A rare, primary low-grade malignant bone tumor that occurs in more than 80% of cases on the anterior surface of the tibia (tibial dyaphysis). Most cases are symptomatic or present with pain, swelling, bowing deformity or pathological fracture. Metastases especially in the lungs may be observed.

Summary:
Epidemiology
AD represent between 0.1 and 0.5% of all primary malignant bone tumors. The life time prevalence in Europe is estimated to be 1/900,000. Males are more commonly affected and in the latter case the tumor is more aggressive.
Clinical description
AD affects individuals over a wide age range (2-86 years), but 75% occurs in the mature skeleton within the second and third decades. AD has an insidious onset and the typical presentation is that of a slow growing and painless swelling on the anterior side of the tibia. Localized pain, pathological fracture and bone deformity are other features which lead the patient to seek medical attention. Most tumors are located in the middle third of the tibial anterior cortex but involvement of bones other than the tibia has been reported and includes the humerus (6 %), ulna (4 %), fibula (3 %), femur (3 %) and radius (1 %). In rare cases, the tumor can be located in the ribs, pelvis, spine, carpus and tarsus. Multiple locations or purely within the cortex may be observed.
Etiology
The etiology of AD is unknown and to date, no known genetic mutations have been identified. A translocation t(7;13)(q32;q14) has been reported in a lung metastasis from an AD of the tibia in a boy. However, an identical translocation was found in his normal father.
Diagnostic methods
On conventional radiography, early stage AD appears as a cortical lucency without a significant periosteal. Cortical thickening, although seen after fracture and presence of a soft tissue mass are rare findings. Detection of tumors at this stage is rare and usually fortuitous, with most patients being diagnosed in more advanced stages. The typical tumors are multiloculated cystic/sclerotic lesions with a characteristic `soap bubble like' appearance. In some cases, the cortex may eventually be disrupted and a soft-tissue component can be found. Lesions are mostly eccentric, expansile and cortically located. AD show low signal intensity on T-1 weighted MRI and high signal intensity on T-2 weighted images. In histopathological terms, AD is characterized by the presence of a variable proportion of epithelial cells within osteofibrous tissue that may be intermingled with each other in various proportions resulting in 2 differentiating patterns: osteofibrous dysplasia-like AD (with a predominance of the osteofibrous component) with intermediate malignancy potential; and classic AD with a predominance of the epithelial component and low grade malignancy.
Differential diagnosis
The main differential diagnosis for AD is fibrous dysplasia of bone but chondrosarcoma, langerhans cell histiocytosis, haemangioendothelioma (see these terms), fibroma (non-ossifying as well as ossifying), and bone cyst should also be excluded.
Management and treatment
Definitive cure can only be achieved after gross total resection with wide resection margins. Chemotherapy and radiotherapy do not play a role in the treatment of ADs. Long-term clinical and radiological monitoring is necessary because of the risk of local recurrence or metastasis, which can occur many years after the initial treatment.
Prognosis
In general ADs have a good outcome. Complete remission can be achieved in around 70% of the cases. However, in 10-50% of cases, the disease may be fatal due to metastases (occuring most often in the lungs and in the lymph nodes, although metastases to liver, bone and brain have been reported). Mean survival of patients with metastatic disease is reported to be 12 years.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr M. [Mario] MAAS  - Pr R.R. [Rick] VAN RIJN


A rare multiple congenital anomalies/dysmorphic syndrome characterized by the combination of congenital distal limb reduction and scalp defects, often accompanied by skull ossification defects.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
The severity of the disorder varies greatly among affected individuals. Aplasia cutis congenita, transverse limb defects and cutis marmorata telangiectasia congenita are characteristic of this condition. The affected patients typically have malformations of the hands and/or feet that range from hypoplastic phalanges to absent fingers and/or toes. AOS may be associated with a variety of physical anomalies including congenital cataract, strabismus and microphthalmia, congenital heart malformations (including tetralogy of Fallot and pulmonary atresia), and hepatoportal sclerosis. Hydrocephalus is the principal cerebral feature and epilepsy may be associated. Extensive lethal anomalies are possible but very rare. Most frequent signs are vertex aplasia, distal limb reduction, intrauterine growth retardation, and neurodevelopmental delay. The penetrance of the disease seems decreased in AOS of autosomal recessive transmission, with intrafamilial variability, and rare patients may present without aplasia cutis congenita and/or limb reduction.
Etiology
The etiopathogenesis remains unclear, but 2 pathways are implied: NOTCH pathway and RAC1/CDC42 pathway. To date, 6 genes have been described in Adams-Oliver syndrome: ARHGAP31 (autosomal dominant; AD), DLL4 (AD), RBPJ (AD), NOTCH1 (AD), EOGT (autosomal recessive; AR), and DOCK6 (AR). An important inter- and intra-familial variability in expression is described, and an incomplete penetrance. Surprisingly, the penetrance seems to be decreased for recessive transmission. There is no obvious phenotypic difference between those who have missense variations and those who have frameshift or stop-gain variations.
Diagnostic methods
Diagnosis is suspected on clinical presentation, with the association of aplasia cutis congenita and distal limb reduction. It can be confirmed by genetic testing (genes panel, exome or genome sequencing).
Differential diagnosis
The principal differential diagnosis is the recently described FOSL2-related neurodevelopmental disorder with scalp and enamel defects (also presenting sometimes with distal limb reduction). Other genetic differential diagnoses present with scalp defects or distal limb reduction associated syndrome such as Poland sequence, SCALP syndrome, or aplasia cutis congenita (non-exhaustive list). This kind of distal limb defects can also be due to constriction rings of amniotic membranes.
Antenatal diagnosis
Antenatal diagnosis can be performed when ultrasounds reveal distal limb anomalies and/or vertex defects. When a pathogenic variant is identified in a family, antenatal diagnosis is possible depending on the severity of the malformations in the family. Antenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known Adams Oliver syndrome variant.
Genetic counseling
Occurrence can be familial or sporadic. Transmission depends on the affected genes; most cases are transmitted as an autosomal dominant trait (ARHGAP31, DLL4, RBPJ, NOTCH1), but some show autosomal recessive transmission (EOGT and DOCK6). Genetic counseling should be offered to at-risk couples: when the transmission is autosomal recessive, there is a 25% risk of having an affected child at each pregnancy, whereas when the transmission is autosomal dominant, there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Limb and scalp defects require orthopedic treatment. Management is multidisciplinary and includes geneticists, orthopedic surgeons and pediatric orthopedics, cardiologists, as well as social support networks.
Prognosis
Life expectancy mostly depends on the severity of the vertex aplasia and of the heart malformation(s). Functionality in everyday life depends on the type and severity of upper-limb anomalies, cerebral malformations, heart and kidney defects, and eyes anomalies.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Dr Perrine BRUNELLE | ITHACA*

                                * European Reference Network


A rare, neurodegenerative disease characterized by progressive cataracts, hearing loss, cerebellar ataxia, paranoid psychosis and dementia. Neuropathological features are diffuse atrophy of all parts of the brain, chronic diffuse encephalopathy and the presence of extremely thin and almost completely demyelinated cranial nerves.


A chronic and rare endocrine disorder due to autoimmune destruction of the adrenal cortex and resulting in a glucocorticoid and mineralocorticoid deficiency. Properly speaking, it designates autoimmune adrenalitis, but it is a term commonly used to describe any form of chronic primary adrenal insufficiency (CPAI).

