions) characteristic of a frontal lobe syndrome. Patients also typically suffer from initially mild, but progressive, memory disturbances. Epileptic seizures are frequently observed. Finally (late neurologic stage), patients progress to a profound dementia, are unable to speak and move, and usually die by the age of 50 years. Occasionally, the disease presents a different course with the neurologic symptoms preceding the osseous ones.
Etiology
NHD is due to mutations in either the TYROBP or TREM2 genes encoding the tyrosine kinase binding adaptor protein and the triggering receptor expressed on myeloid cells 2 respectively. These genes encode components of a signaling complex involved in the regulation of immune responses, the differentiation of dendritic cells and osteoclasts, and in the phagocytic activity of microglia. The exact pathogenic mechanism is unknown.
Diagnostic methods
Diagnosis is based on clinical and radiologic examination. X-ray imaging shows multifocal cystic lesions on the bones of hands, wrists, feet and ankles. Brain computed tomography (CT) or magnetic resonance imaging (MRI) shows frontally accentuated atrophy of the cerebral white matter. Bilateral calcifications of the basal ganglia are typical. EEG is normal in the early stages but shows diffuse slowing and irritative activity in late stages. Histopathologically, loss of axons and myelin as well as fibrillary gliosis are observed. Molecular genetic testing confirms the diagnosis in ambiguous cases.
Differential diagnosis
The combination of frontal-type dementia starting in the fourth decade and radiologically demonstrable polycystic osseous lesions is unique and facilitates the differentiation of NHD from other forms of familial and non-familial frontotemporal dementia such as frontotemporal dementia and parkinsonism linked to chromosome 17 (see this term).
Antenatal diagnosis
Due to the low carrier frequency of the mutation in the general population, prenatal diagnostic procedures are usually not reasonable, except in genetic isolates.
Genetic counseling
Transmission is autosomal recessive. Children of an NHD patient are healthy carriers of the mutation unless they have also inherited a disease-causing mutation in the TYROBP or TREM2 genes from the other parent. Presymptomatic testing is commercially available.
Management and treatment
There is no curative treatment for the disease. Management is supportive. Antiepileptic drugs are prescribed to prevent seizures. A regular orthopedic and neurologic surveillance is recommended.
Prognosis
NHD is a progressive disease that is fatal usually during the fifth decade of life.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Dr Juha PALONEVA


A rare, genetic developmental defect during embryogenesis disorder characterized by sensorineural hearing impairment, childhood-onset cataract, underdeveloped secondary sexual characteristics, spinal muscular atrophy, growth retardation, and cardiac and skeletal anomalies. Sudden death, as well as fatal cardiomyopathy and heart failure, have been described in some cases.


Native American myopathy (NAM) is a neuromuscular disorder characterized by weakness, arthrogryposis, kyphoscoliosis, short stature, cleft palate, ptosis and susceptibility to malignant hyperthermia during anesthesia.

Summary:
Epidemiology
NAM is reported exclusively in Native American Indians (Lumbee Indian population of North Carolina). Within this population, the prevalence of NAM is estimated at approximately 1:5,000.
Etiology
The NAM locus has been localized to 12q13.13-14.1.
Genetic counseling
The disease is transmitted in an autosomal recessive manner.

                            Last update:
                            February 2009


A rare, life-threatening, mitochondrial DNA depletion syndrome disease characterized by severe, progressive sensorimotor neuropathy associated with corneal ulceration, scarring or anesthesia, acral mutilation, metabolic and immunologic derangement, and hepatopathy (which can manifest with fulminant hepatic failure, a Reye-like syndrome or indolent progression to liver cirrhosis, depending on clinical form involved), present in the Navajo Native American population. Clinical presentation includes failure to thrive, distal limb weakness with reduced sensation, limb contractures with loss of function, areflexia, recurrent metabolic acidosis with intercurrent illness, immunologic anomalies manifesting with severe systemic infections, and sexual infantilism.


A rare arrhythmogenic right ventricular cardiomyopathy (ARVC) and a cutaneous phenotype, characterized by peculiar woolly hair and palmoplantar keratoderma.

Summary:
Epidemiology
Naxos disease was first described in families originating from the Greek island of Naxos. Moreover, affected families have been identified in other Aegean islands, Turkey, Israel, Saudi Arabia, India, Argentina and French-Canadian families. A syndrome with the same cutaneous phenotype and predominantly left ventricular involvement has been described in families from India and Ecuador (carvajal syndrome).
Clinical description
Woolly hair appears from birth, palmoplantar keratoderma develop during the first year of life and cardiomyopathy is clinically manifested by adolescence with 100% penetrance. Patients present with syncope, sustained ventricular tachycardia or sudden death. Symptoms of right heart failure appear during the end stages of the disease.
Etiology
Mutations in the JUP gene encoding the desmosomal proteins plakoglobin and desmoplakin have been identified as the cause of Naxos disease. Defects in the linking sites of these proteins can interrupt the contiguous chain of cell adhesion, particularly under conditions of increased mechanical stress or stretch, leading to cell death, progressive loss of myocardium and fibro-fatty replacement.
Diagnostic methods
Diagnosis is suspected on clinical presentation based on palmoplantar keratoderma with hair shaft abnormalities, mostly of woolly hair type present from infancy, fulfilling the diagnostic criteria of ARVC later in adolescence or early adulthood. It is confirmed by the presence of a JUP variant in homozygosity on genetic testing.
Differential diagnosis
Naxos disease should be differentiated from carvajal syndrome that is caused by homozygous variants in desmoplakin (DSP), clinically manifested during childhood and leading more frequently to heart failure. It presents with similar cutaneous features as those of Naxos disease, in infancy, but the cardiac phenotype is compatible with arrhythmogenic cardiomyopathy with left ventricular predominance.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Naxos disease transmission is autosomal recessive. If both individuals are carriers of the disease-causing variant, there is a 25% risk of having an affected child at each pregnancy. Therefore it is recommended that genetic counseling be offered to at-risk couples.
Management and treatment
Implantation of an automatic cardioverter defibrillator is indicated for prevention of sudden cardiac death. Antiarrhythmic drugs are used for preventing recurrences of episodes of sustained ventricular tachycardia and classical pharmacological treatment for congestive heart failure, while heart transplantation is considered at the end stages.
Prognosis
Prognosis in Naxos disease tracks that of other genetic cases of ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy). Patients are at risk of developing life-threatening arrhythmias and heart failure.

                            Last update:
                            August 2023

                            - Expert reviewer(s):
                            Dr Alexandros PROTONOTARIOS  - Dr Adalena TSATSOPOULOU


NDE1-related microhydranencephaly is a rare, hereditary syndrome with a central nervous system malformation as major feature characterized by extreme microcephaly and growth restriction, severe motor delay and mental retardation, and typical radiological findings of gross dilation of the ventricles resulting from the absence (or severe delay in the development) of cerebral hemispheres, hypoplasia of the corpus callosum, cerebellum, and brainstem. Associated features are thin bones and scalp rugae.


A rare skin disease characterized by enlarging, annular plaques with red-brown edges and atrophic, yellow-brown, telangiectatic centers. The lesions are commonly asymptomatic, but affected skin areas may be fragile, and painful ulcerations develop in many cases. In rare cases, development of squamous cell carcinoma within longstanding lesions has been reported. The lower legs, especially the shins, are the most frequently involved site. The condition is often associated with diabetes mellitus.


Necrobiotic xanthogranuloma is a rare, chronic and progressive, non-Langerhans cell histiocytosis disease typically characterized by multiple, indurated, asymptomatic to pruritic, yellow-orange plaques or nodules that tend to ulcerate and are usually located in the periorbital area, trunk and/or extremities. Strong association with paraproteinemia and/or malignant lymphoproliferative disease has been reported.


A rare intestinal disease characterized by potentially life-threatening inflammatory bowel necrosis predominantly affecting preterm neonates. Patients may present with feeding intolerance, lethargy, temperature instability, abdominal distention, blood-stained stools, diarrhea, bilious vomiting, apnea, and signs of sepsis. Radiographic features include pneumatosis intestinalis, portal venous gas, presence of fixed, dilated intestinal loops, bowel wall edema, and (in case of bowel perforation) pneumoperitoneum.


A rare infectious disease characterized by painful, rapidly progressive infection of deep soft tissue structures. Infections can be mono- or polymicrobial and involve gram-positive cocci, enteric gram-negative bacilli, anaerobes, among others. Fungal infections have also been described in rare cases. Physical examination findings are often subtle and may include erythema, bullae, induration of subcutaneous tissues, and tenderness to palpation.


