Chondrodysplasia-difference of sex development syndrome

A rare difference of sex development affecting 46,XY individuals and characterized by complete gonadal dysgenesis (normal external female genitalia, lack of pubertal development, primary amenorrhea, and hypergonadotrophic hypogonadism) in association with severe dwarfism with generalized chondrodysplasia (bell-shaped thorax, micromelia, brachydactyly). Other reported features in the live sibling included eye anomalies (hypoplastic irides, myopia, coloboma of optic discs), dysmorphic features (deep-set eyes, upslanting palpebral fissures, puffy eyelids, large ears and mouth, mild prognathism), muscular hypoplasia, mild intellectual deficiency and severe microcephaly with cerebellar vermis hypoplasia.


Chondroectodermal dysplasia with night blindness is a rare genetic bone development disorder characterized by proportionate short stature, nail dysplasia (enlarged, convex, hypertrophic nails), hypodontia and night blindness. Osteopenia, a tendency to present fractures, talipes varus with abnormal gait, ear infections, and watering eyes due to narrow tear ducts are frequently associated. Radiologically patients present delayed bone age on wrist X-rays, platyspondyly, and broad metaphyses of humeri with dense and thickened growth plates.


A rare bone tumor characterized by a benign lesion composed of lobules of spindle shaped or stellate cells and an abundant myxoid or chondroid matrix. The tumor may occur in almost any osseous location but is most common in long bones, in particular the proximal tibia and the distal femur. Pain is the most common presenting symptom. Prognosis is excellent even in cases with local recurrence.


Chondrosarcoma is a malignant bone tumor arising from cartilaginous tissue, most frequently occuring at the ends of the femur and tibia, the proximal end of the humerus and the pelvis; and presenting with a palpable mass and progressive pain. Chondrosarcoma is usually slow growing at low histological grades and can be well managed by intralesional curettage or en-block wide resection.


Chordoid glioma is an extremely rare glial neoplasm occurring in the region of the anterior third ventricle or hypothalamus, which is non-infiltrative and well-circumscribed and presents most frequently in middle-aged women with symptoms of memory loss and headaches and, because of its location, has a poor prognosis due to surgical morbidity.


Chordomas are rare malignant tumors arising from embryonic remnants of the notochord in axial skeleton.

Summary:
Epidemiology
They are predominantly found in adults, and comprise 0.2% of all central nervous system tumors and 2-4% of all primary bone neoplasms, with an estimated prevalence of 1 in 2 million people and a male-to-female ratio of 2:1.
Clinical description
The clinical presentation depends entirely on the location of the chordoma. The main possible locations are the sacrum, intracranially at the clivus and along the spinal axis. When the tumor is intracranial, the most common presenting symptoms are diplopia, swallowing problems and headache. Other neurologic signs also occur, primarily as cranial nerve palsies. Tumors in the spine can cause pain in the area of the tumor (neck, back or tailbone), as well as arm or leg pain, weakness or numbness, bladder and intestinal disturbances. Chordomas are characterized by slow growth, with local destruction of the bone and extension into the adjacent soft tissue. They can metastasize to lymph nodes, lungs, liver and bone.
Diagnostic methods
Diagnosis is made by radiography, computed tomography or magnetic resonance imaging.
Management and treatment
Treatment should be undertaken by expert neurosurgical and radiation oncology teams. Surgery is the primary mode of treatment but excision often remains incomplete despite repeat operations. Radiation in combination with surgery is then often used. High radiation doses (i.e. with proton beams) are required for local control. The role of chemotherapy or targeted therapies is still under investigation.
Prognosis
Prognosis depends on the extent and completeness of the tumor excision. Long-term follow-up is required because of the high rate of recurrence of these tumors.

                            Last update:
                            November 2006

                            - Expert reviewer(s):
                            Pr Ross PINKERTON


Chorea-acanthocytosis (ChAc) is a form of neuroacanthocytosis (see this term) and is characterized clinically by a Huntington disease-like phenotype with progressive neurological symptoms including movement disorders, psychiatric manifestations and cognitive disturbances.

Summary:
Epidemiology
Prevalence and incidence are not known, but it is estimated that there are around 1,000 cases worldwide. ChAc appears to be more prevalent in Japan, possibly due to a founder effect, and clusters have been found elsewhere in geographically isolated communities (e.g. French-Canadian population).
Clinical description
Onset is in early adulthood and the initial presentation is often subtle cognitive or psychiatric symptoms. However, patients may have developed related psychiatric disorders several years before neurological manifestations. In at least 1/3 of patients, seizures, typically generalized, are the first manifestation. In some cases, seizures may precede the appearance of movement disorders by as much as a decade. During the course, most patients develop a characteristic phenotype including chorea, a very peculiar ''feeding dystonia'' with tongue protrusion, orofacial dyskinesias, limb dystonia, involuntary vocalizations, dysarthria and involuntary tongue- and lip-biting. Gait may have a ''rubber man'' appearance with truncal instability and sudden, violent trunk spasms. Most patients develop generalized chorea and some degree of parkinsonism. Impairment of memory and executive functions is frequent. Psychiatric manifestations are common and may present as schizophrenia-like psychosis or obsessive compulsive disorder (OCD). Myopathy and axonal neuropathy are usually mild. Clinical neuromuscular manifestations include areflexia, sensorimotor neuropathy, and variable weakness and atrophy. ChAc usually progresses slowly over 15-30 years, but sudden death, presumably caused by seizures or autonomic involvement, may occur.
Etiology
ChAc is caused by various mutations in the VPS13A gene (9q21), coding for chorein. No obvious genotype-phenotype correlations have been observed.
Diagnostic methods
Diagnosis may be challenging. Presence of self-mutilating lip and tongue biting, or other self-mutilation is strongly suggestive of ChAc. Determination of acanthocytosis in peripheral blood smears may be negative and does not rule out the disorder. Serum CK is mostly elevated. Patients have absent chorein expression in erythrocytes on Western blot. Confirmatory DNA analysis of the VPS13A gene is difficult due to its size and heterogeneity of mutation sites. Electroneurography may demonstrate sensorimotor axonal neuropathy while electromyography shows neurogenic as well as myopathic changes. Electroencephalographic findings are not specific. Neuroradiologically, there is progressive striatal atrophy affecting especially the head of the caudate nucleus as well as impaired striatal glucose metabolism similar to that seen in HD.
Differential diagnosis
The differential diagnoses depend on the presenting symptoms and include McLeod neuroacanthocytosis syndrome, Huntington's disease, Huntington-like disorders, juvenile Parkinson's disease and Tourette's syndrome (see these terms).
Antenatal diagnosis
Routine methods for prenatal testing can be applied.
Genetic counseling
ChAc is an autosomal recessive disorder and genetic counseling is recommended. The risk of a sibling developing ChAc are 1:4. If the causative genetic defect is known, presymptomatic diagnosis in siblings at disease risk may be offered.
Management and treatment
No curative or disease-modifying treatments are currently available and management is purely symptomatic.
Prognosis
The course is usually relentlessly progressive and overall prognosis is poor. Sudden death may be due to seizures, or possibly autonomic dysfunction. There may be gradual generalized weakness with fatal aspiration pneumonia or systemic infections.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Hans JUNG


Choriocarcinoma of the central nervous system

A rare primary germ cell tumor of central nervous system characterized by a lesion typically in the region of the pineal gland and the suprasellar compartment, composed of cytotrophoblastic elements and multinucleated syncytiotrophoblastic giant cells. Ectatic stromal vascular channels, blood lakes, and extensive hemorrhagic necrosis are the rule. The tumor usually arises in the second decade of life and predominantly in males. Clinical presentation depends on location and size and includes signs of increased intracranial pressure, visual disturbances, and endocrine abnormalities. Prognosis is generally poor.


Choroid plexus carcinoma is a rare and highly aggressive malignant type of choroid plexus tumor (see this term) occurring almost exclusively in children, presenting with cerebrospinal fluid obstruction in the lateral ventricles (most common), the fourth and third ventricles or in multiple ventricles, leading to hydrocephalus and increased intracranial pressure, and manifesting with nausea, vomiting, abnormal eye movements, gait impairment, seizures and enlarged head circumference.


A rare ectodermal dysplasia syndrome, characterized by the association of choroidal atrophy (sometimes regional), together with other ectodermal dysplasia features including fine and sparse hair, absent or decreased lashes and eyebrows, and possibly mild visual loss and dysplastic/thick/grooved nails.


Choroideremia (CHM) is an X-linked chorioretinal dystrophy characterized by progressive degeneration of the choroid, retinal pigment epithelium (RPE) and retina.

Summary:
Epidemiology
The prevalence is estimated between 1/50,000-1/100,000.
Clinical description
Affected males experience nyctalopia in the first or second decade of life followed by peripheral visual field constriction with progression from annular scotomas to concentric visual field loss. Impairment in visual acuity is eventually noticed by mid-adulthood. In parallel, fundus changes are observed that consist initially of pigmentary stippling and focal areas of choroid atrophy in the equatorial fundus. In the final stage, there are extensive degenerative changes of the RPE with only remnants of the choroidal vasculature apparent in the macula, far peripheral retina, and near the optic disc. In the advanced stages, the sclera becomes visible on fundus examination in the areas of total choroidal and RPE atrophy. Female carriers generally show no serious visual impairment, but they can show conspicuous fundus abnormalities such as pigment changes in the periphery closely resembling the fine mottling characteristic of the initial stages of the disease in males.
Etiology
CHM is caused by mutations in the X-linked CHM gene encoding a Ras-related GTPase Rab escort protein (REP)-1. REP-1 is essential for the post-translational activation and subcellular localization of Rab GTP-binding proteins that control vesicle trafficking in secretory and endocytic pathways. Mutations in CHM leads to impaired association of Rab proteins with donor membranes, thus leading to cell death.
Diagnostic methods
The clinical diagnosis is based on the characteristic fundus appearance, defective dark adaptation, peripheral visual field loss, an electroretinogram pattern of rod-cone degeneration, and a family history consistent with X-linked inheritance. CHM genetic diagnosis includes mRNA and DNA CHM gene analysis to detect punctual mutations, deletions involving multiple and single exons, and in rare cases genomic rearrangements.
Differential diagnosis
Differential diagnosis includes retinitis pigmentosa (RP), Usher syndrome type 1, and gyrate atrophy of the choroid and retina (see these terms). X-linked RP is distinguished from CHM by the migration of pigment into the retina. Moreover, choriocapilar and retinal atrophy, leaving areas of bare sclera is only present in CHM. Usher syndrome type 1 is distinguished from CHM by the scalloped areas of significant chorioretinal degeneration that are only typical of CHM. Also, profound deafness and vestibular problems are very rare in CHM cases. Gyrate atrophy is distinguished from CHM by elevated plasma concentration of ornithine.
Antenatal diagnosis
Carrier testing for at-risk female relatives and prenatal diagnosis for pregnancies at increased risk are possible if the mutation has been identified in an affected family member.
Genetic counseling
CHM is inherited in an X-linked manner, with a carrier female having a 50% risk of transmitting the mutation to her offspring.
Management and treatment
Management includes periodic ophthalmologic examination to monitor progression of CHM or appearance of cataract, and the use of UV-blocking sunglasses. Treatment is not currently available but a gene therapy trial is ongoing.
Prognosis
The disease has a progressive course that leads to severely reduced visual acuity.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Carmen AYUSO  - Dr M. LOPEZ MARTINEZ  - Dr José María MILLÁN SALVADOR  - Dr M. PERAITA  - Dr Rosa RIVEIRO ALVAREZ  - Dr María José TRUJILLO TIEBAS