Summary:
Epidemiology
The prevalence of AD is 1/9,000-1/6,900 in the developed countries.
Clinical description
Disease onset peaks around 40 but it 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 AD. Symptoms of postural hypotension and hypoglycemia are late manifestations. Patients may also crave salt. Vitiligo and alopecia areata are often present. AD 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 primary adrenal insufficiency (AAI; see this term), also called an adrenal crisis, can occur if treatment is not followed or during precipitating illnesses and is a life threatening medical emergency.
Etiology
AD results from autoimmune destruction of the adrenal cortex and can be isolated or seen as part of an autoimmune disorder (autoimmune polyendocrine syndrome type 1, 2 or 4, see these terms).
Diagnostic methods
Biochemical tests are needed to diagnose AD. Early morning serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels are measured. Plasma ACTH is much higher in individuals with AD (>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 AD patients. Raised plasma ACTH levels confirm AD diagnosis.
Differential diagnosis
Secondary adrenal insufficiency needs to be eliminated. Causes include pituitary tumors, lymphatic hypophystitis, pituitary tuberculosis and sarcoidosis, all of which are differential diagnoses. Infiltrative disorders and other causes of CPAI should be excluded and include tuberculosis (see this term), fungal infections and AIDS-associated opportunistic infections. Genetic disorders, tumors, and treatment with certain drugs are other less common causes of CPAI.
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 carry a medical alert card, in case of adrenal crisis.
Prognosis
There is no cure for AD but with proper treatment and care taken to prevent AAI there is no decrease in life expectancy. AD is only life threatening when ignored.

                            Last update:
                            November 2012

                            - Expert reviewer(s):
                            Dr Anne BACHELOT


Adducted thumbs-arthrogryposis syndrome, Christian type

A type of arthrogryposis characterized by congenital cleft palate, microcephaly, craniostenosis and arthrogryposis (limitation of extension of elbows, flexed adducted thumbs, camptodactyly and clubfeet). Additional features include facial dysmorphism ('myopathic' stiff face, antimongoloid slanting, external ophthalmoplegia, telecanthus, low-set large malrotated ears, open mouth, mierogenia and high arched palate). Velopharyngeal insufficiency with difficulties in swallowing, increased secretion of the nose and throat, prominent occiput, generalized muscular hypotonia with mild cyanosis and no spontaneous movements, seizures, torticollis, areflexia, intellectual disability, hypertrichosis of the lower extremities, and scleredema (in the first days of life; see this term) are also observed. The disease often leads to early death. Transmission is autosomal recessive. No new cases have been described since 1983.


A rare genetic nephropathy secondary to a disorder of purine metabolism characterized by the formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy.

Summary:
Epidemiology
Prevalence is estimated at 1/50,000 to 1/100,000 in Caucasian, 1/27,000 in Japanese and > 1/15,000 in Icelandic populations. Adenine phosphoribosyltransferase deficiency (APRT) deficiency appears to equally affect children and adults, male or female. In Caucasian populations, heterozygous prevalence is estimated between 0.4% and 1.2%.
Clinical description
Clinical manifestations include symptoms usually associated with urolithiasis. Stones are typically radiolucent. Onset can be between infancy and the 4th decade of life, or sometimes even later. A small portion of patients remain asymptomatic. The disease can present not only as urolithiasis but also as crystalline nephropathy secondary to the precipitation of 2,8-DHA into renal parenchyma (DHA nephropathy). DHA nephropathy occurs most often in patients with repeated misdiagnosed episodes of urolithiasis and progressive worsening of renal function, but it may also present as acute renal failure. Rarely, DHA nephropathy may occur in patients who experienced only a few stone episodes. DHA nephropathy can evolve to end stage renal disease requiring dialysis and transplantation and can recur after transplantation causing rapid loss of graft function if left untreated.
Etiology
APRT deficiency is an autosomal recessive (AR) disorder caused by mutations in the APRT gene (16q24) encoding the APRT enzyme catalyzing AMP synthesis from adenine and 5'-phosphoribosyl-1-pyrophosphate. Two types of APRT deficiencies have been described, according to APRT activity in vitro; type I characterized by a total lack of APRT activity, found primarily in Caucasians, and type II, found only in Japan, characterized by a 10-25% APRT activity. This in vitro distinction has no known clinical significance.
Diagnostic methods
Lack of awareness of APRT deficiency often causes a significant delay between the onset of symptoms and a proper diagnosis. Diagnosis is primarily based on identifying 2,8-DHA by examination of crystals or stones. Crystalluria examination can be used for diagnosis. In DHA nephropathy patients, crystals may also be identified in renal biopsy, although this invasive test is theoretically unnecessary. Crystals and stones should be analyzed by morphologic examination combined with infrared spectrometry and/or x-ray crystallography. Diagnosis can be confirmed by enzyme activity analysis in erythrocyte lysates. Genetic testing may be used for diagnosis but may be useful for familial screening.
Differential diagnosis
Confusion frequently occurs between 2,8-DHA and uric acid stones, which are typically both radiolucent. Contrary to uric acid, 2,8-DHA stones do not respond to alkali therapy. Differential diagnosis also includes other radiolucent stones, such as cystine, xanthine and drugs.
Genetic counseling
Genetic counseling is possible but rarely indicated. However, given the AR transmission, siblings of the affected individual, even if they are asymptomatic, should be screened through DNA analysis or APRT activity.
Management and treatment
To prevent further 2,8-DHA formation, treatment consists of allopurinol daily (usually 10mg/kg per day in children and 300 mg per day in adults) together with a high fluid intake and low purine diet. In cases of acute or chronic renal failure, allopurinol doses should be reduced. Asymptomatic individuals should be treated by allopurinol to prevent renal complications. Febuxostat, another xanthine oxydase inhibitor, may be even more efficacious than allopurinol in reducing DHA excretion. It remains unknown how this translates into improved patient outcomes. Febuxostat should be recommended in allopurinol-intolerant patients and also in rare patients who do not respond well to allopurinol.
Prognosis
Early diagnosis is the key and prognosis depends on progression of this treatable disorder. Allopurinol therapy effectively prevents stone recurrence and can lead to an improvement or stabilization of renal function in most patients. Stone recurrence and renal complications are rare in patients who remain compliant with allopurinol therapy.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Guillaume BOLLEE


A very rare tumor of the intestine, originating from the epithelium of the anal canal (including the mucosal surface, anal glands, and lining of fistulous tracts), macroscopically appearing as a nodular, often ulcerated, invasive mass located in the anal canal. Patients often present with rectal bleeding, as well as difficulty and pain during defecation. Inguinal lymphadenopathy, if present, usually indicates metastatic spread.


Esophageal adenocarcinoma (EAC) is a sub-type of esophageal carcinoma (EC; see this term) affecting the glandular cells of the lower esophagus at the junction with the stomach.