NEK9-related lethal skeletal dysplasia is a rare, lethal, primary bone dysplasia characterized by fetal akinesia, multiple contractures, shortening of all long bones, short, broad ribs, narrow chest and thorax, pulmonary hypoplasia and a protruding abdomen. Short bowed femurs may also be associated.


A rare, acquired, endocrine disease characterized by the triad of diffuse skin and mucosa hyperpigmentation, markedly elevated serum adrenocorticotropin (ACTH) levels and an enlarging corticotroph adenoma, which manifest following total bilateral adrenalectomy performed for the treatment of Cushing's disease. Additionally, patients may present with headaches, visual field defects, cranial nerve palsy, pituitary apoplexy, diabetes insipidus, panhypopituitarism, and, occasionally, paraovarian or paratesticular tumors.


Nemaline myopathy (NM) encompasses a large spectrum of myopathies characterized by hypotonia, weakness and depressed or absent deep tendon reflexes, with pathologic evidence of nemaline bodies (rods) on muscle biopsy.

Summary:
Epidemiology
Annual incidence has been estimated at 1/50,000 live births in a Finnish study but the disease is more common in the Amish community.
Clinical description
The age of onset varies from birth to adulthood. The main clinical manifestations include weakness (usually most severe in the face, the neck flexors and the proximal limb muscles), hypotonia and depressed or absent deep tendon reflexes. Facial weakness may lead to sucking, swallowing and speech difficulties. Respiratory muscles are frequently involved. NM is divided into 6 clinically overlapping subtypes depending on the age at onset and the severity of motor and respiratory involvement. Typical NM (approximately 50% of patients, see this term) is a moderate form of the disease with onset in the neonatal period. Most patients are able to live an independent, active life. Severe congenital NM (10-20% of patients; see this term) is characterized by severe hypotonia and little spontaneous movement. Survival after infancy is rare. Intermediate NM (20% of patients; see this term) is characterized by slow achievement of gross motor milestones, and loss of ambulation and/or independent respiration by age 11 years. Adult-onset NM is usually sporadic (<5% of patients; see this term). Onset is between 20 and 50 years of age. This form is characterized by rapid progression. Mild NM or childhood onset NM (10-15% of patients; see these terms) is characterized by the development of symmetric weakness of ankle dorsiflexion and foot drop around 10 years of age. Weakness is slowly progressive. An Amish NM (see this term) has been observed in several families. It has a neonatal onset and life expectancy rarely exceeds 2 years.
Etiology
Seven genes involved in muscle thin filament structure and function, have been linked to NM: NEB (2q22), TPM2 (9p13), TPM3 (1q21.2), ACTA1 (1q42.13), TNNT1 (19q13.4), CFL2 (14q12) and KBTBD13 (15q22.31). Clear genotype/phenotype correlations have not been established.
Diagnostic methods
Diagnosis is based on clinical examination and histopathological findings on muscle biopsy, which may reveal a change in fiber type proportion and size and, if combined with the Gomori trichrome staining method, show rod-shaped structures (nemaline bodies) in the sarcolemma and more rarely in the nucleus. Muscle imaging studies such as ultrasonography, computed tomography or magnetic resonance imaging (MRI), may help selecting muscles to biopsy and can guide genetic testing. Muscle enzymes are generally normal or mildly increased. Molecular genetic testing may confirm the diagnosis.
Differential diagnosis
The differential diagnosis includes other neuromuscular diseases displaying nemaline bodies: dermatomyositis, myotonic dystrophy type 1 and mitochondrial myopathy.
Antenatal diagnosis
Antenatal diagnosis is feasible since genetic tests are available to detect mutations in ACTA1, NEB, TPM3, TPM2,TNNT1, CFL2 and KBTBD13. It requires prior identification of the familial causative mutation(s).
Management and treatment
A multidisciplinary approach is needed to handle respiratory insufficiency (permanent or intermittent use of mechanical ventilation and treatment of lower respiratory tract infections) and feeding difficulties (feeding techniques and calorie-enriched diets). Scoliosis, joint contractures or speech anomalies must be managed as usual. Cardiac function must be monitored.
Prognosis
Prognosis depends on the NM type, and life expectancy ranges from few months to a near-normal lifespan.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Monique RYAN


Neonatal acute respiratory distress due to SP-B deficiency

A rare genetic interstitial lung disease characterized by progressive, life-threatening, refractory respiratory distress in full-term neonates associated with surfactant protein B deficiency. In most cases, the disease is fatal within the first months of life. Lung biopsy reveals changes characteristic of pulmonary alveolar proteinosis with interstitial fibrosis and inflammation, as well as accumulation of lipid-rich, eosinophilic, proteinaceous, granular material consisting of desquamated type II pneumocytes and foamy macrophages within the alveolar air spaces.


A variant of intermediate severity of the PBD-Zellweger syndrome spectrum (PBD-ZSS) charcterized by hypotonia, leukodystrophy, and vision and sensorineural hearing deficiencies. Phenotypic overlap is seen between NALD and infantile Refsum disease (IRD).

Summary:
Epidemiology
The estimated birth prevalence for PBD-ZSS is 1/50,000 in North America and 1/500,000 in Japan. More than half of patients with PBD-ZSS have the NALD-IRD forms.
Clinical description
NALD has an onset at birth or early infancy, but manifestations may be subtle enough that it is not diagnosed until late infancy or early childhood (or when a leukodystrophy develops). It is characterized by hypotonia, seizures, diffuse encephalopathy, sensorineural hearing loss, peripheral neuropathy, mild facial dysmorphism (hypertelorism and a flat midface), failure to thrive and severely delayed psychomotor development. Eye findings include chorioretinopathy, optic nerve dysplasia and cataracts. Hepatic dysfunction is first displayed in infants with jaundice and later in some with episodes of intracranial bleeding due to vitamin K-responsive coagulopathy. Adrenal insufficiency and renal calcium oxalate stones can present in older children. Vision and hearing dysfunction are progressive and result in blindness and deafness. Osteoporosis and fractures can occur in patients who are less mobile. Neurological regression reflects a leukodystrophy, leading to the loss of previously acquired skills, dementia and ultimately death.
Etiology
PBD-ZSS is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis.
Diagnostic methods
NALD is suspected on physical examination and confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are reduced. Plasma pipecolic acid levels and bile acid intermediates (THCH and DHCA) are increased. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify leukodystrophy, neuronal migration defects or other brain malformations.
Differential diagnosis
The main differential diagnoses include Usher syndrome I and II, other PBD-ZSS disorders (see these terms), single enzyme defects in peroxisome fatty acid beta-oxidation, and disorders that feature severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy. X-linked adrenoleukodystrophy (see this term) should not be confused with NALD.
Antenatal diagnosis
Prenatal screening of cultured amniocytes and chorionic villus sampling for VLCFA and plasmalogen synthesis is possible. If both disease causing alleles in parents have been identified, prenatal diagnosis can be performed as well as preimplantation genetic diagnosis.
Genetic counseling
NALD is inherited in an autosomal recessive manner so genetic counseling is possible.
Management and treatment
There is no cure for NALD and treatment is symptomatic. Cataracts should be removed in early infancy and glasses used to improve vision. Hearing aids are provided to those with hearing impairment, and cochlear implants considered when hearing loss is profound. Hepatic coagulopathy can be treated with vitamin K supplementation and liver function may improve with primary bile acid therapy. A gastrostomy tube may be necessary to allow for adequate calorie intake. Foods rich in phytanic acid (such as cow's milk) should be restricted. Docosahexanoic acid can be provided. Standard epileptic drugs are used for seizures. Lifelong follow up is needed to monitor changes in hearing, vision and liver function.
Prognosis
Prognosis is poor with most patients dying in infancy and early childhood. Some have lived until their teenage years.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Nancy BRAVERMAN


A rare acquired neutropenia characterized by isolated neutropenia in a newborn due to maternal alloimmunization against human neutrophil antigens (HNA) inherited from the father and present on fetal neutrophils, and subsequent increased breakdown of the latter. The condition is self-limiting and resolves after several weeks. It usually presents with only mild bacterial infections or may even be asymptomatic, although severe forms with sepsis and fatal outcome have also been reported.