A rare developmental defect during embryogenesis characterized by intellectual deficit, ataxia, postnatal microcephaly, and hyperkinesis.

Summary:
Epidemiology
Christianson syndrome (CS) prevalence is estimated to affect 1 in 16,000 to 100,000 males worldwide.
Clinical description
Affected males diagnosed with CS typically present with the following core diagnostic features: nonverbal status, intellectual disability (ID), epilepsy, ataxia, postnatal microcephaly, and hyperkinesis. Seizures typically occur prior to the age of three. Secondary symptoms include behaviors associated with autism, Angelman syndrome features, eye movement problems (e.g. strabismus), hypotonia, gastroesophageal reflux disease (GERD), regressions (especially after the 1st decade of life), low height and/weight (progressing with age), and cerebellar vermal atrophy (particularly after the 1st decade). Females with heterozygous NHE6 mutations may present with a wide ranging phenotype ranging from unaffected to more severe neurologic/psychiatric manifestations.
Etiology
Christianson syndrome is caused by loss-of-function mutation of the SLC9A6 gene (Xq26.3), which encodes the endosomal Na+/H+ Exchanger 6 (NHE6) protein.
Diagnostic methods
CS diagnosis is confirmed by molecular genetic testing. Core diagnostic symptoms include nonverbal status, ID, epilepsy, ataxia, postnatal microcephaly, and hyperkinesis.
Differential diagnosis
Differential diagnoses include Angelman syndrome and ID (especially if it appears to follow an X-linked pattern).
Antenatal diagnosis
Prenatal genetic testing is possible if the familial mutation is known.
Genetic counseling
Genetic counseling is advised. Heterozygous females have a 50% risk of transmitting the pathogenic variant in pregnancy.
Management and treatment
Management of symptoms associated with seizures, ID/developmental delay, motor deficits, feeding difficulties, and/or eye problems is common. No specific treatment exists.
Prognosis
Progressive symptoms appear to progress as males age, especially after the 1st decade of life. These include regressions (e.g. walking, talking, and fine/gross motor skills), cerebellar atrophy, and low height/weight. Despite reports of premature mortality in CS males (i.e. ranging from approximately 20-50 years), life expectancy is currently unknown.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Eric MORROW


Chromomycosis is a chronic cutaneous and subcutaneous fungal infection, found mainly in subtropical and tropical areas (in soil and plant debris and transmitted by traumatic inoculation), and characterized clinically by slow growing, verrucous nodules, squamous plaques, or chronic limited lesions which are most commonly found on the lower limbs and which are characterized histologically by the presence of muriform cells. It is caused by dematiaceous fungi, with the main etiological agents being Fonsecaea pedrosoi, Phialophora verrucosa and Cladophialophora carrionii. Rarely, it can be caused by Rhinocladiella aquaspersa.


Chromophobe renal cell carcinoma is a rare subtype of renal cell carcinoma, originating from the intercalating cells of the collecting ducts and macroscopically manifesting as a well-circumscribed, highly lobulated, solid tumor that is usually diagnosed at an early stage. It is frequently asymptomatic, or may present with nonspecific symptoms, such as weight loss, fever or fatigue. The classic presentation observed in renal tumors (hematuria, flank pain and palpable mass) is occasionally observed and usually indicates an advanced stage of the disease. It is most frequently sporadic however, several familial cases, associated with Birt-Hogg Dubé syndrome, have been described.


A genetic male infertility characterized by azoospermia or oligozoospermia due to chromosome Y microdeletion.

Summary:
Epidemiology
Estimated prevalence is 1/2500.
Clinical description
The diagnosis is usually made in adulthood, in the context of a couple's infertility. The spermogram shows non-obstructive azoospermia or oligozoospermia of variable intensity, usually severe.
Etiology
5 to 10% of cases of azoospermia (absent sperm) or severe secretory-type oligospermia (<1 million spermatozoa/mL semen) are associated with microdeletions in the euchromatic portion of the Y-chromosome long arm, at the AZF locus (azoospermia factor). Several subregions are distinguished in the AZF locus. In this region, the structure of the Y-chromosome is rich in repeated palindromes and recombination between two flanking sequences sharing a high degree of homology leads to various deletions: i) AZFa deletions (recombination between the sequences HERV15yq1 and HERV15yq2); the rarest - ii) AZFb or P5/proximal-P1 deletions, iii) AZFb+c deletions, of which two types are distinguished: P5/distal-P1 or P4/distal-P1 and iv) AZFc deletions caused by recombination between palindromes b2 and b4.
Diagnostic methods
Diagnosis is made on the basis of azoospermia or oligozoospermia in otherwise healthy males after exclusion of other causes of infertility. Molecular diagnosis is made by PCR amplification of STS type sequences (sequence-tagged sites) from the AZFa, b, and c regions. AZFc deletions are the most frequent; they are associated with azoospermia or oligospermia, usually severe. Complete deletions of AZFa, AZFb+c and AZFb regions are always associated with azoospermia: testicular histology shows either total lack of germline cells (SCOS or Sertoli cell only syndrome) or more or less systematized arrested maturation of cells from the spermatogenetic cell lineage.
Differential diagnosis
The differential diagnosis includes multiple causes of non-obstructive azoospermia, the most frequent being 47,XXY syndrome, other genetic hypogonadisms like Kallmann syndrome, testis inflammation (orchitis), infectious diseases (i.e. mumps after puberty), treatment (cancer chemotherapy), cryptorchidism, etc. Recent studies have identified numerous variants in multiple genes leading to azoo- or oligozoospermia.
Genetic counseling
Most Y chromosome microdeletions are de novo. Transmission is Y-linked. In case of spontaneous or following assisted reproductive techniques, male offsprings will inherit the paternal deletion.
Management and treatment
All chromosome Y microdeletions do not necessarily lead to infertility: firstly, some deletions (especially some partial deletions) do not result in spermatogenesis defects; secondly, among men with severe oligospermia, some can father children without infertility treatment. Finally, when mature spermatozoa are found in the sperm or in the testicles, the infertility problem can be solved with medically assisted procreation techniques such as TESE (testicular sperm extraction)-ICSI (intracytoplasmic sperm injection). However, there is a risk of transmitting the microdeletion to every male infant.
Prognosis
The condition has no impact on life expectancy. Some patients may be psychologically impacted by learning that their infertility is due to a genetic abnormality.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Dr Florence FELLMANN  - Dr James LESPINASSE


Chronic actinic dermatitis (CAD) is an immunologically mediated photodermatosis usually observed in temperate climates and that typically develops in middle-aged to elderly males. CAD is characterized by eczematous and often lichenified pruritic patches and confluent plaques located predominantly on sun-exposed areas with notable sparing of eyelids, skin folds, and postauricular skin. It is often accompanied by multiple contact allergies and usually occurs in a background of either atopic, contact allergic, or seborrheic dermatitis, although it can occur de novo. Resolution of photosensitivity is reported in up to 50% of individuals after 15 years or more, with contact allergies persisting.


Chronic atrial and intestinal dysrhythmia syndrome

A rare genetic disease characterized by co-occurrence of sick sinus syndrome (manifesting as sinus bradycardia, often requiring pacemaker implantation) and chronic intestinal pseudo-obstruction (which may be of myogenic or neurogenic origin and usually requires total parenteral nutrition), with an age of onset within the first four decades of life. Other cardiac features, such as atrial flutter or fibrillation and valve anomalies, may also be present.


A pneumoconiosis, characterized by granulomatous inflammation, that occurs in individuals who develop beryllium sensitization (BeS), a cell-mediated immune response to environmental and occupational beryllium exposure. BeS precedes the lung disease that may present with chronic dry cough, fatigue, weight loss, chest pain, and increasing dyspnea.