Summary:
Epidemiology
It has an estimated annual incidence of 1/35,000.
Clinical description
The age of onset is between 50-60 years and it is more frequently seen in males. EAC is usually asymptomatic until an advanced disease stage with common presenting symptoms being dysphagia and unintentional weight loss. There is often a history of chronic gastroesophageal reflux disease (GERD). When symptoms are present it often has advanced locally and may have spread through the lining of the esophagus and involve lymph nodes or more distant sites.
Etiology
The exact etiology is unknown. There is a strong association with GERD and obesity. There is no specific, known genetic link. The principal pathologic precursor is Barrett's esophagus (BE; see this term) which is characterized by metaplasia in the lining of the esophagus for variable distances above the stomach, and is identified through endoscopy and pathology. A high percentage of cases of EAC arise in a background of BE.
Diagnostic methods
Endoscopy and a biopsy establish the diagnosis. For staging, a computed tomography (CT) scan of the neck, chest and abdomen, or CT combined with a positron emission tomography (CT-PET) scan will identify the primary tumor in most cases as well as any spread to the lymph nodes and organs such as the liver, lungs and bone. Endoscopic ultrasound (EUS) is also increasingly used for staging, and is of particular value for early cancers. Laparoscopy is used in selected cases for further staging.
Differential diagnosis
Differential diagnoses include idiopathic achalasia, gastric cancer (see these terms) and a benign esophageal stricture.
Management and treatment
Treatment may be with curative intent when the disease is confined to the esophagus and even when local nodes of the primary tumor are involved, and when the patient is fit enough for treatment. The mainstay of treatment of EAC is surgical resection, usually via a transthoracic resection, and occasionally a neck incision. In selected cases a transhiatal esophagectomy (without opening the chest) is performed. In patients diagnosed with early cancers, in particular patients undergoing surveillance for BE, the use of endoscopic surgery, often in combination with radiofrequency ablation (RFA), may supplant the need for open surgery. There is also an increasing use of chemotherapy or of the combination of chemotherapy and radiation therapy before and after surgery. A number of clinical trials support this practice, particularly where the tumor is locally advanced, and this is increasingly the standard of care in Europe and North America. The chemotherapeutic drugs most often used in combination are epirubicin, cisplatin and 5-fluorouracil (known as ECF). Capecitabine and oxaliplatin are less toxic agents that can be used in those with cardiac and renal problems. In patients who are unsuitable for approaches involving surgery, high-dose radiotherapy and chemotherapy is an increasingly used alternative. For palliative approaches, self-expanding metal stents (SEMS) can relieve dysphagia, and chemotherapy, radiation therapy and laser-based approaches are also considered.
Prognosis
As diagnosis often occurs at an advanced disease stage, the prognosis is poor with the overall estimated 5-year survival rate of 10-20%. However, the cure rate is now approximately 40% for patients treated with curative intent, in part because of increased early diagnoses, and in part because of improved treatments.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Dr Claire DONOHOE  - Dr John REYNOLDS


Adenocarcinoma of the gallbladder and extrahepatic biliary tract

A rare epithelial carcinoma, arising either in the gallbladder itself or from the epithelium lining the extrahepatic biliary tree, cystic duct and/or peribiliary gland, characterized by nonspecific symptoms, such as abdominal pain, jaundice and vomiting and sometimes mimicking benign biliary diseases. Chronic biliary epithelial inflammation (e.g. primary sclerosing cholangitis, cholelithiasis, choledocholithiasis, liver fluke infestation) is a major risk factor.


Adenocarcinoma of the liver and intrahepatic biliary tract

A rare hepatic and biliary tract tumor characterized by a growth pattern ressembling that found in hepatocellular carcinomas and cholangiocarcinomas but presenting atypical histological and immunohistochemical features (such as trabecular, organoid, microcystic and/or blastemal-like architecture and inhibin A, cytokeratin 7 and/or cytokeratin 19 positivity) that do not allow a formal diagnosis of the more common aforementioned liver cancers. Patients may present abdominal distension and pain, a palpable abdominal mass and elevated liver enzymes.


An extremely rare penile epithelial neoplasm, histologically composed of nests of epithelilal cells floating in lakes of extracellular, PAS-positive mucin, clinically characterized by a nonhealing ulcer or soft mass in the preputium or glans area, with itching and burning often preceding appearance of the lesion. Lymphadenopathy may indicate dissemination. Mucinous metaplasia of the penis may be a risk factor.


Small bowel adenocarcinoma (SBA) is a rare small intestinal malignancy, most commonly located in the duodenum (55% of cases) but also rarely in the jejunum and ileum, which is usually discovered at an advanced stage in the 6th to 7th decade of life due to non-specific symptoms at presentation such as nausea, abdominal pain and weight loss. In some cases it is asymptomatic, and therefore usually has a poor prognosis.


A rare, acquired pituitary hormone deficiency, a type of primary hypophysitis characterized by an inflammation of anterior pituitary. Clinical presentation is variable and includes headaches, visual disturbances, symptoms of adrenal insufficiency, hyperprolactinemia, hypothyroidism and hypogonadism. It most commonly affects young women during pregnancy or postpartum period.


Adenoid basal carcinoma of the cervix uteri

A rare, slow-growing uterine cancer characterized, histologically, by small, well differentiated nests of basaloid cells resembling basal cell carcinoma of the skin, commonly associated with squamous cell carcinoma or squamous intraepithelial lesions. Patients are usually asymptomatic or present with dysfunctional vaginal bleeding, often with no observable lesion on the cervix. Infection with high-risk HPV-types (16 and 33) has been reported in some cases.


Adenoid cystic carcinoma of the cervix uteri

A rare, highly aggressive uterine cancer, macroscopically appearing as an irregular, slow-growing, non-friable, polypoid mass on the uterine cervix and histologically showing a pseudoglandular or cribriform growth pattern. It presents with vaginal bleeding and discharge and abdominal or pelvic pain. The tumor is highly infiltrative, often associated with vascular, lymphatic and perineural invasion, with subsequent haematogenous spread and early recurrence.


A rare, benign tumor of the pancreas characterized by variable number and size of the cysts lined with glycogen rich epithelial cells. Clinical manifestation may include epigastric or abdominal pain, weight loss, diabetes, jaundice and palpable abdominal mass. Some patients have no symptoms and the tumor is discovered incidentally.


A rare subtype of malignant mixed epithelial and mesenchymal tumor composed of benign or mildly atypical glandular elements and a surrounding low-grade malignant stroma, often containing heterologous elements, such as areas of sex-cord-like or smooth muscle differentiation. It usually presents with vaginal bleeding or discharge, lower abdominal pain and/or a cervical mass or polyp. The tumor may arise from pre-existing endometriosis and patients may have a history of recurrent cervical polyps.


A rare subtype of mixed epithelial-mesenchymal tumor, often presenting as a large, exophytic polypoid lesion, which may extend through the cervix, composed of benign or atypical epithelium and low-grade malignant stroma. It usually presents with dysfunctional bleeding or vaginal discharge and less often abdominal pain. Association with long-term unopposed estrogen therapy, tamoxifen therapy and a history of pelvic radiation has been reported.


Vasculitis due to ADA2 deficiency is a rare, genetic, systemic and rheumatologic disease due to adenosine deaminase-2 inactivating mutations, combining variable features of autoinflammation, vasculitis, and a mild immunodeficiency. Variable clinical presentation includes chronic or recurrent systemic inflammation with fever, livedo reticularis or racemosa, early-onset ischemic or hemorrhagic strokes, peripheral neuropathy, abdominal pain, hepatosplenomegaly, portal hypertension, cutaneous polyarteritis nodosa, variable cytopenia and immunoglobulin deficiency.


Adenosine monophosphate deaminase deficiency

A rare metabolic disorder for which two forms have been described. Lack of activity of the erythrocyte isoform of adenosine monophosphate (AMP) deaminase has been described in subjects with low plasma uric acid levels without obvious clinical relevance and will not be described further. Myoadenylate deaminase deficiency is an inherited disorder of muscular energy metabolism with a lack of AMP deaminase activity in skeletal muscle. It is characterised by exercise-induced muscle pain, cramps and/or early fatigue.

Summary:
Epidemiology
About 1-2% of the Caucasian population carries the genetic defect causing myoadenylate deaminase deficiency, but only a minority of carriers develop symptoms. The prevalence is unknown but several hundred patients with the disorder have been reported in case reports and patient series. Men and women are equally affected.
Clinical description
The vast majority of patients suffer from post-exercise symptoms: rapid fatigue, cramps or myalgias. Approximately equal proportions of the patients first develop symptoms during childhood, adolescence, or as young or older adults. After progression of the symptoms over the first few years, the clinical course usually stabilises. There is no evidence of muscular dystrophy or muscular wasting. The disorder exclusively affects skeletal muscle. Smooth muscle or other organs are not affected as the disorder is associated with a specific lack of skeletal muscle adenylate deaminase activity.
Etiology
The vast majority of patients with this disease are homozygous for the nonsense C34-T mutation in the AMPD1 (adenosine monophosphate deaminase 1) gene. This mutation creates an early stop codon thus preventing the synthesis of an enzymatically active protein. The deficiency disrupts the purine nucleotide cycle, and thus muscle energy production. Surprisingly, however, asymptomatic AMP deaminase-deficient subjects have been reported, indicating that additional factors are likely to be involved in the development of myopathic symptoms.
Diagnostic methods
The diagnosis is based on histochemical staining or biochemical analysis of a muscle biopsy showing a lack of muscle adenylate deaminase activity, or on molecular identification of the disease-causing mutation.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Unfortunately, there is no medical cure for this disorder. Symptoms improve with administration of D-ribose. However, the effects of this sugar are only short-tem and it has no beneficial effect during subsequent days.