Neonatal antiphospholipid syndrome is a rare, secondary, neonatal autoimmune disease characterized by single or recurrent episodes of venous, arterial or mixed thrombosis in a neonate whose mother does not have antiphospholipid syndrome manifestations. Patients present positive antiphospholipid antibodies and may have additional abnormalities associated (e.g. cardiac valve disease, livedo reticularis, thrombocytopenia, nephropathy, neurological manifestations).


A rare, secondary, neonatal autoimmune disease characterized by onset of hemolytic anemia in the neonatal period associated with a positive direct antiglobulin test. Hepatosplenomegaly may be associated.


Neonatal brainstem dysfunction is a rare neurologic disease characterized by the association of suction-swallowing dysfunction, abnormal laryngeal sensitivity and motility (manifesting with dyspnea or obstructive apnea-hypopnea), gastroesophageal reflux (generally resistant to medication) and cardiac vagal overactivity (e.g. brachycardia, vasovagal episodes) of varying degrees of severity. Impaired social interaction has also been reported.


A rare secondary neonatal autoimmune disease characterized by generalized weakness, severe hypotonia, absent or reduced deep tendon reflexes, and highly elevated serum creatine kinase levels presenting in the neonatal period. Perifascicular atrophy in the presence of a diffuse perivascular inflammatory cell exudate is observed on muscle biopsy.


Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome

A rare genetic disease characterized by intrauterine growth retardation, permanent neonatal diabetes mellitus, and congenital hypothyroidism. Additional manifestations include congenital glaucoma, hepatic disease (hepatitis, fibrosis, and cirrhosis), polycystic kidneys, exocrine pancreatic dysfunction, sensorineural hearing impairment, developmental delay, and mild facial dysmorphism (such as flat nasal bridge, epicanthal folds, long philtrum, and low-set ears), among others.


Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome

A rare mitochondrial disease characterized by neonatal onset of severe cardiac and/or neurologic signs and symptoms mostly associated with a fatal outcome in the neonatal period or in infancy, although a milder phenotype with later onset and slowly progressive neurologic deterioration has also been reported. Clinical manifestations are variable and include respiratory insufficiency, hypotonia, cardiomyopathy, and seizures. Serum lactate is elevated in most cases. Brain imaging may show cerebellar atrophy or hypoplasia.


Neonatal epileptic encephalopathy due to glutaminase deficiency

A rare genetic neurometabolic disease characterized by early neonatal refractory seizures, hypotonia, and respiratory failure. Brain imaging reveals simplified gyral pattern of the frontal lobes, white matter abnormalities, gliosis and volume loss in various brain regions, and vasogenic edema. Serum glutamine levels are significantly elevated. Death occurs within weeks after birth.


Neonatal glycine encephalopathy is a frequent, usually severe form of glycine encephalopathy (GE; see this term) characterized by coma, apnea, hypotonia, seizure and myoclonic jerks in the neonatal period, and subsequent developmental delay.

Summary:
Epidemiology
The prevalence of neonatal glycine encephalopathy is not known.
Clinical description
Patients develop disease manifestations within the first hours or days of life. Symptoms include progressive lethargy, hypotonia, myoclonic jerks leading to apnea. In the absence of intubation and ventilation, apnea may be fatal. With supportive measures, most patients regain spontaneous respiration and some show improvement in alertness over time. Subsequently, they have profound intellectual deficit and increasingly intractable seizures over the first year of life, which often require multiple anticonvulsants. In the vast majority of cases (85%), the course is severe, but some patients have a milder course and less severe clinical outcome. In severe cases, patients make little developmental progress and have limited interaction with their environment. Early spasticity, scoliosis and club feet have also been reported. In milder cases, developmental progress is considerably greater with patients learning to walk and interact, and seizures are generally easier to treat.
Etiology
Mutations in two genes are known to cause glycine encephalopathy: GLDC (9p22), AMT (3p21.2-p21.1).
Genetic counseling
Neonatal GE is inherited in an autosomal recessive manner.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                             Shigeo KURE


A rare iron storage disorder present at birth characterized by the association of severe hepatocellular failure with hyperbilirubinemia, signs of hemorrhage, edema, ascites, hypoglycemia, and lactic acidosis with little to no elevation of transaminases. It is a distinct entity that differs from other forms of hemochromatosis with respect to its pathogenesis and molecular origin.


Neonatal hypoxic and ischemic brain injury

A rare neonatal encephalopathy characterized by alterations in mental status ranging from irritability and decreased responsiveness to coma, as well as abnormal primitive reflexes, hypotonia, seizures, and abnormalities in feeding and respiration, with an onset within the first hours of life. The condition is associated with high mortality. Long-term sequelae include a spectrum of signs and symptoms including behavioral deficits, developmental delay, learning disabilities, cognitive impairment, seizures, visual and auditory dysfunction, and cerebral palsy.


Neonatal ichthyosis-sclerosing cholangitis syndrome

Neonatal ichthyosis-sclerosing cholangitis (NISCH syndrome) is a very rare complex ichthyosis syndrome characterized by scalp hypotrichosis, scarring alopecia, ichthyosis and sclerosing cholangitis.

Summary:
Epidemiology
Less than ten patients (from unrelated consanguineous Moroccan families and from Sweden) have been reported so far.
Clinical description
The ichthyosis presents with diffuse white scales sparing the skin folds, and is accompanied by scalp hypotrichosis, cicatricial alopecia, and sparse eyelashes/eyebrows. Additional manifestations may include oligodontia, hypodontia and enamel dysplasia. All patients present with neonatal sclerosing cholangitis with jaundice and pruritus, hepatomegaly, and biochemical cholestasis. Overall, the clinical picture mimics biliary atresia (see this term). Portal hypertension, patent extrahepatic bile duct obstruction and splenomegaly may also be present. Histology shows extensive fibrosis and bile duct proliferation. Leukocyte vacuolization is a common finding. The hepatic disease may have variable expressivity, ranging from a progressive disease resulting in liver failure to regression of cholestasis.
Etiology
NISCH syndrome is caused by a mutation in the CLDN1 gene coding for the tight junction protein claudin-1.
Diagnostic methods
Diagnosis is based on clinical, biochemical and histological features.
Differential diagnosis
The differential diagnosis should include Dorfman-Chanarin syndrome and other syndromic forms of ichthyosis (see these terms).
Genetic counseling
NISCH syndrome shows an autosomal recessive pattern of inheritance.
Management and treatment
Treatments aim at improving symptoms and survival. Liver transplant remains the only effective treatment in case of liver failure. Ichthyosis is managed by hydration of the skin (topical application of creams and emollient oils), retinoids and sunlight exposure.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Pr Dominique VALLA


Neonatal inflammatory skin and bowel disease is a rare, life-threatening, autoinflammatory syndrome with immune deficiency disorder characterized by early-onset, life-long inflammation, affecting the skin and bowel, associated with recurrent infections. Patients present perioral and perianal psoriasiform erythema and papular eruption with pustules, failure to thrive associated with chronic malabsorptive diarrhea, intercurrent gastrointestinal infections and feeding troubles, as well as absent, short or broken hair and trichomegaly. Recurrent cutaneous and pulmonary infections lead to recurrent blepharitis, otitis externa and bronchiolitis.


Neonatal intrahepatic cholestasis due to citrin deficiency

A mild subtype of citrin deficiency characterized clinically by low birth weight, failure to thrive, transient intrahepatic cholestasis, multiple aminoacidemia, galactosemia, hypoproteinemia, hepatomegaly, decreased coagulation factors, hemolytic anemia, variable but mostly mild liver dysfunction, and hypoglycemia.


Neonatal iodine exposure is a rare endocrine disease characterized by the appearance of transient hypothyroidism, usually in preterm newborns, following long or short-term topical iodine exposure. Parenteral exposure from iodinated contrast agents may similarly alter thyroid function in term neonates.


A rare systemic autoimmune disease characterized by cutaneous lesions, hepatic dysfunction, hematological abnormalities, and/or cardiac arrhythmia, and caused by transplacental passage of maternal SS-A and SS-B autoantibodies. The most typical cutaneous manifestation is a macular annular erythema affecting the head, but also trunk and extremities. Other reversible features include anemia, neutropenia, thrombocytopenia, and elevation of liver parameters with hepatomegaly. The most severe presentation of the disease is irreversible congenital total atrioventricular block.


Neonatal Marfan syndrome is a rare, severe and life-threatening genetic disease, occuring during the neonatal period, characterized by classical Marfan syndrome manifestations in addition to facial dysmorphism (megalocornea, iridodonesis, ectopia lentis, crumpled ears, loose redundant skin giving a 'senile' facial appearance), flexion joint contractures, pulmonary emphysema, and a severe, rapidly progressive cardiovascular disease (including ascending aortic dilatation and severe mitral and/or tricuspid valve insufficiency). Additionally, skeletal manifestations (arachnodactyly, dolichostenomelia, pectus deformities) are also associated.