Summary:
Epidemiology
The number of workers exposed to beryllium has been estimated at 1 million in the US, although no accurate figure exists for the US or globally. The prevalence of BeS in those exposed ranges from 1 - 20%. Chronic beryllium disease (CBD) among those with BeS ranges from 15-100%.
Clinical description
Patients with CBD can range from those who are asymptomatic to those with severe lung dysfunction. Manifestations occur a few months to many years after exposure to beryllium and include chronic dry cough, dyspnea on exertion, chest pain, fatigue, fever, night sweats and weight loss. Additional extrapulmonary manifestations of dermatitis and skin granulomas have been reported. Progressive pulmonary fibrosis can eventually lead to cor pulmonale and respiratory failure. An increased risk of lung cancer among workers exposed to high levels of beryllium has also been observed.
Etiology
CBD is caused by occupational or environmental exposure to beryllium and beryllium-containing alloys (usually by inhalation of dust or fumes but also via contact with skin). Over time, in a subset of individuals, a cell-mediated immune response to beryllium may occur, causing the development of sensitized T cells that accumulate within the lungs and eventually form granulomas which can lead to fibrosis. A genetic variant in the HLA-DPB1 gene (6p21.3) with the presence of a glutamic acid at amino acid position 69 has been associated with the development of BeS and CBD.
Diagnostic methods
Diagnosis is based on a history of exposure to beryllium, characteristic clinical findings and laboratory testing. BeS can be detected with the beryllium lymphocyte proliferation test (BeLPT). Chest x-ray, CT scan of the lungs, exercise tolerance testing and pulmonary function tests can also aid in the diagnosis. Sampling of the lung with for example bronchoscopy with biopsy and bronchoalveolar lavage is usually required to demonstrate granulomatous inflammation in the lungs and or sensitization to beryllium
Differential diagnosis
The main differential diagnoses are sarcoidosis (most common), hypersensitivity pneumonitis and tuberculosis as well as other occupational lung diseases (such as silicosis).
Management and treatment
There is no cure for CBD. Treatment involves recommendations for cessation of beryllium exposure as medically prudent, and the use of immunosuppressive therapies, such as corticosteroids (prednisone). Early symptomatic disease may be treated with inhaled corticosteroids along with a short acting bronchodilator. Methotrexate and other immunosuppressive therapies can reduce steroid side effects. The efficacy of corticosteroids may be limited and relapses can occur after cessation of therapy or when dose is lowered. Those with advanced disease and major breathing difficulties may require oxygen supplementation. In severe cases, a lung transplant may be suggested. Patients should refrain from smoking. CBD may be prevented by providing exposed workers with respiratory protective devices and protective clothing and by minimizing exposure through use of workplace administration and engineering controls. The BeLPT is used to identify patients early on and to define workplace areas for modification in order to ultimately reduce additional BeS and CBD cases.
Prognosis
Prognosis varies, with some patients remaining clinically stable for many years and some experiencing a gradual worsening of symptoms over time. A debilitating course resulting in respiratory failure is also possible but regular monitoring and treatment can slow down the disease process.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Dr Lisa MAIER


A rare neurologic disease characterized by the chronic consequences of bilirubin toxicity in the globus pallidus, sub-thalamic nuclei, and other brain regions, after exposure to high levels of unconjugated bilirubin in the neonatal period. Symptoms begin after the acute phase of bilirubin encephalopathy in the first year of life, evolve slowly over several years, and include mild to severe extrapyramidal disturbances (especially dystonia and athetosis), auditory neuropathy spectrum disorder, and oculomotor and dental abnormalities.


A form of cutaneous lupus erythematosus (CLE) that includes five different forms: discoid lupus erythematosus (DLE), chilblain lupus, hypertrophic or verrucous lupus erythematosus, lupus erythematosus tumidus, and lupus erythematosus panniculitis.


Chronic diarrhea due to glucoamylase deficiency

A rare intestinal disease characterized by impaired absorption of starch and short polymers of glucose due to primary small intestinal glucoamylase deficiency. Patients present in infancy or early childhood with chronic diarrhea, abdominal distention, and bloating. Levels of pancreatic amylase are typically normal, and histopathological analysis shows normal morphology of the intestinal mucosa.


Chronic diarrhea with villous atrophy is a rare, genetic gastroenterological disease characterized by the early onset of chronic diarrhea, vomiting, anorexia, lactic acidosis, renal insufficiency and hepatic involvement (mild elevation of liver enzymes, steatosis, hepatomegaly). Partial villous atrophy (with eosinophilic infiltration) is observed on intestinal biopsy. Although diarrhea may resolve, the development of neurologic symptoms (cerebellar ataxia, sensorineural deafness, seizures), retinitis pigmentosa and muscle weakness may complicate disease course and lead to death. There have been no further descriptions in the literature since 1994.


Chronic enteropathy associated with SLCO2A1 gene

A rare genetic gastroenterological disease characterized by the presence of multiple persistent, intractable ulcers of the small intestine, leading to chronic blood and protein loss. Signs and symptoms include abdominal pain, anemia, fatigue, edema, and diarrhea. Morphologically, the condition manifests with multiple sharply demarcated shallow lesions with irregular circular or linear shape.


A rare myeloproliferative neoplasm characterized by a clonal proliferation of eosinophilic precursors with persistent increase of eosinophils in peripheral blood and bone marrow, accompanied by increased blasts (<20%) or clonal cytogenetic or molecular genetic abnormalities. Cases with BCR-ABL1, PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 fusion, or rearrangement of PDGFRA, PDGFRB, or FGFR1, are not included in this entity. Infiltration of the liver and spleen, as well as a variety of other organs, is typical. Patients may present with constitutional symptoms and signs and symptoms of organ involvement, such as endomyocardial fibrosis, peripheral neuropathy, central nervous system manifestations, respiratory symptoms, or rheumatological findings. Acute transformation is common.


Chronic Epstein-Barr virus infection syndrome is a rare infectious disease characterized by familial, primary, chronic Epstein-Barr virus infection which typically manifests with persistent mononucleosis-like signs and symptoms, in the absence of secondary immunodeficiency.


A rare primary immunodeficiency, mainly affecting phagocytes, which is characterized by an increased susceptibility to severe and recurrent bacterial and fungal infections, along with the development of granulomas.

Summary:
Epidemiology
Chronic granulomatous disease (CGD) average worldwide birth prevalence is estimated between 1/100,000 and 1/217,000.
Clinical description
CGD can present at any age but is most commonly diagnosed before the age of 5 years. Manifestations include severe and recurrent infections most often due to a characteristic group of pathogens (including Staphylococcus aureus and Aspergillus spp) as well as granulomatous lesions mainly localized to the lung, lymph nodes, gastrointestinal tract and liver. Up to 50% of patients present with diarrhea, abdominal pain, and failure to thrive. Pneumonia, abscesses, cellulitis, adenitis and osteomyelitis are common. Mycobacterial diseases are usually limited to tuberculosis or regional and disseminated Bacillus Calmette-Guérin (BCG) infections. Invasive fungal infections are frequent. Dysregulated inflammation and granuloma formation can cause chorioretinal lesions, functional gastric outlet obstruction, inflammatory bowel disease (IBD), and wound dehiscence. Most female carriers are asymptomatic (unless >80% of their neutrophils are dysfunctional). Autoimmune disorders such as discoid lupus erythematosus and antiphospholipid syndrome can occur in some.
Etiology
CGD is caused by mutations in any one of the 6 genes encoding the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits or a critical stabilizer. A mutation in the CYBB gene (Xp21.1) is seen in 65% of cases in North America and Western Europe. The other 35% of cases are due to mutations in the CYBA (16q24), NCF1 (7q11.23), NCF2 (1q25), NCF4 (22q13.1) and CYBC1(17q25.3) genes. A deficiency in the NADPH oxidase enzyme complex leads to decreased production of reactive oxygen species (used by phagocytes to kill bacteria and fungi). The X-linked form of CGD typically presents with infection or IBD earlier than the NCF1-related form. To date, the NCF4-related form has only been associated with IBD but no severe infections.
Diagnostic methods
Diagnosis is suspected on clinical findings and confirmed by laboratory tests. Nitroblue tetrazolium (NBT) or dihydrorhodamine (DHR) oxidation assays measure the neutrophil superoxide production by the NADPH oxidase complex, which is absent or greatly reduced. Molecular genetic testing can be used to confirm the diagnosis and identify the specific subunit affected, but is not necessary unless gene therapy or allogeneic transplantation are anticipated. Immunoblot analysis can confirm the absence of the specific NADPH oxidase complex subunit involved.
Differential diagnosis
Differential diagnosis includes cystic fibrosis, Crohn disease, hyper-IgE syndrome, allergic bronchopulmonary aspergillosis, glutathione synthetase deficiency, and secondary hemophagocytic lymphohistiocytosis. Myeloperoxidase deficiency must also be excluded, as it gives a false positive for the DHR assay test.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a disease-causing mutation.
Genetic counseling
CGD follows an X-linked pattern of inheritance in those with a CYBB mutation. It can also be inherited autosomal recessively (due to CYBA, NCF1, NCF2, NCF4 and CYBC1 mutations). Genetic counseling is possible in families when a disease-causing gene has been identified.
Management and treatment
Antibacterial and antifungal prophylaxis is essential in preventing the infections seen in CGD. Lifelong daily doses of trimethoprim-sulfamethoxazole (antibacterial) and itraconazole (anti-fungal) are recommended. Interferon-gamma, 3 times weekly, is also recommended. Hematopoietic stem cell transplantation may be curative and is increasingly used. Gene therapy has been successful in a few cases and is expanding. In those with severe infections, granulocyte transfusions are sometimes used.
Prognosis
The prognosis has greatly improved with the use of antibacterial and antifungal prophylaxis therapy, with most patients living well into adulthood.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Dr Steven HOLLAND


Chronic hiccup is a rare movement disorder characterized by involuntary spasmodic contractions of the inspiratory muscles synchronized with larynx closure lasting for more than 48 hours.