                            Last update:
                            February 2007


Adenovirus infection in immunocompromised patients

A rare viral disease characterized by invasive and/or disseminated adenovirus infection in immunocompromised patients, either acquired de novo or arising from reactivation of persistent latent infection. The clinical picture comprises a wide range of manifestations including pneumonia, colitis, hepatitis, hemorrhagic cystitis, tubulointerstitial nephritis, encephalitis, and disseminated disease, among others. Severity varies with age and immune status, and life-threatening courses may occur.


A disorder of purine metabolism characterized by intellectual disability, psychomotor delay and/or regression, seizures, and autistic features.

Summary:
Epidemiology
The prevalence and incidence of ADSL deficiency are unknown. More than 80 cases have been reported to date, mostly from Europe and the Mediterranean region. The disorder may be underdiagnosed as it is probably panethnic.
Clinical description
ADSL covers a continuous clinical spectrum with three major forms: fatal neonatal, severe (type I), and mild to moderate form (type II). Clinical variability is found, even in patients from the same family. Onset is generally between birth and early childhood. Cases ranging from fatal neonatal encephalopathy (presenting with hypokinesia, intractable seizures and respiratory failure) to mild intellectual disability have been reported. Intellectual disability is found in all patients, epilepsy of various types in most, and autistic features in about one third (failure to make eye contact, hypersensitivity to noise and light, repetitive behavior, agitation, temper tantrums, autoaggression and self-mutilation). Other less common manifestations include psychomotor delay, hyperactivity, speech impairment, muscular hypotonia, muscle wasting, and spasticity. Severely affected patients often have microcephaly. Prenatal manifestations are also reported: impaired intrauterine growth, microcephaly, fetal hypokinesia, and loss of fetal heart rate variability.
Etiology
ADSL is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways. Biochemically, this defect manifests by the presence in the biologic fluids of two dephosphorylated substrates of ADSL enzyme: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). The underlying defect is associated with mutations in the ADSL gene (22q13.1). No strict genotype-phenotype correlations have been found.
Diagnostic methods
Final diagnosis requires demonstration of succinylpurines in extracellular fluids such as plasma, cerebrospinal fluids (CSF) and/or urine using HPLC or HPLC-MS and/or genomic cDNA sequencing of the ADSL gene and characterization of mutant proteins. For selective screening, rapid methods are used (Bratton-Marshall or TLC). Reported findings on brain magnetic resonance imaging (MRI) include white matter anomalies, atrophy of the cerebral cortex, corpus callosum, cerebellar vermis, lack of myelination, delayed myelination, and lissencephaly (see this term).
Differential diagnosis
The differential diagnoses include neurological disorders with intractable seizures and encephalopathy, and other inborn errors of purine and pyrimidine metabolism with neurological manifestations.
Antenatal diagnosis
Prenatal diagnosis is possible when a disease-causing mutation has been identified in an affected family.
Genetic counseling
ADSL deficiency follows an autosomal recessive pattern of inheritance.
Management and treatment
There is currently no effective treatment for ADSL deficiency. Treatment is primarily supportive, aimed at controlling seizures. The aim of treating epilepsy is to control or at least decrease seizure frequency with minimal side effects. Treatment with anticonvulsive drugs (e.g. valproic acid, phenobarbital, carbamazepine, topiramate, levetiracetam, phenitoin, clobazam) depends on the type of seizures. Patients often require polypharmacy with the use of two or more anticonvulsants. Drug resistance is common.
Prognosis
Life expectancy in ADSL deficiency is variable. Neonatal forms may lead to early death, whereas onset in early childhood usually entails a stable course.

                            Last update:
                            March 2015

                            - Expert reviewer(s):
                            Dr Agnieszka JURECKA  - Pr Anna TYLKI-SZYMANSKA


Adenylosuccinate synthetase-like 1-related distal myopathy

A rare autosomal recessive distal myopathy characterized by slowly progressive diffuse muscle weakness in childhood, followed by predominantly distal muscle weakness in adolescence, and quadriceps muscle weakness in the fourth decade. Facial muscle weakness is commonly reported. Muscle biopsy shows fiber size variation, increased internal nuclei, fiber splitting, rimmed vacuoles, and focal endomysial fibrosis.


A rare disorder of subcutaneous tissue characterized by the development of painful, adipose tissue with multiple subcutaneous lipomas, in association with overweight or obesity.

Summary:
Epidemiology
Prevalence is unknown. It is 5-30 times more common in women.
Clinical description
The onset may be abrupt or indolent and most commonly occurs between 35 and 50 years of age. The main symptoms are obesity and painful adipose tissue. The most common locations for lipomas are the extremities, the trunk, the pelvic area, and the buttocks. The pain is often described as burning or aching but the pain experience varies between different individuals. A number of associate symptoms have been described. Some of them can be induced by obesity per se, such as weakness and susceptibility to fatigue. Others, such as depression and psychiatric manifestations, are common in all diseases involving pain. Therefore, such symptoms should not be seen as diagnostic for the disease. Other symptoms, such as easy bruisability, rapid heartbeat, shortness of breath, thyroid disease, diabetes and constipation have only been described in case reports and in a questionnaire study; however there is no evidence to support the association with adiposis dolorosa. Adiposis dolorosa can clinically be classified into: i) generalised diffuse form with diffusely widespread painful adipose tissue without clear lipomas ii) generalised nodular form with general pain in the adipose tissue as well as in and around lipomas iii) localised nodular form with pain in and around lipomas iv) juxta-articular form with solitary deposits of excess fat around one or several joints.
Etiology
The etiology remains unknown but several hypotheses have been proposed including endocrine dysfunction, nervous system dysfunction, mechanical pressure on the nerves, adipose tissue dysfunction, inflammation, infection and induced by trauma or medications. Most of the hypotheses are based on case reports and there is no convincing evidence for any of the etiologies.
Diagnostic methods
The basic diagnostic criteria for adiposis dolorosa are i) generalised overweight or obesity and ii) chronic pain (for greater than 3 months) in the adipose tissue. The diagnosis should be based on systemic physical examination and thorough exclusion of differential diagnoses. There are no laboratory markers for the disease. The pathohistological picture of adipose biopsies is generally indistinguishable from that of lipomas. Radiological findings overlap with other lipodystrophies, although lymphovascular anomalies and MRI patterns with fatty lesions in the subcutaneous fat have been described in single cases. Laboratory tests, biopsies, and radiology can be useful to exclude differential diagnoses.
Differential diagnosis
In cases of general diffuse forms of adiposis dolorosa, the differential diagnosis should include other conditions with general pain, such as fibromyalgia, lipoedema, panniculitits, endocrine disorders comprising pain and obesity, and psychiatric conditions comprising pain, especially in combination with obesity. In nodular forms of adiposis dolorosa, the differential diagnosis should include other multiple lipoma syndromes such as familial multiple lipomatosis, multiple symmetric lipomatosis, myoclonic epilepsy with red ragged fibres (MERRF) syndrome, neurofibromatosis type 1, and multiple endocrine neoplasia type 1 (MEN1). In case of single lesions, adipose tissue tumors, such as sarcoma, have to be excluded.
Genetic counseling
The majority of reported cases are sporadic. Autosomal dominant inheritance has been suggested in several case reports; however, there are no described mutations.
Management and treatment
Treatment is symptomatic. Few convincing larger studies have been conducted. Methods that have been described for pain relief include liposuction or surgical resection of lipomas and traditional analgesics (NSAIDs). The following treatments have only been described in case reports or case series: lidocaine, corticosteroids, combinations of mexiletine and amitriptyline, or infliximab, calcium-channel modulators, D-thyroxine interferon alfa-2b, methotrexate, metformin, deoxycholic acid, rapid cycling hypobaric pressure, and transcutaneous electrical stimulations. Only one case of treatment with bariatric surgery in adiposis dolorosa has been described. There are no studies on the effect of weight loss in adiposis dolorosa.
Prognosis
The disease course is chronic. Case reports have suggested that pain increases with time. A study with a five-year follow-up has suggested that the average pain is relatively constant over time.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Håkan BRORSON  - Pr Emma HANSSON


A rare syndromic intellectual disability characterized by global developmental delay, gastrointestinal problems, hypotonia, delayed speech, behavioral and sleep problems, pain insensitivity, seizures, structural brain anomalies, dysmorphic features, visual problems, early tooth eruption and autistic features.