A rare secondary neonatal autoimmune disease characterized by neonatal-onset of erythematous skin lesions with a linear appearance that gradually become indurated and hyperpigmented and progressively present skin atrophy. Positive serum antibodies (in particular antinuclear antibodies and/or rheumatoid factor) may be associated.


Neonatal severe cardiopulmonary failure due to mitochondrial methylation defect

A rare mitochondrial disease characterized by a variable clinical phenotype ranging from fetal hydrops and postnatal hypotonia, bradycardia, and respiratory failure, resulting in death in the neonatal period, to infantile onset of episodes of acute cardiopulmonary failure associated with severe lactic acidosis, and slowly progressive muscle weakness. Muscle biopsy shows reduced activity of mitochondrial complexes I, III, and IV.


Neonatal severe primary hyperparathyroidism (NSHPT) is characterized by severe hypercalcemia (> 3.5 mM) from birth and associated with major hyperparathyroidism.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
The clinical manifestations are early (with onset occurring during the first days of life) and severe, including respiratory distress due to hypotonia and rib cage deformities, bone under mineralization, and multiple fractures, all of which influence the immediate vital prognosis.
Etiology
NSHPT is associated in most cases with homozygous inactivating mutations in the CASR gene, localized to 3q21.1. This gene encodes the calcium-sensing receptor (CaSR), a member of the subfamily of G protein-coupled transmembrane receptors. CaSR plays a key role in the regulation of phosphocalcic metabolism by controlling parathyroid hormone (PTH) secretion and calcium urinary excretion in response to variations in serum calcium levels.
Diagnostic methods
Biologically, children present with extremely high serum calcium and serum PTH levels and a relative hypocalciuria, but in some cases they present with a markedly elevated calciuria.
Differential diagnosis
'Familial hypocalciuric hypercalcemia (FHH; see this term) is a differential diagnosis. Hypercalcemia is usually milder and PTH levels are lower in FHH than in NSHPT and FHH is asymptomatic in most cases.'
Antenatal diagnosis
Prenatal diagnosis might be proposed to parents if they are both suffering from FHH.
Genetic counseling
NSHPT represents the homozygous form of FHH and is transmitted as an autosomal recessive trait. However, sporadic forms of NSHPT occur and are associated with a heterozygous de novo mutation in the CASR gene. To date, there have been no reports of severe neonatal hyperparathyroidism with homozygous mutations in those with FHH type 2 or 3 (see these terms) but their molecular identification is still too recent to make any definite conclusions.
Management and treatment
The control of hypercalcemia is often obtained through progressive therapeutic intervention involving the use of bisphosphonates, dialysis or even calcimimetics. If this is unsuccessful, a total parathyroidectomy is required. After parathyroidectomy, life-long treatment with 1-alpha hydoxylated vitamin D is required.
Prognosis
Patients can die from complications of hypercalcemia during the neonatal period from respiratory distress and dramatic hypercalcemia.

                            Last update:
                            May 2014

                            - Expert reviewer(s):
                            Pr Anne LIENHARDT-ROUSSIE


Neovascular glaucoma is the most common type of secondary glaucoma, usually caused by diabetic retinopathy, central retinal vein occlusion and carotid artery obstruction but sometimes by trauma, uvietis or ocular tumors, and characterized by severe eye pain, synechial angle glaucoma, high intraocular pressure and leading to loss of vision.


A rare malignant renal tumor, typically affecting the pediatric population, characterized by an abnormal proliferation of cells that resemble the kidney cells of an embryo (metanephroma), leading to the term embryonal tumor.

Summary:
Epidemiology
The annual incidence is estimated at about 1/10,000 births and it affects boys as well as girls.
Clinical description
Nephroblastoma mainly affects young children, between the ages 1 and 5 years, but 15% of nephroblastomas occur before the age of 1 year and 2% after the age of 8 years. Adult forms are very rare. An abdominal mass (unilateral in most cases) is frequently present. Patients sometimes experience abdominal pain (around 10% of cases), hypertension, fever (20% of cases), hematuria and anemia. The evolution of the disease is very rapid, with regional dissemination in the retroperitoneal space, lymph nodes, vessels (renal vein and inferior vena cava) and in the peritoneal cavity in cases of tumor effraction, and a strong likelihood of metastases in the lungs and liver.
Etiology
Nephroblastoma is sporadic in 99% of cases and, among these cases, 10% are associated with congenital anomalies (aniridia, hemihypertrophy, genitourinary defects) or form part of specific syndromes (Beckwith-Wiedemann, Denys-Drash, WAGR or Perlman syndromes; see these terms). Genetic anomalies found in different chromosomal regions, including 11p13 (containing the WT1 gene), 11p15.5 (containing the H19 gene), 16q, 1p, 1q and 17p, have been found within the tumors. Familial forms are very rare (1% of cases) and are transmitted in an autosomal dominant fashion.
Diagnostic methods
Diagnosis is based on imagery, particularly CT or MRI scans. The concentration of urinary metabolites of catecholamines is normal. Analysis of the extent of the disease is also conducted using imagery (ultrasound and abdominal CT analyzing particularly the liver and contralateral kidney, and thoracic radiography and CT).
Differential diagnosis
Differential diagnoses include other renal tumors in children such as mesoblastic nephroma (especially in infants), clear cell sarcoma, neuroblastoma (extremely rare in the kidney but may invade the kidney by contiguity), rhabdoid tumors (see these terms) and metanephric stromal tumors.
Management and treatment
Disease management is multidisciplinary and may involve chemotherapy and surgery with or without radiotherapy. Chemotherapy enables preoperative reduction in tumor size and eradicates metastases. Surgery should be accomplished without tumor effraction, which usually means that total nephrectomy is required. Nephroblastoma can be confirmed on microscopic examination, which also allows the stage of the tumor in the kidney to be evaluated. This in turn determines the choice of post-operative chemotherapy. Radiotherapy is reserved for the most extensive cases or cases with the least favorable histology.
Prognosis
In the majority of cases, the prognosis is favorable with a survival rate of over 90%. Adult forms have the same prognosis and should be treated following the same methods, even when adult patients tolerate chemotherapy less well than children (which may lead to a reduction in treatment and as a result a worse prognosis).

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Catherine PATTE


Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare genetic disorder of water balance, closely resembling the far more frequent syndrome of inappropriate antidiuretic secretion (SIAD), and characterized by euvolemic hypotonic hyponatremia due to impaired free water excretion and undetectable or low plasma arginine vasopressin (AVP) levels.

Summary:
Epidemiology
NSIAD is a very rare disease with 21 cases of hyponatremia due to NSIAD having been reported to date, the majority of them coming from 5 families. NSIAD affects mainly males.
Clinical description
Age at diagnosis can range from the first day of life to more than 70 years. When disease onset occurs in childhood, it generally presents with hyponatremic seizures. Asymptomatic female carriers have also been described. Symptoms of NSIAD are the classical symptoms of hyponatremic encephalopathy (cerebral edema) such as nausea, vomiting, dizziness and gait disturbances. The life-threatening symptoms of acute and severe hyponatremia (altered consciousness, respiratory arrest and death) have never been reported in NSIAD but can theoretically occur.
Etiology
NSIAD is due to a gain of function mutation in the type 2 AVP receptor (AVPR2) gene (location Xq28), thus representing the mirror image of nephrogenic diabetes insipidus (see this term). This mutation leads to constant activation of the AVPR2 receptor on renal collecting duct cells, which causes an increase in free water reabsorption and an increase in urine concentration. Three mutations in this gene have been identified, 2 of them have been described in only one patient.
Diagnostic methods
The first step in diagnosing NSIAD is to diagnose SIAD. The diagnostic criteria are as follows: euvolemic hypotonic hyponatremia, increased urinary osmolality (> 100 mosm/kg), increased urinary sodium (> 30 mmol/l), normal thyroid, adrenal, cardiac and renal function and no use of diuretics. The circumstances in which the AVPR2 mutation should be screened are 'idiopathic' SIAD with low or undetectable plasma AVP levels, familial history of NSIAD or unexplained SIAD in childhood. A mutation in the AVPR2 gene confirms diagnosis.
Differential diagnosis
The main differential diagnosis is idiopathic SIAD.
Genetic counseling
NSIAD is an X-linked disorder, affecting mainly males, with females often being asymptomatic carriers (only 3 cases of symptomatic hyponatremic females have been reported). Genetic counseling is possible.
Management and treatment
Treatment of NSIAD is lifelong. Fluid restriction is the cornerstone of treatment. It is generally sufficient to avoid episodes of hyponatremia and is well tolerated (good compliance). There is a concern of restricting fluids in young infants due to the risk of malnutrition. Oral urea is the second step of treatment and acts by increasing free water clearance (osmotic diuresis). It is safe and well tolerated in children and adults, even over long-term use. Intermittent urea intake (non-daily) can be an option in some patients. Urea can also be used to correct an acute episode of hyponatremia. Non-peptide vasopressin receptor antagonists (vaptans), which have received market authorization for the management of SIAD, have shown inefficacy in a patient with mutant R137C - V2R but could be of interest in patients with the recently described mutant F229V-V2R on the basis of in vitro data. Patients must be monitored when increased water intake is anticipated (sports, heat wave) or in case of postoperative perfusion.
Prognosis
The prognosis of NSAID is good, if episodes of severe hyponatremia are avoided.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Frederic VANDERGHEYNST