Summary:
Epidemiology
The disorder is thought to affect approximately 1/100,000 individuals. Chronic hiccup affect males more often than females.
Clinical description
The involuntary spasmodic contractions of the inspiratory muscles followed by the rapid closure of the vocal cords known as hiccups usually last for no more than a few minutes or at most a few hours with spontaneous resolution, and can affect people of any age. In rare pathological cases, hiccups may last for more than two days (chronic /persistent hiccup). Recurrent episodes over long periods are also called chronic hiccup. Clinical repercussions of these episodes may include dehydration, weight loss and malnutrition due to difficulty eating, sleep disorders, depression and exhaustion.
Etiology
The hiccup is poorly understood. According to experimental data it is probably a coordinated ventilatory movement mixing bronchial ventilation, suction and deglutition components. Chronic hiccup is mainly an esophageal and gastric disorder. Other causes may include fever, brain lesions/tumors, cardiovascular disorders (stroke, myocardial infarction), renal failure, metabolic imbalance, peripheral nerve stimulation, or other injuries, drugs (chemotherapy, benzodiazepines, corticosteroids, barbiturates, morphine, and anesthetics), and alcohol. Other triggers include placement of medical instruments, certain foods and beverages, spices and tobacco. Cases also sometimes develop in a context of surgery (pleural, peritoneal or intracranial).
Diagnostic methods
Clinical diagnosis is usually straightforward given the nature of the involuntary spasms. Imaging or laboratory tests to identify the underlying cause should focus primarily on the esophagus.
Differential diagnosis
Hiccups are extremely specific and can rarely be mistaken for another condition.
Management and treatment
Many anecdotal treatments have been described with varying success. Management should ideally focus on identifying and treating the underlying cause, especially esophageal. No specific treatments have proven efficacy in the absence of controlled studies. Pharmacological approaches that have been attempted in cases where no gastroesophageal treatment works include baclofen, chlorpromazine, carbamazepine, haloperidol, metoclopramide, gabapentin, serotoninergic agonists, prokinetics, lidocaine, nifedipine, carvedilol and marijuana. Alternative therapy includes hypnosis and acupuncture. Phrenic nerve blockade is of little benefit since it yields only partial relief at the expense of respiratory insufficiency. Long-term treatment of the frequent esophageal cause can be very useful.
Prognosis
Persistent hiccups can reduce quality of life. Very long intractable disease may be debilitating.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Pr Jean CABANE


Chronic infantile diarrhea due to guanylate cyclase 2C overactivity

A rare, genetic, intestinal disease characterized by early-onset, chronic diarrhea and intestinal inflammation due to overactivity of guanylate cyclase 2C. Additional manifestations include meteorism, dehydration, metabolic acidosis and electrolyte disturbances. Intestinal dysmotility, small-bowel obstruction and esophagitis (with or without esophageal hernia), as well as irritable bowel syndrome (without severe abdominal pain) and Crohn's disease, are frequently associated.


Chronic inflammatory demyelinating polyneuropathy

A chronic monophasic, progressive or relapsing symmetric sensorimotor disorder characterized by progressive muscular weakness with impaired sensation, absent or diminished tendon reflexes and elevated cerebrospinal fluid (CSF) proteins.

Summary:
Epidemiology
Prevalence is about 1/200,000 children and 1-7/100,000 adults, but it is generally accepted that the frequency is underestimated.
Clinical description
Onset may occur at any age but is more common in the 5th and 6th decades. Main clinical manifestations include progressive symmetrical weakness in both proximal and distal muscles of lower and/or upper limbs with partial or complete recovery between recurrences, associated with impaired sensation and absent/diminished tendon reflexes. Disease course is relapsing in 30% of cases, chronic and progressive in 60%, and monophasic with full generally permanent recovery in 10%. In 5-30% of cases, cranial nerve dysfunction may occur. Neuropathic pain, respiratory muscle and sub-clinical CNS involvement have been reported. Autonomic system dysfunction can occur. Children have a more rapid onset, greater disability at the peak and a more frequent relapsing course. CIDP may be associated with hepatitis C, inflammatory bowel disease, lymphoma, HIV, organ transplant, melanoma, or connective tissue disorders.
Etiology
CIDP could be due to an immune reaction, resulting in segmental and multifocal demyelination that may induce axonal loss with time.
Diagnostic methods
To be diagnosed with CIDP, patients have to present a 2 month history of progression of demyelinating neuropathy (DN), some have a history of infection. CIDP may also appear more than 8 weeks after Guillain-Barré syndrome (GBS, so-called ``acute CIDP''; see this term). Diagnosis is based primarily on clinical and electrophysiological findings. The need for CSF examination and nerve biopsy depends on the level of clinical diagnostic certainty. When manifestations are present for at least 2 months, electroneuromyogram (ENMG) confirms the diagnosis if 3 of the following criteria are present on several nerves: partial motor-nerve (M-N) conduction blocks, reduced M-N conduction velocity, prolonged distal M-N and F-wave latencies. MRI may demonstrate gadolinium enhancement and proximal nerve/root enlargement. Elevated CSF proteins, with no cells, and demyelination/remyelination, often with inflammation, in nerve-biopsy specimens can provide additional supportive data. Biopsy is currently only recommended in cases of clinical suspicion of CIDP in which ENMG is not conclusive. CIDP should be suspected in virtually any multifocal or generalized neuropathy of unknown cause.
Differential diagnosis
Differential diagnoses include chronic acquired polyneuropathies (monoclonal gammopathies, diabetes, toxic neuropathies) or inherited neuropathies (Charcot-Marie-Tooth disease or transthyretin amyloid neuropathy; see these terms).
Management and treatment
The decision to treat depends on initial disease severity, age, general health status and potential contraindications to the 3 validated treatments: steroids, intravenous immunoglobulins (IVIg) or plasma exchanges. Patients with pure motor CIDP should be treated with IVIg rather than steroids. In milder forms, clinical observation and possibly steroid therapy (depending on ENMG results) are advised. Plasmapheresis or a combination of steroids and IVIg can be started if none of these treatments are effective. Refractory cases can be treated with intensive immunosuppression. The effect of interferon beta-1a and alpha, etanercept or rituximab remains uncertain. Neuropathic pain can be treated with antiepileptic medications or tricyclic antidepressants.
Prognosis
Quadriplegia, respiratory failure and death can occur but are rare. Patients may present residual symptoms that can lead to reduced quality of life. However long-term prognosis is usually good.

                            Last update:
                            December 2010

                            - Expert reviewer(s):
                            Pr Jean-Michel VALLAT


Chronic intestinal failure (CIF) is a chronic type of intestinal failure characterized by a nonfunctioning small bowel (that may be reversible or irreversal) where the body is unable to maintain energy and nutritional needs through absorption of food or nutrients via the intestinal tract (despite being metabolically stable) and which therefore necessitates long-term parenteral feeding. CIF may be the result of congenital digestive diseases (such as gastroschisis, atresia of small intestine), short bowel syndrome, intra-abdominal or pelvic cancer, or progressive and devastating gastrointestinal or systemic benign diseases (such as Crohn disease).


A rare and heterogeneous gastroenterological clinical syndrome characterized by recurrent symptoms of intestinal obstruction with radiological features of dilated small or large intestine in absence of any mechanical occlusive lesion. Permanent alterations in neural, muscular, or mesenchymal structures of the intestinal wall or its extrinsic neural control, chronically impair tonic and propulsive motor functions in one or more segments of the gut.

Summary:
Epidemiology
The incidence of the pediatric form of CIPO has been estimated ≤ 1/40,000 live births. In Japan, the prevalence of CIPO in children < 15 years of age was 1/270,000 and in adults with onset age > 15 years was 1/100,000 and 1/125,000 and the annual incidence was 1/476,000 and 1/435,000 in males and females, respectively.
Clinical description
Patients present with chronic abdominal pain and distention; in between, acute episodes of severe abdominal pain and vomiting suggest a mechanical obstruction. Patients have diarrhea due to small bowel bacterial overgrowth or constipation due to delayed transit. Weight loss results from malabsorption and inadequate food intake.
Etiology
CIPO is often associated with diseases in which treatment and prognosis are those of the underlying condition. In the remaining ''primary'' cases two subgroups can be recognized: those in whom CIPO is caused by an abnormal autoimmune/inflammatory response against neuromuscular structures of the gut and those in whom an inherited or de novo genetic mutation underlies the impairment of muscle, neural, or interstitial cell function. ACTG2 gene variants account for approximately 50% of the genetic cases. Other genes were reported, most of which in single-cases.
Diagnostic methods
Abdominal MRI or CT scan should confirm the chronic dilatation of the small or large intestine and should exclude a mechanical obstruction. Patients should therefore be investigated for the presence of numerous diseases that are associated with CIPO, such as Hirshsprung's disease, mitochondrial or paraneoplastic diseases, for the use of drugs that impair gastrointestinal motility, and for family history of similar symptoms. Esophageal, antroduodenal and anorectal manometry play a supportive role in the diagnosis; low amplitude contractions suggest a myopathic disorder whereas disorganized motor patterns suggest a neuropathic disorder. Full-thickness biopsies are usually not recommended but might be indicated to confirm an ongoing inflammatory visceral neuropathy or myopathy before starting immunotherapies. Genes that should be investigated in the case of CIPO include ACTG2, MYH11 and FLNA. Screening of TYMP and POLG should be considered in case of suspected mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The genetic screening of FLNA (NM_001110556.1) in the context of CIPO could be limited to exon 1, as pathogenic mutations resulting in a visceral phenotype are confined to the longer isoform, which is specifically expressed in intestinal smooth muscle cells.
Differential diagnosis
The differential diagnosis includes mechanical obstruction, acute colonic pseudoobstruction, enteric dismotility and slow transit constipation.
Antenatal diagnosis
Antenatal diagnosis of the ACTG2 mutation can be proposed when fetal bladder dilation is observed. Antenatal diagnosis of other genes is theoretically possible but has not been reported in the literature. Antenatal diagnosis is possible when a pathogenic variant has been identified in a family member with the disease.
Genetic counseling
Genetic counseling is recommended when cases of chronic intestinal pseudoobstruction are recurrent within the same family or when the physician suspects a genetic etiology.
Management and treatment
Management depends on the cause of the disorder, the extent and location of intestine involved, and the severity of symptoms. General measures include low residue diets, oral and/or enteral nutrition to prevent malnutrition, prokinetic agents (prucalopride), neostigmine or pyridostigmine to reduce intestinal dilatation and cycles of antibiotics to control bacterial overgrowth. Autoimmune/inflammatory forms might benefit from immunosuppressive treatments. Surgery should be avoided except in selected cases; ostomies can provide safe and effective detention of segmental bowel distention. Intestinal transplantation has become a therapeutic option in selected cases.
Prognosis
CIPO is a clinical syndrome characterized by disabling and potentially life-threatening complications over time. Treatment and long-term outcome is heterogeneous and often unsatisfactory.

                            Last update:
                            June 2024

                            - Expert reviewer(s):
                            Dr Guido BASILISCO  - Dr Margherita MARCHI


Chronic lymphoproliferative disorder of natural killer cells

A rare large granular lymphocyte leukemia characterized by persistent (> 6 months) natural killer cell lymphocytosis in the absence of clinical diagnosis of leukemia/lymphoma, autoimmune disease, or chronic viral infections. The clinical course is variable, but generally indolent. Patients often remain asymptomatic, or may present with clinical manifestations including vasculitic skin lesions, neutropenic infections, musculoskeletal symptoms, peripheral neuropathy, or splenomegaly.