Summary:
Epidemiology
The point prevalence of ADNP syndrome is approximately 1-2/100,000 individuals. The syndrome represents 0.17% of the autism spectrum disorder cases.
Clinical description
The ADNP syndrome phenotype includes intellectual disability (ID) of various severities, severely delayed speech including oral apraxia, behavioral problems (anxiety, obsessive compulsive disorder, aggressive behavior, temper tantrums, attention deficit hyperactivity disorder), motor development delays of various severities. ADNP patients have higher rates of ID but less severe social affect symptoms and high levels of stereotyped motor behaviors compared to high levels of restricted interests in idiopathic ASD. Other ADNP symptoms may include delayed toilet training, pain insensitivity, sleep problems, seizures, structural brain anomalies, distinct dysmorphic facial features, sensory problems including mostly visual problems, occasional hearing problems, autistic traits and hypotonia or in rare cases, hypertonia. Gastrointestinal problems are most frequently encountered. Congenital heart defects, short stature, skin cell deficiencies and hormonal deficiencies/abnormalities as well as recurrent infections are also apparent. About 80% of the children harboring ADNP mutations show early deciduous dentation.
Etiology
A single de novo ADNP mutation presumably occurs during the formation of the sperm/egg or during early embryonic development. The condition occurs in families with no history of the disease. Most frequent ADNP protein coding mutations include STOP or frameshift-STOP autosomal dominant mutations.
Diagnostic methods
Whole exome sequencing, or specific ADNP gene sequencing for mutation. Early deciduous tooth eruption (almost fully erupted dentition by 1 year of age).
Differential diagnosis
Some similarities are found with Okihiro syndrome plus developmental delay, Angelman syndrome, Rett syndrome, Noonan syndrome, Kleefstra syndrome, Smith-Magenis syndrome, and other Coffin-Siris syndrome related disorders.
Antenatal diagnosis
Prenatal testing and preimplantation genetic diagnosis (PGD) are possible options.
Genetic counseling
The ADNP syndrome is expressed in an autosomal dominant manner. Given that affected individuals were reported to have the disorder as a result of a de novo ADNP pathogenic variant, the risk to other family members is presumed to be low. C-terminal mutations were reported to be inherited, the severity of these mutations (if any) is yet to be explored.
Management and treatment
Routine symptomatic care by primary care professionals is recommended and includes: speech, occupational, and physical therapy, specialized individualized learning programs, treatment of neuropsychiatric features including sleep disorders, behavioral problems, and/or seizures. Nutritional/hormonal support, routine treatment of cardiac, ophthalmologic and auditory findings are also recommended.
Prognosis
With developmental delays, it is expected that children with ADNP syndrome will start walking and talking relatively late. Depending on the precise ADNP mutation, independent walking can be established at 3.5 years of age or later. Speech may be acquired even later. However, in longitudinal observations, progress is noticed over the years. To date, there is only a paucity of adults that are known to have the ADNP syndrome.

                            Last update:
                            January 2019

                            - Expert reviewer(s):
                            Pr Illana GOZES  - Pr Frank KOOY


Adrenocortical carcinoma with pure aldosterone hypersecretion

A very rare surgically-correctable form of primary aldosteronism (PA) due to an aldosterone-secreting adrenal malignancy.

Summary:
Epidemiology
The prevalence of adrenocortical carcinoma with pure aldosterone hypersecretion is unknown.
Clinical description
Pure APAC is characterized by renin suppression, unilateral aldosterone hypersecretion and moderate to severe hypertension that may be associated with hypokalemia, and the presence of a large adrenal tumor. Hypokalemia may be symptomatic and present as muscular weakness, cramps, paresthesia or palpitations with or without atrial fibrillation.
Etiology
Etiology is unknown.
Diagnostic methods
The diagnosis of carcinoma is suggested by CT scan, showing a tumor exceeding 4 cm in diameter, and possible metastases and/or invasion of the inferior vena cava.
Management and treatment
Open laparotomy enables resection of the tumor and possible metastases or adjacent organs. Unless unresectable tumor or metastases are present, adrenalectomy abolishes aldosterone hypersecretion and hypokalemia in most patients. Adjuvant mitotane therapy may be indicated based on tumor scoring using the Weiss score or ENS@T score.
Prognosis
The prognosis of pure APAC is the same as for others adrenocortical carcinomas: 5-year survival is 15% in patients with metastatic adrenocortical carcinomas.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Pr Laurence AMAR  - Pr Pierre-François PLOUIN  - Dr Olivier STEICHEN


A rare cancer that arises from the adrenal cortex.

Summary:
Epidemiology
It represents 0.2% of childhood malignancies and has an international incidence of 1 in 2,000,000. It is more frequent in girls than in boys (ratio 1.5:1).
Clinical description
Adrenocortical carcinoma (ACC) occurs in childhood with a peak incidence at 3.5 years of age. Most ACCs in children and adolescents are hormone-secreting and the clinical presentation reflects the pattern of adrenocortical hormones secreted by the tumor. Signs and symptoms of virilisation are present in over 90% of cases, hypertension may also be present. Hirsutism, acne and deepening of the voice may be apparent in both sexes. Girls may also present with cliteromegaly and facial hair, while boys present with phallomegaly and early virilisation. Cushing's syndrome (see this term) occurs in a third of cases with the most common signs being a moon-like facies, centripetal fat distribution and plethora. There is an increased incidence of ACC in patients with isolated hemihypertrophy, Wiedemann-Beckwith syndrome, congenital adrenal hyperplasia (CAH) and Li-Fraumeni syndrome (LFS) (see these terms).
Diagnostic methods
Diagnosis is based on the results of urine and blood tests, dexamethasone suppression tests, abdominal ultrasound, CT and MRI scans.
Differential diagnosis
Differential diagnosis should include phaeochromocytoma and neuroblastoma (see these terms).
Genetic counseling
At least 50 % of ACCs have an inherited basis and hence referral to a cancer genetics service is recommended.
Management and treatment
Complete, radical surgical resection is the treatment of choice and may be curative, especially for small tumors. In patients with incomplete resection or metastatic spread, treatment options include chemotherapy and/or mitotane, which obtained EU marketing authorisation in 2004 as an Orphan drug for symptomatic treatment of advanced (unresectable, metastatic or relapsed) ACC.
Prognosis
ACC has a poor prognosis (5-year actuarial survival is 36%) except in case of small tumours that are completely resected.

                            Last update:
                            June 2007

                            - Expert reviewer(s):
                            Pr Bernadette BRENNAN


A form of the peroxisomal disease X-linked adrenoleukodystrophy, characterized by progressive myelopathy and peripheral neuropathy, and often associated with peripheral adrenal insufficiency in males. Onset is typically in adulthood.