Nephrogenic systemic fibrosis (NSF) is a rare systemic fibrosing condition observed in renally impaired patients and characterized by a hardening and thickening of the skin with fibrotic plaques or papules, pruritus, joint pain and stiffness, muscle weakness, limitation of range of motion, and yellowed eyes. It is generally associated with administration of gadolinium-based magnetic resonance imaging contrast agents (GBCA) in patients with kidney disease.


A rare, genetic, renal ciliopathy characterized by reduced ability of the kidneys to concentrate solutes, chronic tubulointerstitial nephritis, occasional presence of cysts, and progression to end stage renal disease (ESRD). The three clinical subtypes are characterized by the age of onset of ESRD which includes infantile, juvenile and late onset.

Summary:
Epidemiology
The prevalence is unknown; however, at birth it is estimated at 1: 80,000 in Finland. Nephronophthisis (NPHP) is responsible for 2.4 to 15% of ESRD in children.
Clinical description
Three main forms have been described. Juvenile NPHP, the most frequent form, progresses to end-stage renal failure at median age of 13 and is responsible for 15% of cases of childhood ESRD. Infantile NPHP can present in utero with oligohydramnios sequence or postnatally with reduced kidney function and progresses to ESRD before age 3. Late-onset NPHP is a rare form of the disease and presents clinical and histological signs similar to the juvenile form but with ESRD occurring later (median age of 19 years). The typical clinical symptoms include polyuria, polydipsia with regular fluid intake, impaired sodium reabsorption that cause hypovolemia and hyponatremia, anemia and growth delay. Renal ultrasonography in early stages is normal or shows unspecific changes with increased renal echogenicity, with advancing kidney disease poor cortico-medullary differentiation is described; corticomedullary cysts are present in the 70% of patients. Renal histopathology in NPHP is characterized by the triad of tubular cysts, tubular basement membrane disruption, and interstitial fibrosis with interstitial cell infiltration. Retinal degeneration is the most frequent extrarenal findings (10%), cerebellar vermis aplasia, liver fibrosis and skeletal defects could be also present. Extrarenal phenotypes are distinct but they overlap in some syndromic forms of NPHP (such as Joubert syndrome, Senior-Loken syndrome, Meckel-Gruber syndrome).
Etiology
To date, mutations in 14 genes have been identified in affected individuals. The majority of these genes encode for ciliary proteins that cluster to distinct subcellular localizations. The NPHP1 gene, that encodes for nephrocystin-1, is deleted or mutated in 25% of juvenile NPHP. Mutations in the gene INVS  (9q31.1), coding for inversin, is frequently responsible for infantile NPHP. Mutations in NPHP3 (3q22.1), NPHP4 (1p36.31), NEK8 (17q11.2) genes give rise to late-onset nephronophthisis, however these genes are associated also with the Senior-Loken syndrome and Meckel-Gruber syndrome and predispose to multiorgan polycystic disease.
Diagnostic methods
The diagnosis is suggested by clinical features and confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes early onset autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease and congenital anomalies of kidney and urinary tract (CAKUT). Furthermore, juvenile NPHP forms part of a spectrum of NPHP-related ciliopathies which includes Joubert syndrome, Senior-Loken syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome and Skeletal Ciliopathies (Oral-facial-digital syndrome, Cranioectodermal dysplasia, Short-rib thoracic dysplasia). The infantile form should also be distinguished from renal hypodysplasia.
Antenatal diagnosis
Once the pathogenic variants have been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis can be considered.
Genetic counseling
The pattern of inheritance is autosomal recessive, with homozygous or compound heterozygous mutations possible. The parents are obligate heterozygotes (carriers) and are asymptomatic with no risk of developing the disorder. Each sib of an affected individual has a 50% risk of being an asymptomatic carrier, 25% to be affected, and 25% to be unaffected and not a carrier. Offspring of an affected individual will be obligate carriers.
Management and treatment
The management is supportive to maintain fluid and metabolic balance including: correction of water and electrolyte imbalances; anemia treatment, and proteinuria treatment if necessary. For the ESRD management, dialysis or renal transplantation are necessary.
Prognosis
The prognosis is dependent on the age of ESRD onset. Despite the risk of complications, transplant outcomes are excellent with no recurrence of the disease.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Luisa MURER | ERKNet* - Dr Susanna NEGRISOLO | ERKNet*

                                * European Reference Network


A rare syndromic deafness characterized by renal failure without hematuria, parathyroid hyperplasia and sensorineural deafness. There have been no further reports since 1989.


Nephrosis-deafness-urinary tract-digital malformations syndrome

A rare, genetic, multiple congenital anomalies syndrome characterized by urinary tract anomalies, nephrosis, conductive deafness, and digital malformations, including short and bifid distal phalanges of thumbs and big toes. There have been no further descriptions in the literature since 1962.


Nephrotic syndrome-epidermolysis bullosa-sensorineural deafness syndrome

A rare, genetic, renal disease characterized by hereditary nephritis leading to nephrotic syndrome and end-stage renal failure associated with sensorineural hearing loss and pretibial skin blistering followed by atrophy. Other reported manifestations include bilateral lacrimal duct stenosis, dystrophic teeth and nails, bilateral cervical ribs, unilateral kidney, distal vaginal agenesis and anemia due to beta-thalassemia minor.


Nestor-Guillermo progeria syndrome is a rare, genetic, progeroid syndrome characterized by a prematurely aged appearance associated with severe osteolysis (notably on mandible, clavicles, ribs, distal phalanges, and long bones), osteoporosis, generalized lipoatrophy and absence of cardiovascular, atherosclerotic and metabolic complications, presenting a relatively long survival. Additional characteristics include growth retardation, joint stiffness (mainly of fingers, hands, knees, and elbows), wide cranial sutures, dysmorphic facial features (prominent eyes, convex nasal ridge, malocclusion, dental crowding, thin lip vermillion, microretrognathia) and persistent eyebrows, eyelashes and scalp hair.


Netherton syndrome (NS) is a skin disorder characterized by congenital ichthyosiform erythroderma (CIE), a distinctive hair shaft defect (trichorrhexis invaginata; TI) and atopic manifestations.