A rare form of mast cell leukemia characterized by the presence of at least 20% mast cells in bone marrow aspirate smears but often mature mast cell morphology, low proliferation rate, and absence of organ damage and C findings (cytopenias, hepatomegaly, ascites, portal hypertension, splenomegaly, skeletal lesions, malabsorption). The disease course is less aggressive than in the acute form, although patients may later progress.


A rare primary immunodeficiency characterized by persistent, debilitating and/or recurrent infections of the skin, nails, and mucus membranes, mainly with the fungal pathogen Candida albicans.


Chronic myeloid leukaemia (CML) is the most common myeloproliferative disorder accounting for 15-20% of all leukaemia cases.

Summary:
Epidemiology
Its annual incidence has been estimated at between 1 and 1.5 cases per 100,000 and its prevalence at around 1 in 17,000.
Clinical description
The disease is typically triphasic with a chronic phase (CML-CP), accelerated phase (CML-AP) and blast phase (CML-BP). The majority of patients are diagnosed in the chronic phase and may be either asymptomatic (diagnosed through a routine white blood cell count) or present with fatigue, anaemia, weight loss, night sweats or splenomegaly.
Etiology
CML is characterised by the presence of the Philadelphia chromosome, an abnormality resulting from a balanced translocation between chromosomes 9 and 22 (t(9;22)(q34;q11.2)). This translocation generates a BCR/ABL gene fusion encoding a constitutively active tyrosine kinase. CML does not appear to be an inherited disease and the factors leading to predisposition for the disorder remain largely unknown.
Management and treatment
Although an allogeneic bone marrow transplant is viewed as the only curative treatment option, the prognosis for patients improved dramatically with the targeted development of imatinib mesylate. Imatinib mesylate is a competitive inhibitor of BCR/ABL tyrosine kinase activity and has held EU marketing authorisation as an Orphan drug for the treatment of CML since 2001.

                            Last update:
                            May 2007


A rare myelodysplastic/myeloproliferative neoplasm characterized by a spectrum of clinical, hematological, and morphological features, ranging from predominantly myelodysplastic to mainly myeloproliferative in nature, with blood monocytosis (> 1G/L, constituting > 10% of circulating leukocytes). Is it often associated with blood cytopenia and/or ''proliferative features'' (increased leukocyte counts, splenomegaly), with marrow dysplasia and risk of progression to acute myeloid leukemia (AML).

Summary:
Epidemiology
The global annual incidence is approximately 1/147,000 with an important male predominance. The median age at diagnosis is 70.
Clinical description
The clinical symptoms are a consequence of blood cytopenias, mainly anemia (e.g. fatigue, dyspnea, possible angina, etc.), and less often of thrombocytopenia (spontaneous bleeding) or myeloproliferation (splenomegaly, serous effusions, and other nonspecific symptoms). The disease is associated with a 30% risk of transformation into AML.
Etiology
The etiology is unknown in 90% of the cases. It has acquired causes for the remaining 10%, including previous treatment with chemotherapy or radiotherapy, and occupational exposure to benzene derivatives or ionizing radiation. Marrow cell analysis by NGS method shows at least one somatic myeloid-lineage associated mutation in 90% of the cases, especially epigenetic (TET2, ASXL1, IDH), spliceosome (SRSF2) or other genes mutations (RUNX, NRAS or KRAS).
Diagnostic methods
The diagnosis is based on the following features: 1) Blood count reveals persistent monocytosis (>1G/L of circulating monocytes) with monocytes representing >10% of leukocytes (with or without increased leukocytes to >10G/L) and ''myelemia'' (myelocytes, metamylocytes) with or without cytopenias: anemia, aregenerative and often macrocytic, with or without thrombocytopenia. Infiltration of the liver, spleen, lymph nodes, and other organs is common. 2) Bone marrow morphology (from aspirate or biopsy) is generally hypercellular, with dysplasia in one to three myeloid lineages, without (<5%) or with (5-20%) excess blasts, and usually monocytosis. 3) Immunophenotyping of circulating monocytes reveals >94% of classical monocytes (MO1, CD14++/CD16−). 4) Bone marrow cytogenetics reveals acquired clonal abnormality in 30 % of the cases, especially chromosome loss (-7) or gain (+8). 5) NGS analysis reveals somatic mutation(s) in > 90% of the cases, especially TET2, SRSF2, ASXL1, RUNX1, NRAS or KRAS, while TP53 mutations are rare.
Differential diagnosis
The differential diagnosis mainly includes typical or atypical chronic myeloid leukemia (CML).
Management and treatment
Management and treatment of patients depends on their risk stratification level (of progression into AML). High risk CMML patients should have allogeneic bone marrow transplantation when possible, and otherwise hypomethylating agent-based treatment (azacytidine, decitabine). Lower risk CMML patients need treatment of their anemia with erythropoietin or derivatives. Myeloproliferation is treated by hydroxyurea, and thrombocytopenia (which often has a peripheral component) by the usual treatments used in peripheral thrombocytopenia.
Prognosis
Prognosis depends on the types and importance of cytopenias, the marrow blast percentage, marrow cytogenetic abnormalities, proliferative features (mainly leukocyte count) and somatic mutations, accounted for in a CMML prognostic scoring system (CPSS) which separates patients into low and high risk of progression into AML.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Pr Pierre FENAUX | EuroBloodNet*

                                * European Reference Network


Chronic myeloproliferative disease, unclassifiable

A rare hematological neoplasm characterized by clonal proliferation of myeloid precursors in the bone marrow, blood and other tissues (spleen, liver), with clinical, morphological and molecular features ofmyeloproliferative neoplasms (MPN), failing to meet criteria of a specific MPN. The presentation is nonspecific and variable and often includes leukocytosis, thrombocytosis and anemia. Splenomegaly, hepatomegaly as well as fatigue, malaise or weight loss may appear in advanced stages.


A rare myeloproliferative neoplasm characterized by sustained peripheral blood neutrophilia, bone marrow hypercellularity due to neutrophilic granulocyte proliferation, and hepatosplenomegaly. Other organs may be infiltrated in addition. Microscopically, the bone marrow shows an increase in proportion of myelocytes and mature neutrophils, but no significant dysplasia in any of the cell lineages. Peripheral blood neutrophils are mostly segmented, although band forms may also be substantially increased. Cytogenetic abnormalities are absent in most cases. The disease is slowly progressive with progredient neutrophilia followed by anemia and thrombocytopenia. Transformation to acute myeloid leukemia may occur.


Chronic nonbacterial osteomyelitis/Chronic recurrent multifocal osteomyelitis

Chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), is a chronic autoinflammatory syndrome that is characterized by multiple foci of painful swelling of bones, mainly in the metaphyses of the long bones, in addition to the pelvis, the shoulder girdle and the spine.

Summary:
Epidemiology
Depending on the studies, prevalence of CNO/CRMO has been grossly estimated at between 1/ 160,000 to 1/ 2,000,000 and incidence at between 1/ 250,000 to 1/ 1,000,000. The disease affects predominantly females.
Clinical description
CNO/CRMO occurs mainly in children and adolescents with an average age of onset of 10 years old. It is characterized by the insidious onset of recurrent episodes of local pain, tenderness, or swelling at the areas of bone inflammation. Inflammation can occur at any site of the skeleton. Metaphyses and epiphyses of the long bones are most frequently affected, in addition to the pelvis, the shoulder girdle and the spine. The neurocranium is almost never affected. Pain occurs predominantly during day hours, but may also be present at night time. The symptoms may induce a limited range of motion, since joints may be affected by arthritis. The severity and time course may vary widely among patients, oscillating between acute exacerbations and spontaneous remission. Systemic manifestations like fever, malaise, weight loss are frequent and the disease may be associated with inflammatory disorders of the skin such as psoriasis vulgaris, palmoplantar pustulosis, acne, pyoderma gangrenosum and rarely Sweet's syndrome, and /or of the intestine, like Crohn's disease, or ulcerative colitis. Adult-onset forms are reported that resemble SAPHO syndrome. It is not clear whether SAPHO syndrome and CNO/CRMO are two separate entities or if they are part of the same disease spectrum with CNO/CRMO being the pediatric equivalent of SAPHO syndrome.
Etiology
The exact pathogenetic mechanism is unknown. An infectious origin is excluded as no apparent infectious agents are detectable at the site of the bone lesion. A genetic component is suspected for CNO/CRMO susceptibility. Immune dysregulation, particularly of the IL-10 and also the IL-1 pathway function, may play a role in the etiology of the disease.
Diagnostic methods
Diagnosis is based on a combination of clinical, radiological and histological exams. The classic findings on magnetic resonance imaging (MRI) are initial bone edema, generally followed by osteolytic or sclerotic, then hyperostotic bone lesions, as well as periosteal and soft tissue reaction. Bone lesion biopsies are typically sterile, and along with blood tests and an extensive microbial workup, show nonspecific inflammatory changes.
Differential diagnosis
Differential diagnosis includes mainly acute or subacute bacterial osteomyelitis, juvenile idiopathic arthritis, hypophosphatasia, Langerhans cell histiocytosis, and malignancies like osteosarcoma, Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, leukemia, and lymphoma. Rare monogenetic syndromes with CNO/CRMO as a component must also be excluded, such as Majeed syndrome, PAPA syndrome and DIRA syndrome (sterile multifocal osteomyelitis with periostitis and pustulosis).
Genetic counseling
Most cases are sporadic.
Management and treatment
Non steroid anti-inflammatory drugs (NSAIDs) are the treatment of choice. Oral steroids, bisphosphonates and TNFα blockers can be used as an alternative treatment in cases unresponsive to NSAIDs, or during flares and in order to prevent relapses. The anti-inflammatory action of azithromycin may also contribute to a positive clinical therapeutic effect.
Prognosis
The disease is characterized by alternating periods of remission and relapse, but generally has a ''benign'' course and can eventually resolve. In some cases, bone deformities may occur that can induce long-term disabilities (e.g. vertebra plana, hyperostosis, pain syndrome). Long term evolution towards spondyloarthropathy has been described.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Pr Hermann GIRSCHICK


Chronic pneumonitis of infancy is a rare pediatric form of interstitial lung disease (ILD, see this term).