An extremely rare genetic endocrine disease characterized by primary adrenal insufficiency, dystrophic myopathy, hepatic steatosis, severe psychomotor delay, megalocornea, failure to thrive, chronic constipation, and terminal bladder ectasia which can lead to death. There have been no further descriptions in the literature since 1982.


Adult acute respiratory distress syndrome

A very severe form of acute pulmonary failure secondary to capillary permeability impairment. The symptoms include dyspnea, hypotension and multivisceral failure. The disease is characterized by bilateral pulmonary infiltrates and severe hypoxemia due to increased alveolar-capillary permeability. The severity depends on the degree of alveolar epithelial injury, with a mortality rate of 30-50%.


Adult familial nephronophthisis-spastic quadriparesia syndrome

A rare, genetic, renal disease characterized by the association of familial adult medullary cystic disease with spastic quadriparesis. There have been no further descriptions in the literature since 1990.


A rare carcinoma of the liver characterized by one to several or many nodules occurring anywhere within the liver, composed of neoplastic epithelial cells with hepatocellular differentiation. The vast majority of tumors are associated with chronic liver disease (such as hepatitis B or C, or steatohepatitis) or exposure to a variety of exogenous agents. Patients may present with signs and symptoms related to the tumor, as well as to the underlying condition. Common manifestations include right upper quadrant abdominal pain, weight loss, hepatosplenomegaly, jaundice, and ascites. Symptomatic tumors generally have poor prognosis.


A moderate form of hypophosphatasia (HPP) characterized by adult onset osteomalacia, chondrocalcinosis, osteoarthropathy, stress fractures and dental anomalies.

Summary:
Epidemiology
The prevalence of adult hypophosphatasia is not known. However the prevalence of moderate HPP (childhood, adult and odontoHPP) cases taken together has been estimated at 1/6300.
Clinical description
Adult HPP is clinically very heterogeneous. In its mildest form it is the least severe form of hypophosphatasia (HPP), characterized by non-specific symptoms in later age, such as osteoporosis, musculoskeletal pain, chondrocalcinosis. Most patients present features during middle age but some may have had a history of mild rickets or other musculoskeletal manifestations in childhood. Cardinal features include stress fractures and pseudo-fractures of the lower limbs, along with foot, thigh, and hip pain. The most common fracture types are metatarsal and tibial and femoral pseudofractures. Osteomalacia, chondrocalcinosis, and osteoarthropathy may develop with age. Some patients report history of early loss of primary dentition. Loss of permanent dentition is also common and some cases of enamel hypoplasia and tooth mobility are described. Patients with the adult form of HPP may have had some manifestations in early life between the prenatal period and childhood (prenatal benign HPP or childhood HPP). The presence of bone symptoms (osteomalacia, fractures) distinguish adult HPP from odontohypophosphatasia.
Etiology
Mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia.
Diagnostic methods
Diagnosis is based on clinical presentation, alkaline phosphatase assay and confirmed by genetic testing.
Differential diagnosis
The main differential diagnosis is osteogenesis imperfecta.
Genetic counseling
Inheritance may be autosomal recessive (rare) or autosomal dominant (the vast majority of cases).
Management and treatment
Management is typically supportive.
Prognosis
Overall prognosis is typically good, although affected individuals may experience some physical limitations depending on the extent and progression of the disease.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Severine BACROT  - Dr Etienne MORNET


A rare acquired immunodeficiency disease characterized by adult-onset absolute neutrophil counts less than 1.5 x 10^9/L on at least 3 occasions in a 3 month period that cannot be attributable to drugs or a specific genetic, infectious, inflammatory, autoimmune or malignant cause. Recurrent aphtous stomatitis and a history of mild bacterial infections are typically associated. A benign outcome with a low rate of severe infections and no secondary malignancies is observed.


A very rare form of botulism, a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), and is due to intestinal colonization by Clostridium botulinum leading to toxin-mediated infection with toxemia.

Summary:
Epidemiology
Exact prevalence is unknown. To date, about 20 cases have been reported.
Clinical description
The disease affects adults and older children. Clinical manifestations are similar to other forms of botulism (flaccid and symmetrical cranial nerve palsy, followed by symmetrical flaccid descending motor paralysis). Compared to foodborne botulism (see this term), the onset is generally gradual and less dramatic. In some cases, diarrhea due to C. difficile co-infection has been reported.
Etiology
The disease results from prolonged intestinal absorption of small quantities of BoNTs produced in situ by C. botulinum type A and B, or rarely by C.botulinum type C (one case) or by neurotoxigenic strains of C. baratiitype F or C. butyricum type E, that can temporarily colonize the intestinal tract. Colonization is generally associated with anatomical abnormalities of the gastrointestinal tract or alteration of protective endogenous microflora by broad-spectrum antibiotics following inflammatory intestinal disease or surgery. Some patients who underwent laparotomy for suspected appendicitis have shown worsening paralysis probably due to the post-surgical antibiotic therapy. Presence of Meckel's diverticulum may be a predisposing factor for intestinal colonization by C. butyricum.
Diagnostic methods
Diagnosis is based on clinical presentation. Confirmation of adult intestinal botulism is based on the detection of BoNTs in serum and stools. In addition, stools can be screened for BoNT-producing Clostridia. Diagnosis is also performed by demonstration of prolonged excretion of microorganisms and toxin in the stool in patients with sporadic botulism and no known contaminated food or wound.
Differential diagnosis
Differential diagnosis includes myasthenia gravis, Guillain-Barré syndrome (Miller Fisher syndrome), Lambert-Eaton syndrome and foodborne and wound botulism (see these terms).
Management and treatment
The antitoxin therapy must be associated with supportive care in an intensive care unit (ICU). Equine antitoxin treatment for adults has a half-life of 5-8 days. In Europe, the formulation currently available for adults is trivalent (anti A, B, E). A heptavalent (anti A to G) product is also available. In the USA, a bivalent (anti A, B) and a monovalent (anti E) antitoxin are available. Antibiotic therapy is ineffective on the toxin action and can exacerbate the neuromuscular blockade, but it is useful when secondary infections are present. In the severe forms, respiratory failure and paralysis may require ventilation for weeks as well as intensive care.
Prognosis
When treatment is administered early and with appropriate intensive care, the prognosis is generally good, no long-term side effects have been observed, and death resulting from respiratory failure is extremely rare. Complications can occur during hospitalization including nosocomial adverse events.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr Lucia FENICIA


A glycogen storage disease of adults characterized by progressive upper and lower motor neuron dysfunction, progressive neurogenic bladder and cognitive difficulties that can lead to dementia.