Summary:
Epidemiology
Incidence is estimated at 1/200,000 births.
Clinical description
Patients generally present at birth with generalized erythroderma and scaling, and failure to thrive. Frequent complications include hypernatremic dehydration, recurrent infections, and diarrhea and intestinal malabsorption. The disease course is heterogeneous: the generalized erythroderma may persist in some patients, but more frequently it evolves during childhood into ichthyosis linearis circumflexa (ILC). ILC is a milder and highly characteristic skin disorder marked by migratory erythematous plaques with a double-edged scale. Hair anomalies usually become apparent after infancy, with sparse and brittle hair caused by TI (bamboo hair viewed by light microscopy) and other hair shaft anomalies (pili torti and/or trichorrhexis nodosa). Eyebrows and eyelashes are also affected. The large majority of NS patients develop atopic manifestations including asthma, atopic dermatitis, food allergies, urticaria, angioedema, and elevated IgE levels. Other clinical findings are delayed growth and development, short stature, and, rarely, intermittent aminoaciduria. Intellectual deficit has been associated in some cases.
Etiology
NS is caused by mutations in the SPINK5 gene (5q31-q32) encoding the serine protease inhibitor LEKTI. LEKTI deficiency results in an increase in trypsin-like hydrolytic activity in the stratum corneum (SC) leading to SC premature desquamation and a severe skin barrier defect.
Diagnostic methods
Early diagnosis may be problematic as the most distinctive findings (TI and ILC) do not generally become apparent until childhood. Immunohistochemistry of skin biopsies revealing LEKTI deficiency has been proposed as a useful diagnostic test for NS, but identification of the disease-causing mutation allows molecular confirmation of the diagnosis.
Differential diagnosis
Differential diagnoses include other infantile erythrodermas, particularly nonbullous congenital ichthyosiform erythroderma (see this term) and erythrodermic psoriasis. Atopic dermatitis, lamellar ichthyosis (see this term), primary immunodeficiency syndromes, seborrheic dermatitis, and acrodermatitis enteropathica (see this term) should also be excluded.
Antenatal diagnosis
Molecular prenatal diagnosis is feasible.
Genetic counseling
NS is an autosomal recessive disorder and genetic counseling should be proposed for affected families.
Management and treatment
Treatment is symptomatic and requires prompt management of the neonatal complications and long-term use of emollients for treatment of the skin disorder. Use of topical steroids and topical immunomodulators (tacrolimus and pimecrolimus) has been described as beneficial in some cases, but these agents are not indicated for long-term use or treatment of large surface areas as the skin barrier defect allows increased systemic drug absorption.
Prognosis
The prognosis may be severe in neonates with life-threatening complications and postnatal lethality is high. The skin manifestations and hair anomalies persist throughout life, but the disease usually improves with age and most patients begin to thrive during the second year of life.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


Neu-Laxova syndrome (NLS) is a rare, multiple malformation syndrome characterised by severe intrauterine growth retardation (IUGR), severe microcephaly with a sloping forehead, severe ichthyosis (collodion baby type), and facial dysmorphism.

Summary:
Epidemiology
About 60 cases of this syndrome have been reported from diverse ethnic backgrounds.
Clinical description
Severe central nervous system (CNS) defects are present: lissencephaly type III, hypoplastic cerebellum and brainstem, enlarged ventricles, and sometimes intracerebral calcifications, Dandy-Walker anomaly or agenesis of the corpus callosum. Facial features include severe proptosis with ectropion (giving the impression of missing eyelids), hypertelorism, micrognathia, flattened nose, and malformed ears. The lips are thick with a round, gaping mouth. Other inconstant malformations include abnormal limbs (contractures and, sometimes, radial ray defects), abnormal external genitalia, and arthrogryposis multiplex. Clinical features show significant intra and interfamilial variation.
Diagnostic methods
The diagnosis is easily made at birth on the basis of the clinical malformations. The histopathological findings include a triad of dermatological features (ichthyosis, massive fat with hypertrophy of fat cells, oedema), poor formation of the cortical bone, and central nervous system (CNS) anomalies.
Antenatal diagnosis
Routine ultrasonography (at 19 to 20 weeks of gestation) may show polyhydramnios, IUGR, hypoechogenic skeletal structures, microcephaly, prominent eyes, retrognathism, hypomobility with flexion deformities. It also shows massive swelling of the scalp, knee, elbow joints, hands and feet, giving the impression of absent digits. At risk pregnancies should be carefully monitored by ultrasonography: at 6-8 weeks for accurate dating, at 12-16 weeks for analysis of activefoetal limb movements, and at 16-24 weeks for the detection of facial and skeletal anomalies, IUGR and polyhydramnios.
Genetic counseling
The syndrome is transmitted in an autosomal recessive manner. Parents should be informed of a 25% recurrence rate in future offspring.
Prognosis
The prognosis is poor: affected newborns either are stillborn or die immediately after birth.

                            Last update:
                            October 2006

                            - Expert reviewer(s):
                            Pr Alain VERLOES


Neuhauser anomaly is a rare cardiovascular morphological anomaly due to maldevelopment of embryonal aorta resulting in right aortic arch and left ligamentum arteriosum characterized by tracheoesophageal compression symptoms (stridor, dyspnea, dysphagia, apnoeic episodes, recurrent respiratory infections).


A rare genetic neurological disorder characterized by infantile or childhood onset of recurrent acute encephalopathic episodes with cerebellar and extrapyramidal involvement following febrile illnesses. During the episodes, patients typically show sudden onset of truncal ataxia, occasionally accompanied by lethargy and impairment of speech, as well as choreic and athetoid movements, seizures, loss of deep tendon reflexes, and presence of pathological reflexes. Episodes last from day to weeks and may leave residual symptoms such as speech impairment and poor coordination. There have been no further descriptions in the literature since 1983.


A rare disorder of the peripheral nervous system characterized by the sudden onset of extreme pain in the upper extremity followed by rapid multifocal motor weakness and atrophy and a slow recovery in months to years. NA includes both an idiopathic (INA, also known as Parsonage-Turner syndrome) and hereditary (HNA) form.

Summary:
Epidemiology
The minimum incidence of NA is estimated at 1/50,000-1/30,000 but under recognition and initial misdiagnosis is common. HNA is thought to be 10 times less common than INA.
Clinical description
NA can occur at any age but is most frequently seen in those between the 3rd-7th decades of life and is more frequent in men. Those with HNA usually present earlier than those with INA but clinically they are virtually indistinguishable. The classic presentation (71% of cases) manifests with sudden onset of aching, burning, or stabbing pains, most often in the shoulders, neck, and/or arm region, showing an upper brachial plexus distribution. Weakness in the periscapular and periglenohumeral muscles follows hours to weeks after the initial onset of pain. These pains are usually relentless, worse at night and last for about 3 weeks. Other manifestations may occur due to the involvement of nerves outside the brachial plexus such as the lumbosacral plexus or phrenic nerves. Certain patients with HNA (with a R88W point mutation) display characteristic physical features (ex. hypotelorism, slanted eyes, epicanthal folds, oval face, cleft palate). Some patients experience a relapsing/remitting course with symptom-free intervals while others have an incomplete recovery with persisting neurologic deficit. Recurrences can occur (75% in HNA and 25% in INA) and persistent musculoskeletal pain develops in 2/3 of patients.
Etiology
The exact etiology is unknown but genetic, autoimmune and external factors are thought to play a role. The brachial plexus has an underlying predisposition to mechanical injury and attacks caused by an immune-mediated response in this nerve. A viral infection or immunization can precede NA. Bacterial and parasitic infections, surgery, anesthesia, rheumatic disease, trauma, pregnancy and childbirth have all been implicated as possible contributing factors of NA attacks. HNA is associated with a point mutation or duplication of the susceptibility gene SEPT9 on chromosome 17q25.3 in 50% of cases.
Diagnostic methods
Diagnosis is based on the typical clinical features and the exclusion of other disorders (ex. neuroborreliosis, cervical radiculopathy or Pancoast syndrome) using laboratory tests, electromyography and imaging of the cervical spine and brachial plexus. In those where HNA is suspected, a molecular genetic test can be used to identify a SEPT9 mutation, but since HNA is genetically heterogeneous, a negative test does not exclude the diagnosis.
Antenatal diagnosis
Antenatal diagnosis is not routinely offered.
Genetic counseling
Genetic counseling is possible in families with the HNA susceptibility gene.
Management and treatment
Treatment in the acute stage involves pain management, relying mostly on a combination of long-acting opioids and nonsteroidal anti-inflammatory drugs. Those with chronic pain can be given co-analgesics. Oral prednisone decreases the duration of pain and accelerates recovery in some patients if given in the first weeks of an attack. A daily dose of 1mg/kg for 1 week which is tapered during the 2nd week is recommended. Follow-up is recommended every 6 months. Rehabilitation therapy is now considered important and excessive strain to the affected area should be avoided.
Prognosis
The prognosis is variable but thought to be good with patients recovering 70-90% of their previous health after 1-2 years. However, many are left with exercise intolerance and poor muscular coordination in the affected and compensating muscles. Quality of life can be affected in those with an incomplete recovery but early diagnosis and proper treatment increase the chances of a full functional recovery.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Dr N. [Nens] VAN ALFEN


A rare, congenital, non-syndromic malformation of neurenteric canal, spinal cord and column, characterized by intraspinal, predominantly intradural-extramedullary cystic mass located typically ventral to the spinal cord. Histopathology reveals columnar or cuboidal epithelium with or without cilia and mucus globules. Patients may be asymptomatic or present with signs and symptoms of compression of the spinal cord and associated nerve roots, such as focal weakness, progressive paresis, paresthesias, gait disturbance, or radicular pain. Concomitant congenital vertebral anomalies are frequently observed.