Summary:
Epidemiology
Prevalence of this disease is not known.
Clinical description
The clinical and radiologic features are similar to those observed in other forms of ILD (cough, tachypnea, and infiltrative opacities on chest imaging). Specific histological abnormalities include diffuse thickening of alveolar septa, hyperplasia of type 2 alveolar epithelial cells (AEC), and presence of primitive mesenchymal cells within the alveolar septa. In some cases, foci of pulmonary proteinosis-like material have been observed in air spaces.
Prognosis
The prognosis is poor with a high mortality rate.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr Annick CLEMENT


Chronic primary adrenal insufficiency (CPAI) is a chronic disorder of the adrenal cortex resulting in the inadequate production of glucocorticoid and mineralocorticoid hormones.

Summary:
Epidemiology
It is a rare disease with a prevalence of about 1/ 7, 100 and an annual incidence of about 1/ 250, 000 in Western populations.
Clinical description
Disease onset peaks around 40 but can occur at any age. It presents insidiously with nonspecific symptoms that can be mistaken for other more prevalent conditions. Common manifestations include fatigue, loss of energy, malaise, weight loss, nausea, anorexia (failure to thrive in children), muscle and joint pain. Pigmentation of skin and mucous membranes (darkening of the skin especially in the palmar creases, knuckles, scars, oral mucosa and sites of friction) is a cardinal sign of CPAI. Symptoms of postural hypotension and hypoglycemia are late manifestations. Patients may also crave salt. Vitiligo (see this term) and alopecia areata are often present when an autoimmune disorder is the cause. CPAI also causes dehydroepiandrosterone deficiency causing additional symptoms seen only in women (loss of axillary/pubic hair, absence of pubarch in children, reduced libido and dry skin). Acute adrenal insufficiency (AAI; see this term) can occur if treatment is not followed or during precipitating illnesses and is a life threatening medical emergency.
Etiology
The most common cause of CPAI in the developed world is Addison disease (AD; see this term), also known as autoimmune adrenalitis , seen in 80%-90% of cases. Autoimmune adrenalitis can be isolated or seen as part of an autoimmune disorder (autoimmune polyendocrine syndrome type 1, 2 or 4; see these terms). Infiltrative disorders are another cause of CPAI and include tuberculosis (see this term), fungal infections and AIDS-associated opportunistic infections. Genetic disorders (i.e. congenital adrenal hyperplasia; see this term), tumors, and treatment with certain drugs are other less common causes.
Diagnostic methods
Biochemical tests are needed to diagnose CPAI. Early morning serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels are measured. Plasma ACTH is much higher in individuals with CPAI (>22 pmol/L) and morning serum cortisol levels are usually low (<83nmol/L) but can fluctuate. A stimulation test observing the cortisol response to exogenous ACTH is a useful tool in confirming a diagnosis. In healthy subjects serum cortisol concentrations increase (>500 nmol/L) after exogenous ACTH administration but no increase is seen in CPAI patients. Raised plasma ACTH levels confirm adrenal origin of the disease.
Differential diagnosis
Secondary adrenal insufficiency needs to be eliminated. Causes include pituitary tumors (see this term), lymphatic hypophystitis, pituitary tuberculosis and sarcoidosis (see this term), all of which are differential diagnoses.
Management and treatment
Management is life-long and requires a multidisciplinary team. Glucocorticoid replacement with oral hydrocortisone (10-25 mg daily taken in 2-3 doses) is given to mimic physiological cortisol secretion patterns. Oral fludrocortisone is given to replace mineralocorticoid hormones. Dehydroepiandrosterone replacement is optional. Glucocorticoid levels can be adjusted during times of stress to prevent AAI. The dose of hydrocortisone is maintained on the basis of clinical assessment and responses, taking into account a patient's well-being and presence of signs of over-replacement or under-replacement. An assessment of plasma renin activity is helpful in optimizing the dose of fludrocortisone. Growth and development in children must be monitored. Patients should carry a ready to inject hydrocortisone preparation and wear a medical alert card, in case of adrenal crisis.
Prognosis
There is no cure for CPAI but with proper treatment and care taken to prevent AAI there is no decrease in life expectancy. CPAI is only life threatening when ignored.

                            Last update:
                            November 2012

                            - Expert reviewer(s):
                            Dr Anne BACHELOT


Chronic relapsing inflammatory optic neuritis

A rare inflammatory optic neuropathy characterized by severe and persistent pain followed by subacute visual loss, a relapsing-remitting course, and steroid-dependence. Involvement of both optic nerves is common and is usually sequential. Serum antibodies against aquaporin 4 are absent in most cases. Magnetic resonance imaging shows contrast enhancement of the acutely inflamed optic nerves.


Chronic respiratory distress with surfactant metabolism deficiency is a rare, genetic, primary interstitial lung disease with a highly variable clinical presentation, ranging from neonatal respiratory distress syndrome to mild to severe interstitial lung disease (typical symptoms include cough, tachypnea, hypoxia, clubbing, crackles, failure to thrive). Lung biopsy reveals diffuse alveolar damage, interstitial thickening with inflammatory infiltrates, fibroblast proliferation, collagen deposition, and multiple foci of fibrosis, alveolar type II cell hyperplasia, abundant foamy alveolar macrophages and granular lipoproteic material in the alveolar lumen. Imaging shows cystic spaces and ground-glass opacities that are typically homogenously diffuse.


A rare complication of acute pulmonary embolism (PE), either symptomatic or not, that is characterized by fibrotic intravascular material occlusion of pulmonary arteries in combination with a secondary microvasculopathy of vessels less than 500 µm. The consequence is an increase in pulmonary vascular resistance (PVR) and progressive right heart failure.

Summary:
Epidemiology
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease but the true prevalence is difficult to evaluate since the disease is potentially underdiagnosed. Epidemiological analysis of CTEPH in different countries estimate incidence ranging from 1/20,000-33,000 in the USA and Europe. CTEPH is usually considered as a complication of pulmonary embolism (PE), since 50-75% of patients have a history of PE and from a large meta-analysis, the weighted pooled incidence of CTEPH after an episode of PE is estimated at 0.56-3.2%.
Clinical description
Patients commonly present with progressive dyspnea on exertion with or without signs of right heart dysfunction. A period between the initial event (acute PE) and the development of clinical signs is common and may last from a few months to many years (median time of 14 months between symptom onset and diagnosis in expert centers).
Etiology
The pathophysiology of CTEPH is assumed to be associated with obstruction of pulmonary arteries by unresolved organized fibrotic clots and a secondary microvasculopathy in pulmonary vessels of less than 500 µm in diameter. The underlying causes of the disease remain unknown.
Diagnostic methods
The diagnosis of CTEPH is suspected when ventilation/perfusion (VQ) lung scan shows mismatched perfusion defects and echocardiography shows high or intermediate probability of pulmonary hypertension (PH). The diagnosis is confirmed by right heart catheterization and pulmonary vascular imaging including CT pulmonary angiography (CTPA) and/or digital subtraction angiography (DSA) which should be performed in expert centres after at least 3 months of effective anticoagulation in order to discriminate this condition from PE. Specific diagnostic signs for CTEPH seen by multidetector CTPA or DSA include ring-like stenoses, webs/slits and chronic total occlusions (pouch lesions or tapered lesions).
Differential diagnosis
Differential diagnosis includes idiopathic pulmonary artery hypertension, Takayasu arteritis, congenital proximal interruption of a pulmonary artery, tumor thrombus, Von Recklinghausen disease, Osler-Weber-Randu disease or, very rarely, primary sarcoma of the pulmonary artery, and right heart failure with acute pulmonary thromboembolism.
Management and treatment
Patients should be treated with lifelong anticoagulation. In addition, three treatment options have been successfully developed: pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and PH medications. PEA is the treatment of choice for operable patients. Operability is determined by multiple factors including surgical accessibility of the organized thrombi and comorbidities which are assessed during a multidisciplinary meeting in expert centres. Non-operable patients should be treated by PH-targeted therapy with or without BPA. Monotherapy with riociguat is currently the standard-of-care in inoperable CTEPH or persistent/recurrent PH after PEA. More recently, subcutaneous treprostinil, a prostacyclin analogue, has been also approved for the treatment of patients with inoperable CTEPH or persistent/recurrent PH after PEA. Other PH medications or oral combination therapy may be used off-label. Eligibility for BPA depends on the location and type of lesions which are also assessed through a multidisciplinary team approach and many expert centres use PH-targeted therapy prior to BPA to improve its safety by optimizing pre-BPA pulmonary hemodynamics. Multimodality treatment approach needs to be confirmed by further studies and is currently considered in selected patients after multidisciplinary team assessment in expert centers.
Prognosis
Prognosis depends on several factors such as operability, hemodynamic impairment and patient's comorbidities. A survival of 89% at 3 years and 72% at 10 years was reported in operated patients. Encouraging observations on improved survival with BPA and PH-targeted therapy in the inoperable CTEPH population have been observed but long-term results are missing.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                            Dr Xavier JAIS  - Dr Mitja JEVNIKAR


Chronic visceral acid sphingomyelinase deficiency

A rare autosomal recessive, chronic, acid sphingomyelinase deficiency characterized clinically by onset in childhood with hepatosplenomegaly, growth retardation, interstitial lung disease and absence of neurodegenerative disorders.