Summary:
Epidemiology
The prevalence is unknown. More than 50 cases have been described to date in Ashkenazi (in most cases) and non-Ashkenazi Jewish individuals.
Clinical description
APBD presents after the age of 40, with urinary incontinence (indicative of neurogenic bladder) often being the first manifestation. Progressive spasticity and weakness are also present due to upper and lower motor neuron involvement and patients have difficulty walking. Severity of gait difficulties varies between patients with some requiring a wheelchair at an advanced disease stage. Sensory loss in the distal lower extremities occurs in most individuals and can lead to foot injuries. Cognitive difficulties (such as problems with executive functioning) can be mild but in some cases can lead to dementia.
Etiology
APBD is caused by a mutation in the GBE1 gene, encoding the glucan (1, 4-alpha-) branching enzyme 1 (GBE). Without this enzyme, glycogen is not synthesized properly, regulation of glycogen synthase is dysfunctional and deposition of amylopectin-like polyglucosan bodies in neural tissue occurs. Other mutations in this gene are responsible for a more severe and earlier onset form of the disease known as glycogen storage disease type IV (see this term).
Diagnostic methods
Diagnosis is based on the presence of clinical manifestations of the disease along with the characteristic laboratory findings. Typically, magnetic resonance imaging (MRI) demonstrates cerebral white matter changes in the subcortical and periventricular areas, the posterior limb of the internal capsule and in the brainstem. Cerebral, cerebellar and spinal cord atrophy may also be seen at various stages of the disease. Reduced GBE activity is observed in cultured skin fibroblasts and peripheral blood lymphocytes of patients with APBD and sural nerve biopsy shows the presence of polyglucosan bodies in the nerve. Genetic testing is essential for the diagnosis and makes nerve biopsy unnecessary.
Differential diagnosis
The motor neuron dysfunction seen in APBD may be similar to that seen in amyotrophic lateral sclerosis (see this term). Primary urologic dysfunction, multiple sclerosis and Alzheimer's disease should also be considered, as well as other causes of adult onset myeloneuropathy and leukoencephalopathy.
Antenatal diagnosis
Antenatal diagnosis can be performed but is rarely done as the disease has an adult onset.
Genetic counseling
APBD is inherited autosomal recessively and genetic counseling can be given to those with the GBE1 gene mutations in the family. Pre-symptomatic testing can be performed if considered essential for genetic counseling.
Management and treatment
Treatment requires a multidisciplinary team including specialists in physical medicine rehabilitation, psychology and urology. Urologic management may require antispasmodic bladder medications as well as an indwelling or an in-and-out bladder catheter. Ambulation aids such as canes, walkers and wheelchairs may be needed depending on the severity of gait dysfunction in order to move around safely. A neuropsychometric analysis can identify any cognitive impairment and appropriate cognitive aids and behavioural modification can be given. Follow up is needed to monitor bladder function and prevent urosepsis as well as assess levels of cognition, sensation in the distal lower extremities and gait function. Triheptanoin diet therapy is another possible treatment but, as of yet, the clinical benefits observed have been limited.
Prognosis
The prognosis is variable depending on the severity of the disease and the level of care given to patients. In most cases it does not decrease life-expectancy but quality of life is most definitely affected.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Alexander LOSSOS


A rare ectodermal dysplasia syndrome characterized by ectrodactyly, syndactyly, mammary hypoplasia, and excessive freckling as well as other typical ectodermal defects such as hypodontia, lacrimal duct anomalies, hypotrichosis, and onychodysplasia.


A rare, virus associated tumor due to human T-cell leukemia virus type 1 or human T-cell lymphotropic virus type 1 (HTLV-1) and is characterized by the presence of anti-HTLV-1 antibodies, and malignant, mature, medium-sized T cells with condensed chromatin and polylobated nuclei. The malignant cells exhibit a mature CD4+ T cells phenotype and express CD2, CD5, CD25, CD45RO, HLA-DR, and T-cell receptor αβ. Presentation is heterogeneous and is typically of aggressive leukemia or lymphoma, variable skin eruptions, and visceral organ involvement.


Adult-onset autosomal dominant leukodystrophy

A rare, slowly progressive neurological disorder involving central nervous system demyelination, leading to autonomic dysfunction, ataxia and mild cognitive impairment.

Summary:
Epidemiology
More than 20 families in different ethnic groups have been reported to date. Exact prevalence and incidence data are however lacking.
Clinical description
Unlike most forms of leukodystrophy which appear in childhood, ADLD occurs in the 4th to 6th decade of life. ADLD may clinically resemble multiple sclerosis in the initial phase. In most patients, the initial manifestation of the disease is autonomic dysfunction resulting in micturition urgency, bladder retention, constipation, postural hypotension and erectile dysfunction in affected males. Decreased sweating is reported in some cases. Some patients develop autonomic dysfunction later in the disease course. The other features are cerebellar dysfunction (gait ataxia, nystagmus, dysmetria, loss of fine motor control, and action tremors), pyramidal signs (spasticity, weakness of both upper and lower extremities, hyperreflexia), and cognitive impairment possibly with personality changes. These manifestations may not develop for years following initial presentation. Neuroradiological characteristics include extensive symmetrical white matter changes, corpus callosum atrophy, and brain stem and spinal cord atrophy. The disease follows a slow progressive course with an eventual loss of walking ability and slightly shortened lifespan.
Etiology
ADLD is caused by chromosomal rearrangements with duplications of the LMNB1 gene (5q23.2) or a ''position effect'' due to a genomic deletion upstream of the gene causing its upregulation. Overexpression of LMNB1 causes myelin disruption in the central nervous system for which the precise underlying pathogenic mechanisms have not been elucidated. Alteration of splicing patterns suggests that ADLD is a spliceopathy.
Genetic counseling
Genetic counseling should be provided to affected families indicating the autosomal dominant pattern of inheritance.

                            Last update:
                            July 2015

                            - Expert reviewer(s):
                            Pr Alfredo BRUSCO


Adult-onset autosomal recessive cerebellar ataxia

A rare, genetic, autosomal recessive cerebellar ataxia disease characterized by adulthood-onset of slowly progressive spinocerebellar ataxia, manifesting with gait and appendicular ataxia, dysarthria, ocular movement anomalies (e.g. horizontal, vertical, and/or downbeat nystagmus, hypermetric saccades), increased deep tendon reflexes and progressive cognitive decline. Additional variable features may include proximal leg muscle wasting and fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration and cataracts. Brain imaging reveals marked cerebellar atrophy and electromyography shows evidence of lower motor neuron involvement.


Adult-onset autosomal recessive sideroblastic anemia

A very rare non-syndromic autosomal recessive pyridoxine-refractory sideroblastic anemia due to a splice defect of glutaredoxin-5 (GLRX5) described in a single patient with adult onset microcytic hypochromic anemia with liver iron overload and type 2 diabetes.


Adult-onset cervical dystonia, DYT23 type

A rare, genetic, isolated dystonia characterized by adult-onset, non-progressive, focal cervical dystonia typically manifesting with torticollis and occasionally accompanied by mild head tremor and essential-type limb tremor.


Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy

A rare mitochondrial disease characterized by adult onset of progressive external ophthalmoplegia, exercise intolerance, muscle weakness, manifestations of spinocerebellar ataxia (e.g. impaired gait, dysarthria) and mild motor peripheral neuropathy. Respiratory insufficiency has been reported in some cases.


Adult-onset distal myopathy due to VCP mutation

A rare, genetic distal myopathy disorder characterized by middle age-onset of distal leg muscle weakness, atrophy in the anterior compartment resulting in foot drop, without proximal or scapular skeletal muscle weakness. Rapidly progressive dementia, Paget disease of bone and hand weakness have been reported. Muscle biopsy shows pronounced myopathic changes with rimmed vacuoles.


A rare neurodegenerative disease usually presenting before the age of 30 and which is characterized by dystonia, L-dopa-responsive parkinsonism, pyramidal signs and rapid cognitive decline.

Summary:
Epidemiology
Prevalence is unknown. Only 14 cases have been reported to date.
Clinical description
Disease onset occurs in late adolescence or early adulthood (usually before the age of 30) and usually presents with parkinsonism (tremor, rigidity, bradykinesia), dystonia and rapid cognitive decline. Eye movement abnormalities (supranuclear vertical gaze palsy, eyelid opening apraxia), pyramidal tract signs, and psychiatric features such as depression and personality changes have also been reported in some patients. Dopaminergic treatment is initially successful with regard to parkinsonism, but the development of prominent dyskinesias often follows.
Etiology
Adult-onset dystonia-parkinsonism is caused by mutations in the phospholipase A2, group VI (PLA2G6) gene located on chromosome 22q13.1.
Genetic counseling
Adult-onset dystonia-parkinsonism is inherited in an autosomal recessive manner, and genetic counseling is possible and recommended.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


Adult-onset foveomacular vitelliform dystrophy

A rare, genetic, macular dystrophy characterized by blurred vision, metamorphopsia and mild visual impairment secondary to a slightly elevated, yellow, egg yolk-like lesion located in the foveal or parafoveal region.