Neuroacanthocytosis (NA) syndromes are a group of genetic diseases characterized by the association of red blood cell acanthocytosis (deformed erythrocytes with spike-like protrusions) and progressive degeneration of the basal ganglia.

Summary:
Epidemiology
NA syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5/1,000,000 for each disorder.
Clinical description
NA syndromes include choreacanthocytosis, McLeod neuroacanthocytosis syndrome, pantothenate-kinase-associated neurodegeneration, and Huntington disease-like 2 (see these terms) which have a Huntington disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. Cardiomyopathy including arrhythmias may occur in McLeod syndrome.
Etiology
NA syndromes are caused by disease-specific genetic mutations. The mechanisms by which these mutations cause neurodegeneration are not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal ganglia, however, suggests a common pathogenetic pathway.
Genetic counseling
Choreacanthocytosis follows an autosomal recessive pattern of inheritance, McLeod neuroacanthocytosis syndrome an X-linked pattern, and Huntington disease-like 2 an autosomal dominant pattern.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Hans JUNG


Neuroblastoma is a malignant tumor of neural crest cells, the cells that give rise to the sympathetic nervous system, which is observed in children.

Summary:
Epidemiology
It represents about 10% of solid tumors in infants and children under the age of 15, with an annual incidence of about 1/70,000 in children in this class of age.
Clinical description
In 90% of cases the neuroblastoma is diagnosed before the age of five. The clinical presentation of neuroblastoma is very variable and depends on the stage and location of the tumor, which can develop at any site in the sympathetic nervous system (around 80% of cases develop in the abdomen). Localized forms are discovered fortuitously or are revealed by the presence of an abdominal or thoracic mass that can be associated with pain. At the time of diagnosis, metastatic forms represent about 50% of cases. The most frequent metastatic sites are bone marrow, bone, liver and skin. Symptoms of metastasis including bone pain, limp, paralysis, hepatomegaly (Pepper's syndrome), and exophthalmia (Hutchinson's syndrome), indicate metastatic neuroblastoma. The disease can also be associated with arterial hypertension, fever, and an altered general state (weight loss, pain, irritability, and anemia).
Etiology
Neuroblastoma has been linked to numerous genetic anomalies which affect prognosis: amplification of the oncogene MYCN (2p24.3) is a factor for poor prognosis; triploidy, numerical anomalies of chromosomes are associated with a good prognosis, while di- or tetraploidy and segmental chromosomal anomalies (including loss from 1p, from 11q, or gains of 17q) are associated with poor prognosis. Recently, a mutation of the ALK gene has been described in about 12% of cases.
Diagnostic methods
Diagnosis is based on evidence of an elevated level of metabolites of urinary catecholamines (VMA, HVA, and dopamine) and on an image of the initial tumor by ultrasound and brain scan or by MRI. MIBG (iodine-131-meta-iodobenzylguanidine) scintigraphy and medullary analysis are useful for finding metastases. Tumor biopsy confirms the diagnosis, allows histological classification and helps find amplification of MYCN.
Differential diagnosis
Differential diagnoses include nephroblastoma, which makes it necessary to systematically check urinary catecholamines in case of an abdominal tumor. Bone pain and limp can be interpreted as synovitis of the hip. Possible bilateral peri-orbital hematomas, caused by orbital metastases, should not lead to a diagnosis of maltreatment.
Antenatal diagnosis
Neuroblastoma can be identified using antenatal ultrasound and therefore adequate management after the birth can be provided.
Management and treatment
Localized forms of neuroblastoma are treated by surgical resection, sometimes preceded by chemotherapy. Treatment of metastatic forms in children of more than one year and forms with amplification of MYCN is by: conventional chemotherapy, surgery of the initial tumor, high dose chemotherapy with hematopoietic stem cell transplantation, local radiotherapy and maintenance therapy with retinoic acid.
Prognosis
The majority of localized tumors have an excellent prognosis after surgery. Children under one year have a better prognosis than older children. Some tumors may even show spontaneous regression. In contrast, approximately 60% of children older than one year with neuroblastoma present metastatic disease at diagnosis with poor outcome, even with intensive treatment. In children older than one year, the five-year survival rate varies between 95% for some localized tumors to 30% in cases of metastatic neuroblastoma.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Dr Dominique VALTEAU-COUANET


Neurocutaneous melanocytosis (NCM) is a rare congenital neurological disorder characterized by abnormal aggregations of nevomelanocytes within the central nervous system (leptomeningeal melanocytosis) associated with large or giant congenital melanocytic nevi (CMN; see this term). NCM can be asymptomatic or present as variably severe and progressive neurological impairment, sometimes resulting in death.

Summary:
Epidemiology
Prevalence is estimated at 1/50,000-1/200,000. The incidence of symptomatic NCM appears to be approximately a third to a half of these.
Clinical description
A large, or giant, CMN is a pigmented skin lesion of more than 20 cm projected adult diameter (40 for "giant"), composed of aggregated melanocytes in a delimited area of the body, and presenting with an elevated risk of malignant transformation. Leptomeningeal melanocytosis nearly always presents with CMN, though not conversely; a case with no pigmented lesions and another with only café-au-lait spots have been reported. Symptoms of NCM, when they do occur, generally appear before the age of five and can include headaches, seizures, vomiting, visual disorders, movement and learning disorders, paralysis, intellectual deficit, papilledema, and/or hydrocephalus associated with other brain malformations, such as Dandy-Walker complex. NCM has also been reported with Chiari malformation of the brainstem, congenital heart anomalies (transposition of the great arteries, ventricular septal defect), renal agenesis, skeletal malformations, lipomatosis, or hemihypertrophy.
Etiology
NCM is believed to result from the prenatal, abnormal proliferation of neural crest-derived melanocytes in the central nervous system, but the pathogenic mechanism is still unclear. Their common origin with forebrain-specific pericytes may favor the differentiation and dissemination of nevomelanocytes in situ during meningeal development.
Diagnostic methods
Diagnosis is based on physical examination and neuroimaging. CMN patients with more than twenty CMN or with a large/giant CMN covering the posterior midline axis are more likely to have NCM, though these signs are not in themselves pathognomic. Neuroimaging is based on MRI examination of either symptomatic or asymptomatic NCM, that may reveal areas of increased signal on T1 corresponding to melanocyte aggregation, generally involving the anterior temporal lobes, amygdala, or cerebellum. Biopsy shows variable degrees of differentiation of proliferating nevomelanocytes, ranging from benign-looking cells to atypical melanoma-like cells within the leptomeninges and focally invading the brain.
Differential diagnosis
Differential diagnosis includes primary central nervous system melanoma, meningeal melanocytoma (see these terms), idiopathic hydrocephalus, idiopathic epilepsy, and meningeal melanoma.
Genetic counseling
Only sporadic cases of NCM have been reported to date.
Management and treatment
Close dermatologic and neurologic follow-up for asymptomatic patients is recommended at least annually. In cases with hydrocephalus, ventriculo-peritoneal shunt is generally performed to reduce intracranial pressure with a reported risk of clogging the shunting catheter with the proliferating nevomelanocytes. Seizures have been successfully treated with standard temporal lobotomy.
Prognosis
Asymptomatic NCM shows a normal life expectancy. Symptomatic NCM has a poor prognosis in retrospective studies, though this can be extremely variable (from weeks to months). Death can result from complications of hydrocephalus or from the development of melanocytoma or CNS melanoma.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr Heather ETCHEVERS


Neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency is characterised by delayed motor development, hypotonia and progressive neurodegeneration. To date, it has been described in four boys. The syndrome is caused by mutations affecting the two alleles of the  HIBCH gene, encoding 3-hydroxyisobutyryl-CoA hydrolase. The mode of transmission has not yet been established.


Neurodegeneration with brain iron accumulation (NBIA, formerly Hallervorden-Spatz syndrome) encompasses a group of rare neurodegenerative disorders characterized by progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis), iron accumulation in the brain and the presence of axonal spheroids, usually limited to the central nervous system.