Summary:
Epidemiology
Epidemiological data is not available specifically for Niemann-Pick disease type B (NPD-B); however, the estimated birth prevalence of acid sphingomyelinase deficiency (both NPD types A and B combined) is between 1/167,000-250,000 in Europe.
Clinical description
NPD-B is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, osteopenia, and atherogenic lipid profile. Most patients are diagnosed in infancy or childhood. The degree of hepatosplenomegaly ranges from mild to massive. Those with significant organomegaly have hypersplenism with secondary thrombocytopenia. Pulmonary involvement is common in affected individuals of all ages. Most affected individuals have evidence of interstitial lung disease. Abnormal linear growth and delayed skeletal maturation are common in children and adolescents, and can result in significant short stature in adulthood. A proatherogenic lipid profile is seen early in the disease course and some patients develop coronary artery disease. Neurologic manifestations occur infrequently and most of patients had minor and non-progressive findings. Up to one third of individuals with NPD-B have a cherry-red macula.
Etiology
NPD-B is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene (locus 11p15.4), leading to decreased activity of acid sphingomyelinase (ASM), which results in lysosomal accumulation of sphingomyelin (SM) and secondary elevation of cholesterol and other lipids.
Diagnostic methods
The diagnosis of NPD-B is established by detection of biallelic pathogenic variants in SMPD1 and/or residual acid sphingomyelinase enzyme activity (in peripheral blood lymphocytes, cultured skin fibroblasts or dry blood spots (DBS)). The de-acylated form of sphingomyelin (lyso-SPM) is increased in NPD-B and could be measured in plasma and DBS. Histology shows lipid-laden macrophages (foam-cells) in the bone marrow.
Differential diagnosis
Differential diagnosis includes other lysosomal storage diseases such as Gaucher disease, GM2-gangliosidosis, Niemann-Pick disease type C, lysosomal acid lipase deficiency, hematological malignancy, and primary hepatic disease (e.g., fatty liver, autoimmune, chronic hepatitis B-related, cryptogenic cirrhosis).
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is possible by testing of ASM enzyme activity or by DNA- analysis if both SMPD1 pathogenic variants in the family are known.
Genetic counseling
NPD-B is inherited in an autosomal recessive manner. Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Currently, only supportive care is available for patients with NPD-B and includes management of coagulopathy and end-stage liver disease manifestations; supplemental oxygen for symptomatic pulmonary disease, and treatment of hyperlipidemia and osteopenia/osteoporosis. Enzyme replacement therapy (ERT) with recombinant human acid sphingomyelinase is in clinical development for the treatment of the non-neurologic manifestations of the disease.
Prognosis
Patients with NPD-B may live till late childhood or early adulthood. However, they develop many complications of the disease, significantly affecting the quality of life. The leading cause of death is progressive loss of pulmonary function.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Ekaterina ZAKHAROVA


CHST3-related skeletal dysplasia is a very rare bone disorder characterized clinically by short stature of prenatal onset; dislocation of the knees, hips or elbows; club feet; limitation of range of motion of large joints; progressive kyphosis; and occasional scoliosis. In a few patients, minor heart valve dysplasia has also been described. Intellect, vision and hearing are normal.


Chudley-McCullough syndrome is a rare, genetic, syndromic deafness characterized by severe to profound, bilateral, sensorineural hearing loss (congenital or rapidly progressive in infancy) associated with a complex brain malformation including hydrocephalus, varying degrees of partial corpus callosum agenesis, colpocephaly, cerebral and cerebellar cortical dysplasia (bilateral medial frontal polymicrogyria, bilateral frontal subcortical heteropia) and, in some, arachnoid cysts. Major physical abnormalities or psychomotor delay are usually not associated.


Chuvash erythrocytosis is a rare, genetic, congenital secondary polycythemia disorder characterized by increased hemoglobin, hematocrit and erythropoietin serum levels and normal oxygen affinity, which usually manifests with headache, dizziness, dyspnea and/or plethora. Patients present an increased risk of hemorrhage, thrombosis and early death.


Chylomicron retention disease (CRD) is a type of familial hypocholesterolemia characterized by malnutrition, failure to thrive, growth failure, vitamin E deficiency and hepatic, neurologic and ophthalmologic complications.

Summary:
Epidemiology
About 55 cases have been described to date.
Clinical description
Chylomicron retention disease manifests in infancy or early childhood. Features include an abnormal lipid profile, failure to thrive, chronic malabsorptive diarrhea, vomiting and abdominal distension in early infancy (1-6 months), and vitamin E deficiency. Cardiomyopathy and muscular manifestations have also been described. Essential fatty acid (EFA) deficiency is especially severe early in life. Poor mineralization and delayed bone maturation can occur. Hepatic steatosis is common and hepatomegaly is reported to occur in about 20% of CRD patients. Neurologic complications (areflexia, ataxia, myopathy, sensory neuropathy) and ophthalmologic complications (minor visual abnormalities) are less severe in CRD than in other types of familial hypocholesterolemia.
Etiology
The SAR1B gene has been identified as the cause of CRD. More than 14 different mutations in about 30 patients have been described. This gene encodes the Sar1b protein, which is involved in the transport of chylomicrons (carriers of dietary lipids) from the endoplasmic reticulum to the Golgi apparatus. This mutation results in accumulation of pre-chylomicron transport vesicles in the cytoplasm of enterocytes. Genotyping has revealed that Anderson's disease and CRD are in fact the same condition.
Diagnostic methods
Diagnosis is often delayed because symptoms are nonspecific and hypocholesterolemia may be attributed to malnutrition secondary to chronic diarrhea. Diagnosis is based on a history of chronic diarrhea with fat malabsorption and a characteristic abnormal lipid profile: generally a 50% decrease in total cholesterol, LDL-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) in the presence of normal triglycerides. Upper endoscopy and histology reveal fat-laden enterocytes. Elevated creatine kinase (CK) in patients with hypocholesterolemia may be suggestive of CRD. Genotyping makes it possible to identify the SAR1B gene mutations. Parental lipid screening may clarify the diagnosis. An absence of hypocholesterolemia in both parents favors CRD. Consanguinity is frequent in patients with the disorder.
Differential diagnosis
Differential diagnosis includes abetalipoproteinemia and other genetic hypocholesterolemias characterized by decreased LDL-C, such as homozygous hypobetalipoproteinemia (HBL; see these terms), and acquired disorders associated with low HDL-C.
Genetic counseling
The disease follows an autosomal recessive pattern of inheritance.
Management and treatment
Follow-up should be directed toward monitoring nutrition and growth, and treatment compliance. Management should focus on prevention and early detection of complications (hepatic, neuromuscular, retinal and bone). Control of vitamin E deficiency plays a key role in preventing neurological complications. Treatment includes fat-soluble vitamin supplements and large amounts of vitamin E. Vitamin A, in combination with vitamin E, may help to prevent ophthalmologic complications. Early vitamin D treatment makes it possible to prevent osteopenia. Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet. Dietary counseling is needed not only to monitor fat intake and improve symptoms, but also to maintain sufficient caloric and EFA intake.
Prognosis
Very long-term follow-up into adulthood is poorly documented.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Pr Emile LEVY


Chylous ascites is a rare form of ascites caused by accumulation of lymph in the peritoneal cavity, usually due to intra-abdominal malignancy, liver cirrhosis or abdominal surgery complications, and present with painless but progressive abdominal distension, dyspnea and weight gain.


Chédiak-Higashi syndrome (CHS) is a rare severe genetic disorder generally characterized by partial oculocutaneous albinism (OCA, see this term), severe immunodeficiency, mild bleeding, neurological dysfunction and lymphoproliferative disorder. A classic, early-onset form and an attenuated, later-onset form (Atypical CHS; see this term) have been described.

Summary:
Epidemiology
Exact prevalence is difficult to determine; fewer than 500 cases have been reported. Many patients likely remain undiagnosed because of variability in clinical signs. No gender or ethnic predilection has been found.
Clinical description
Patients with CHS mostly have partial OCA involving the hair, skin, and eyes. Reduced iris pigmentation may be associated with nystagmus, and visual acuity may be impaired. Infections that are predominantly bacterial, but also of viral or fungal origin, begin to occur in infancy and may be severe, affecting primarily the skin and upper respiratory tract. Periodontitis has often been reported. Manifestations of increased bleeding tendency are generally mild and include epistaxis, gum bleeding and easy bruising. Cognitive deficits are often noted in childhood. Most patients develop neurological features by early adulthood as the disease progresses including ataxia, tremor, absent deep-tendon reflexes, and peripheral neuropathy. Some patients have Parkinsonian features with bradykinesia and rigidity. About 85% of CHS patients develop the accelerated phase, a lymphoproliferative disorder which involves fever, anemia, neutropenia, and occasionally thrombocytopenia, as well as lymphadenopathy and hepatosplenomegaly.
Etiology
Loss-of-function mutations in the LYST lysosomal trafficking regulator gene (1q42.1-q42.2) are associated with the severe, childhood-onset form of CHS. Missense mutations appear to underlie the atypical form.
Diagnostic methods
Diagnosis is suspected in individuals with partial OCA, a history of severe or frequent infections, and minor bleeding tendency. The main criterion is peroxidase-positive giant inclusions in white blood cells identified on the peripheral blood smear. Deficiency of platelet-dense bodies found via whole-mount electron microscopy is also characteristic. Molecular genetic testing supports diagnosis.
Differential diagnosis
Differential diagnoses include oculocutaneous albinism, Hermansky Pudlak syndrome (specifically HPS-2 caused by mutations in AP3B1), Cross syndrome and Griscelli disease (see these terms).
Antenatal diagnosis
Prenatal diagnosis of CHS is available clinically by amniocentesis or chorionic villus sampling and requires prior identification of the genetic mutation in the family.
Genetic counseling
CHS follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to asymptomatic carriers and to affected adults.
Management and treatment
The hematological and immunological manifestations can be treated by allogenic hematopoietic stem cell transplantation (HSCT) upon diagnosis. HSCT is more successful when performed before the accelerated phase, but does not alter progression of neurological dysfunction. Management of the acceleration phase involves combination therapy with etoposide, dexamethasone, and cyclosporine (the same as for familial hemophagocytic lymphohistiocytosis (HLH); see this term). Infections should be treated promptly with antibiotics or antivirals and exposure to infectious agents avoided. Desmopressin can be used for bleeding prophylaxis. Standard therapeutic measures should be adopted to improve visual acuity and to manage neurological manifestations. Patients should use sunscreen and wear protective UV sunglasses.
Prognosis
Without treatment, prognosis is very poor. Primary causes of mortality in the first 10 years of life are development of the accelerated phase and overwhelming infection. Neurologic manifestations occur in individuals despite bone marrow transplantation.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Dr Wendy INTRONE


CIDEC-related familial partial lipodystrophy

A rare, genetic lipodystrophy characterized by abnormal subcutaneous fat distribution, resulting in preservation of visceral, neck and axilliary fat and absence of lower limb and femorogluteal subcutaneous fat. Additional clinical features are acanthosis nigricans, insulin-resistant type II diabetes mellitus, dyslipidemia, and hypertension, leading to pancreatitis, hepatomegaly and hepatic steatosis.