Summary:
Epidemiology
An estimated prevalence of 1-3/1,000,000 has been suggested based on observed cases in a population. The most common form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN; see this term), which accounts for approximately 50% of cases.
Clinical description
NBIA can present as early onset with rapid progression: classic pantothenate kinase-associated neurodegeneration (PKAN), infantile neuroaxonal dystrophy (INAD) and atypical neuroaxonal dystrophy (atypical NAD) (see these terms); or later onset with slower progression: atypical PKAN, neuroferritinopathy and aceruloplasminemia (see these terms). Idiopathic NBIA can have either type of onset and progression.
Etiology
Classic and atypical PKAN are caused by mutations in the PANK2 gene (20p13-p12.3), infantile and atypical neuroaxonal dystrophy are caused by mutation in the PLA2G6 gene (22q13.1), aceruloplasminemia is caused by mutation of the ceruloplasmin (CP) gene (3q23-q24) and neuroferritinopathy is caused by mutations in the ferritin light chain (FTL1) gene (19q13.3-q13.4). Idiopathic NBIA is likely caused by several additional, as yet undiscovered genes.
Diagnostic methods
This heterogeneous group of disorders can be differentiated by clinical, radiographic, and molecular features. Brain MRI is standard in the diagnostic evaluation of all forms of NBIA. Individuals with PKAN and HARP syndrome, which is considered part of the PKAN disease spectrum, show a characteristic "eye of the tiger''sign on MRI, a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. Infantile and atypical NAD have characteristic axonal swellings throughout the central and peripheral nervous system. Diagnosis of aceruloplasminemia is based on the absence of serum ceruloplasmin in combination with MRI findings of iron accumulation.
Genetic counseling
The majority of NBIA types are transmitted in an autosomal recessive manner, except neuroferritinopathy which is transmitted in an autosomal dominant manner with high penetrance.
Management and treatment
At this time most treatments for NBIA are palliative. Research is currently underway to identify additional NBIA genes and improve treatment possibilities by characterizing the underlying causes of these disorders.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Allison GREGORY  - Pr Susan HAYFLICK


Neurodevelopmental delay-seizures-ophthalmic anomalies-osteopenia-cerebellar atrophy syndrome

A rare, genetic, syndromic intellectual disability characterized by global developmental delay, early-onset seizures, cerebellar atrophy, osteopenia, nystagmus and dysmorphic facial features, including bitemporal narrowing, prominent forehead, anteverted nares. Dysarthria, dysmetria, ataxic gait, spasticity and dysmorphic features have also been associated.


Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, craniofacial dysmorphism (such as ridged metopic sutures, long palpebral fissures, broad nasal bridge, hypoplastic alae nasi, low-set, prominent ears, prominent midline tongue groove, and downturned mouth), congenital heart defects, and variable skeletal abnormalities including hip dysplasia, vertebral anomalies, and scoliosis. Additional reported manifestations include high pain tolerance and genitourinary anomalies. Brain imaging may show a thin corpus callosum or white matter abnormalities.


A rare genetic neurological disease characterized by silvery hair, profound dysfunction of central nervous system, abnormal melanocytes and melanosomes and abnormal inclusion bodies in fibroblast and other cells.

Summary:
Epidemiology
Fewer than 20 cases have been reported worldwide; the prevalence is less than 1/1 000 000 worldwide.
Clinical description
Presentation is in neonates with silver-leaden hair of the scalp, eyebrows and eyelashes, and a silvery sheen present over the body hair. Over time, sun-exposed skin becomes hyperpigmented with a bronze color with generalized hypopigmentation of covered skin. Neurological dysfunction presents either in early infancy or in childhood, manifesting with seizures, severe hypotonia and intellectual disability, and typically progressing to either flaccid or spastic hemiplegia, quadriplegia and ataxia. Individuals with childhood onset initially have normal psychomotor development but subsequently suffer sudden severe neurological regression, including loss of speech, mobility, the ability to feed ones-self, and typically remain bed-ridden. Affected individuals have a wide spectrum of ocular abnormalities including mild vascular sheathing with features of papilledema, nystagmus, diplopia, amaurosis, and absence of pupillary reflex. Brain imaging may show abnormalities including cerebellar and cortical atrophy.
Etiology
The disease is associated with MYO5A mutations. The hyperpigmentation results from defective transfer of melanin from melanocytes to keratinocytes. Neurological abnormalities are linked to impaired function of a molecule playing a common role in melanocytic and neuronal organelle function.
Diagnostic methods
Diagnosis requires light microscopic examination of skin and hair shafts, immunological and peripheral blood smear evaluation. Skin biopsy shows irregular distribution and size of melanin granules in the basal layer, and inclusion bodies in fibroblasts. Hair shafts demonstrate large melanin clumps irregularly distributed along the shaft. Additional laboratory analysis should exclude immunological impairment, abnormal giant intracytoplasmic granules in neutrophils and connective tissue disease.
Differential diagnosis
The disease appears to be related or allelic to Griscelli syndrome type 1. Two other silvery hair syndromes, Griscelli syndrome type 2 and Chédiak-Higashi syndrome, are excluded due to lack of accelerated phase and presence of immunological impairment.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Familial cases indicate that the pattern of inheritance is autosomal recessive, with a sibling recurrence risk of 25%.
Management and treatment
Management and treatment are symptomatic. Steroids, anticonvulsants and antipyretics have been used without success. Seizures have been reported to show improvement in one patient with ACTH therapy.
Prognosis
The disease typically results with death in childhood due neurological complications; the oldest patient reported was 12 years old and had achieved some developmental milestones.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Dr Lokesh LINGAPPA  - Dr Prithuja PODYAL


A rare neuroendocrine neoplasm of pancreas characterized by a high-grade malignant epithelial tumor with neuroendocrine differentiation. Based on histopathologic appearance, a small cell (composed of diffuse sheets of cells) and a large cell type (showing a nesting/trabecular pattern) are distinguished. Synaptophysin and chromogranin are positive on immunohistochemistry. The Ki-67 proliferation index is typically very high (>60 - 80%). Patients present with back pain, jaundice, and/or non-specific abdominal symptoms. Serum hormone activity is unusual. The tumor is highly aggressive with poor prognosis.


Neuroendocrine cell hyperplasia of infancy (NCHI) is a non-lethal pediatric form of interstitial lung disease (ILD, see this term) characterized by tachypnea without respiratory failure.

Summary:
Epidemiology
Prevalence of this disease is not known. It appears to affect young infants (mean age 3.8 months found in a large series) but cases have been reported in older children.
Clinical description
Clinical presentation is typically persistent tachypnea.
Etiology
High-resolution computed tomography (HRCT) shows patchy central ground-glass opacifications and air trapping. Lung biopsy shows hyperplasia of neuroendocrine cells within bronchioles documented by bombesin immunohistochemistry.
Management and treatment
Follow-up reveals in some cases the persistence of tachypnea and oxygen requirement for several months.
Prognosis
The prognosis is usually good.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr Annick CLEMENT


A rare sporadic neoplasm of the appendix and the second most common type of digestive endocrine tumor, often with no specific clinical presentation. They are divided into either classic endocrine tumor of the appendix or the more aggressive goblet cell carcinoma (GCC).


A group of esophageal epithelial neoplasms characterized by neuroendocrine differentiation, comprising well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms, an umbrella category including mixed adenoneuroendocrine carcinoma. The tumors typically occur in the lower esophagus, often in association with Barrett mucosa. NECs may also arise in other parts of the esophagus. On endoscopy, NETs usually appear as small polypoid or nodular submucosal masses, while NECs are large, infiltrative, and ulcerated. Patients most commonly present with dysphagia, pain, weight loss, and sometimes melena. Metastatic NETs may be associated with carcinoid syndrome.


A group of rare tumors characterized by predominantly neuroendocrine differentiation, potentially arising in most organs of the body, including the central nervous system, respiratory tract, larynx, gastrointestinal tract, thyroid, skin, breast, and urogenital system. The gastrointestinal tract and lungs are the most common primary tumor sites. Based on clinical behavior, histology, and proliferation rate, the tumors may be categorized as well differentiated (low grade to intermediate grade) neuroendocrine tumors and poorly differentiated (high grade) neuroendocrine carcinomas. They may or may not be associated with clinical hormone hypersecretion syndromes.


A are epithelial tumor of the anal canal arising from enterochromaffin cells in the colorectal-type epithelium above the dentate line and in the anal transition zone. The tumors are slow growing and the majority of cases are diagnosed in later advanced stages. It may present with symptoms related to the anatomical location of the tumor (rectal mass, rectal bleeding and pain, tenesmus or changes in bowel habits), symptoms of carcinoid syndrome (flushing and increased gut motility) or nonspecific symptoms of advanced disease (hepatomegaly, fever, weight loss, anorexia, malaise).