A rare, genetic, cryopyrin-associated periodic syndrome (CAPS) characterized by neonatal onset of systemic inflammation, urticarial skin rash and arthritis/arthralgia resulting in severe arthropathy and central nervous system involvement (including chronic aseptic meningitis, brain atrophy and sensorineural hearing loss).

Summary:
Epidemiology
Whilst the exact prevalence of chronic infantile neurological, cutaneous, and articular (CINCA) syndrome is unknown, it is estimated that the whole spectrum of CAPS has a prevalence of 1/360,000 in France, CINCA being the less common form. In the Eurofever registry, collecting information on over 250 patients with NLRP3 mutation, about 25% of the patients present the most severe CINCA phenotype.
Clinical description
Disease onset typically occurs within the first hours/days of life with an urticarial rash, persistent elevation of acute phase reactants, and intermittent fever (which may be low-grade or absent). Typical facial features include frontal bossing and saddle back nose. The rash is typically non-pruritic and changes distribution during the day, without vasculitic alterations. Central nervous system manifestations include chronic aseptic meningitis, which, if left untreated, leads to brain atrophy, severe intellectual disability and sensorineural hearing loss. Typical neurological symptoms include chronic irritability, headache, early morning nausea, vomiting and, rarely, seizures. Ocular manifestations may include conjunctivitis, papilledema, optic nerve atrophy and progressive vision loss. Early degenerative arthropathy frequently involves large joints and causes deformities and contractures.
Etiology
Mutations (usually de novo ) in the NLRP3 gene (chromosome 1q44) are identified in the majority of patients; however 30-35% of affected individuals lack a detectable mutation. Most of these patients display a somatic mosaicism for NLRP3. The NLRP3 gene plays a key role in innate immunity, encoding a component of the NLRP3-inflammasome, with gain of function mutations leading to overproduction of interleukin 1beta (IL-1beta).
Diagnostic methods
The general consensus is that the clinical picture of CINCA is sufficient for diagnosis. Laboratory analyses document a nonspecific inflammatory syndrome with anemia, granulocyte hyperleukocytosis, elevated erythrocyte sedimentation rate (ESR) and elevated concentrations of C reactive protein. No autoantibodies or immune deficiencies are detected. Skin biopsy shows a neutrophilc dermatosis with massive perivascular neutrophil infiltration without signs of vasculitis. Brain MRI shows evident signs of meningitis with a possible inflammatory involvement of the inner ear. Ophthalmological examination may reveal papilledema. Genetic testing usually detects de-novo NLRP3 mutations but is not obligatory for diagnosis. In the absence of a positive standard genetic test, NLRP3 somatic mosaicism should be investigated
Differential diagnosis
An infectious disease is often suspected at disease onset. CINCA should be differentiated from similar monogenic or multifactorial autoinflammatory diseases, including, systemic onset juvenile idiopathic arthritis, tumor necrosis factor receptor 1 associated periodic syndrome, and the severe form of mevalonate kinase deficiency, CANDLE syndrome as well as the milder phenotype associated to mutations of NLRP3 (familial cold urticarial and Muckle-Wells syndrome).
Genetic counseling
The pattern of inheritance is autosomal dominant. Affected patients carrying a germinal mutation have a 50% risk of transmitting the disease to each child. In case of somatic mosaicism, risk depends on the possible presence of somatic mutations in reproductive organs of the parents.
Management and treatment
Therapeutic approaches using numerous anti-inflammatory drugs and immunosuppressants have provided disappointing results. Corticosteroids can partially improve the symptoms but at the cost of high toxicity. Anakinra (a receptor antagonist of interleukin-1) and canakinumab (a monoclonal antibody against IL-1beta) have proved to be efficient against inflammatory signs, as well as against intracranial hypertension and hearing loss.
Prognosis
Without adequate and timely treatment, quality of life is often poor. Syndrome severity is wide-ranging and the functional prognosis depends on the degree of neurological manifestations (such as intellectual disability and hearing loss) and the occurrence of tendinous retractions.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Marco GATTORNO


A rare acquired epidermal dysplasia characterized by annular, well-circumscribed patches of erythematous depressed skin.

Summary:
Epidemiology
So far, it has been reported in a little over 110 patients, but the condition is likely to be underdiagnosed as it was only recognized in 2002. The majority of reported patients are middle-aged or elderly women in the United States, Japan, and Spain, but cases have also been reported in other European and Asian countries.
Clinical description
The lesions are well-circumscribed, usually round and measuring 5-15 mm in diameter, erosion-like plaques that generally occur on the palms or soles and are usually solitary, although a few patients have been reported with two or more lesions. These lesions are asymptomatic but may be mildly pruritic, tender or painful.
Etiology
The etiology is unknown; the lesions may result from a disordered epidermal differentiation or desquamation process. Exceptional congenital cases have been reported.
Diagnostic methods
Accurate diagnosis requires histopathological analysis. The characteristic features are a decrease of the horny layer's thickness with a sharp stair-like boundary separating the affected and normal skin, and a slightly diminished granular cell layer.
Differential diagnosis
The absence of cornoid lamellation allows exclusion of porokeratosis of Mibelli.
Management and treatment
Treatment is not strictly necessary as the lesions are asymptomatic and, by definition, benign; they may be treated with excision, cryotherapy and application of topical calcipotriol.
Prognosis
The condition is chronic and benign. The lesions enlarge slowly over time, before stabilizing. Rarely, the epidermis may show (pre)neoplastic changes.

                            Last update:
                            December 2022

                            - Expert reviewer(s):
                            Pr Jean KANITAKIS


A rare disorder of manganese transport characterized by childhood onset of extrapyramidal movement disorder (including dystonia, tremor, and bradykinesia), liver cirrhosis, polycythemia, and hypermanganesemia. Cases with spastic paraparesis without extrapyramidal dysfunction have also been reported. Cognitive functions are preserved. Brain imaging findings are consistent with deposition of manganese in the basal ganglia, dentate nucleus, brain stem, and anterior pituitary.


A rare autosomal recessive urea cycle defect characterized clinically by recurring episodes of hyperammonemia and associated neuropsychiatric symptoms in the adult-onset form (citrullinemia type II), and by transient cholestasis and variable hepatic dysfunction in the neonatal form (neonatal intrahepatic cholestasis due to citrin deficiency).


Citrullinemia type I is a rare autosomal recessive urea cycle defect characterized biologically by hyperammonemia and clinically by progressive lethargy, poor feeding and vomiting in the neonatal form (Acute neonatal citrullinemia type I, see this term) and by variable hyperammonemia in the later-onset form (Adult-onset citrullinemia type I, see this term).


A severe subtype of citrin deficiency characterized clinically by adult onset (20 and 50 years of age), recurrent episodes of hyperammonemia and associated neuropsychiatric symptoms such as nocturnal delirium, confusion, restlessness, disorientation, drowsiness, memory loss, abnormal behavior (aggression, irritability, and hyperactivity), seizures, and coma.


Citrullinemia is an autosomal recessively inherited disorder of urea cycle metabolism and ammonia detoxification (see this term) characterized by elevated concentrations of serum citrulline and ammonia. The disease presents with a large range of manifestations including neonatal hyperammonemic encephalopathy with lethargy, seizures and coma; hepatic dysfunction in all age groups; episodes of hyperammonemia and neuropsychiatric symptoms in children or adults, or, can be asymptomatic in some cases (detected in newborn screening programs). Citrullinemia is divided into two main groups that are encoded by different genes: citrullinemia type I (comprised of acute neonatal citrullinemia type I and adult-onset citrullinemia type I) and citrin deficiency (comprised of adult-onset citrullinemia type II and neonatal intrahepatic cholestasis due to citrin deficiency) (see these terms).


CK syndrome is a rare, genetic, X-linked syndromic intellectual disability disorder characterized by mild to severe intellectual disability, infancy-onset seizures, post-natal microcephaly, cerebral cortical malformations, dysmorphic facial features (including long, narrow face, almond-shaped palpebral fissures, epicanthic folds, high nasal bridge, malar flattening, posteriorly rotated ears, high arched palate, crowded teeth, micrognathia) and thin body habitus. Long and slim fingers/toes, strabismus, hypotonia, spasticity, optic disc atrophy, and behavioral problems (aggression, attention deficit hyperactivity disorder and irritability) are additional features.


A rare, complex, vascular malformation syndrome characterized by capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of face and limbs, and partial or generalized overgrowth involving one or more body segments.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, obesity, macrocephaly, behavioral abnormalities (such as aggressive tantrums and autistic-like behavior), and delayed speech development. Dysmorphic facial features include large, square forehead, prominent supraorbital ridges, broad nasal tip, large ears, prominent lower lip, and minor dental anomalies such as small upper lateral incisors and central incisor gap.


Class I glucose-6-phosphate dehydrogenase deficiency

A rare constitutional hemolytic anemia due to an enzyme disorder characterized by severe glucose-6-phosphate dehydrogenase deficiency (typically <10% residual enzyme activity) associated with chronic non-spherocytic hemolytic anemia of highly variable severity. Patients are at risk of developing neonatal jaundice (potentially leading to kernicterus), gallstones, and reticulocytosis and splenomegaly. They have an increased susceptibility to oxidizing agents provoking episodes of acute hemolysis. Favism, which describes the occurrence of an acute hemolytic reaction in response to the ingestion of fava beans, is more common in infants and young children.


Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form

A form of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency characterized by abnormal genital development with variable levels of virilization in females and normal genitalia in males in association with glucocorticoid insufficiency with salt-wasting due to aldosterone deficiency, accelerated growth velocity and bone maturation, premature adrenarche and precocious puberty leading to reduced adult height.


Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

A form of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency characterized by abnormal genital development with variable levels of virilization in females, and normal genitalia in males in association with glucocorticoid insufficiency with absence of salt-wasting, accelerated growth velocity and bone maturation, premature adrenarche and precocious puberty leading to reduced adult height. Females have a normal uterus and various degrees of abnormal vaginal development.