Summary:
Epidemiology
The prevalence of AOFVD is unknown.
Clinical description
The clinical onset is typically between the fourth and sixth decade of life. In the early stages of AOFVD, patients are visually asymptomatic or have mild complaints of scotoma, visual blur or metamorphopsia in one or both eyes. The visual acuity usually ranges from 20/50 to 20/25. As the disease progresses, vision loss may become more severe. Choroidal neovascularization (CNV) or central retinal pigment epithelium (RPE) atrophy may result. Color vision has been reported to be slightly impaired (tritan defect).
Etiology
The mechanism underlying the physiopathology of AOFVD is still unknown but it has been postulated that there is an abnormal accumulation of lipofuscin that may be caused by the increased workload of metabolism and phagocytosis on the RPE cells in conjunction with other disease-related factors (such as age, genetic predisposition, and environmental causes). As a result, the RPE layer is separated from the photoreceptor layer by hyper-reflective material. Mutations in the genes BEST1 (11q12), PRPH2 (6p21.1) or IMPG1 (6q14.2-q15) (encoding bestrophin-1, peripherin and SPACR respectively) have been found in some individuals with AOFVD.D.
Diagnostic methods
Diagnosis of AOFVD relies on complete ophthalmologic examination, including measurement of best-corrected visual acuity (values range between 20/20-20/100), fundus biomicroscopy, fundus autofluorescence (FAF) imaging, and fluorescein angiography of optical coherent tomography when choroidal neovascularization is suspected. The minimal criteria for AOFVD diagnosis is the presence of a macular round, yellowish, more or less homogeneous lesion with fundus examination, showing hyper-autofluorescence. Electrooculogram (EOG) and electroretinogram (ERG) show normal or subnormal results (normal Arden ratio). Optical coherence tomography (OCT) reveals a vitelliform lesion located at the level of RPE or between the RPE and photoreceptors. This technique is extremely helpful in differentiating AOFVD from age-related macular degeneration (AMD; see this term).
Differential diagnosis
The differential diagnosis of AOFVD includes Best vitelliform macular dystrophy, Stargardt disease, central areolar choroidal dystrophy, central serous retinopathy (CSR), pigmented epithelial detachment (PED), basal laminar drusen, acute exudative polymorphous vitelliform maculopathy (AEPVM) (see these terms) and occult CNV secondary to AMD.
Genetic counseling
An autosomal dominant inheritance with variable expression and incomplete penetrance is suggested but AOFVD can also be sporadic without evidence of a familial inheritance pattern.
Management and treatment
There is no effective therapy for AOVFD and patients should be managed with a comprehensive eye examination, including dilation, once or twice a year to rule out any possible complications, such as CNV, full-thickness macular holes, or retinal detachments. If vision is impaired, patients should be referred for low vision testing and rehabilitation. Ranibizumab intravitreal injections may be effective in the short-term.
Prognosis
The visual prognosis of AOVFD is relatively good because the disease typically causes slow progressive vision loss, and most patients maintain decent vision in at least one eye until very late in the disease evolution. The vitelliform lesion typically disappears later in life; however, vision loss, development of a full-thickness macular hole or a retinal detachment in the late atrophic stages of the disease may be observed.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                             Stephanie CHAN  - Pr Ian MACDONALD


Adult-onset immunodeficiency with anti-interferon-gamma autoantibodies

A rare acquired immunodeficiency disorder characterized by the appearance of susceptibility to disseminated opportunistic infections (in particular, disseminated nontuberculous mycobacterial infection, salmonellosis, penicillosis, and varicella zoster virus infection) in previously healthy (HIV-negative) adults, associated with the presence of acquired autoantibodies to interferon gamma. Typical clinical manifestation includes lymphadenopathy (cervical or generalized), fever, weight loss and/or reactive skin lesions.


Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

Hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia is a rare autosomal dominant disease characterized by a complex phenotype including progressive dementia, apraxia, apathy, impaired balance, parkinsonism, spasticity and epilepsy.


Adult-onset multiple mitochondrial DNA deletion syndrome due to DGUOK deficiency

An extremely rare multiple mitochondrial DNA deletion syndrome with markedly decreased deoxyguanosine kinase (DGUOK) activity in skeletal muscle characterized by a highly variable phenotype. Clinical manifestations include progressive external ophthalmoplegia, mitochondrial myopathy, recurrent rhabdomyolysis, lower motor neuron disease, mild cognitive impairment, sensory axonal neuropathy, optic atrophy, ataxia, hypogonadism and/or parkinsonism.


A rare autoimmune disorder of the neuromuscular junction characterized by fatigable muscle weakness with frequent ocular signs and/or generalized muscle weakness, and occasionally associated with thymoma.

Summary:
Epidemiology
Estimated prevalence varies geographically: 1/5,000 in the USA, about 1/3,000 in the UK in adults. Adult-onset represents 85-90% of MG forms in Europe and USA. The male:female sex ratio is 1:3 in patients below 40 years of age, equal in those aged 40 to 50, and about 1.5:1 in elderly patients.
Clinical description
Patients typically present with ocular symptoms, specifically diplopia and unilateral or bilateral ptosis. About 15% of patients with ocular signs do not progress to generalized myasthenia. Within 2 to 3 years of initial manifestations, a majority of patients (about 80%) develop generalized fluctuating muscle weakness, worsening with exertion and improving with rest. Symptoms, often exacerbated at the end of the day, include fatigue, dysphagia, dysphonia, exertional dyspnea or orthopnea; in severe cases difficulty chewing, choking, and nasal regurgitation may be observed. Upper limb weakness is more common than lower limb weakness. Head drop, expressionless face, and neck pain may also be found. In severe cases, a myasthenic crisis may develop, involving acute respiratory failure requiring mechanical ventilation and nasogastric tube feeding. Myasthenic crisis occurs in about 20% of affected patients, mainly in the absence of treatment. 10-15% of patients have associated thymoma, which is malignant in most cases, and more than 50% of young patients (especially females) present a thymic follicular hyperplasia.
Etiology
The exact pathogenesis is not known, but MG is mediated by circulating antibodies to various muscle receptors, including acetylcholine receptor (AChR), muscle-specific receptor tyrosine kinase (MuSK), and low density lipoprotein receptor-related protein 4 (LRP4). The thymus is thought to trigger antibody production in the form with anti-AChR antibodies. The disorder can also be drug-induced.
Diagnostic methods
The diagnosis is suspected on the basis of fluctuating muscle weakness. A thorough history to identify this pattern is essential. Easy fatigability is a classic sign. Applying ice to the eye in patients with ptosis (ice test) leads to improvement of the condition in most patients. The diagnosis can be confirmed through specific laboratory tests for antibodies to AChR or to MuSK, present in 85% and about 6% of patients, respectively. Some patients display antibodies to LRP4. Antibody-negative cases are however found. Radiography, computed tomography (CT) or magnetic resonance imaging (MRI) are required to detect thymoma or thymic follicular hyperplasia.
Differential diagnosis
Differential diagnoses include congenital MG, Lambert-Eaton myasthenic syndrome, ALS, mitochondrial myopathy, botulism and polymyositis (see these terms).
Management and treatment
The vast majority of MG patients respond well to treatment. A wide range of drugs can be used to control the disease symptoms and to suppress autoimmune response. These include acetylcholinesterase inhibitors (patients with AChR antibodies), immunosuppressants such as oral steroids, azathioprine, mycophenolate mofetil, methotrexate, and tacrolimus. Ciclosporin and cyclophosphamide have been used, as well as rituximab in severe cases. Myasthenic crisis and rapid deterioration can be treated with intravenous immunoglobulins (IVIg) and plasmapheresis. Thymectomy is indicated for young patients with anti-AChR antibodies, and for patients with thymoma.
Prognosis
The natural course of MG is gradual improvement but rare severe cases may be life-threatening. The overall prognosis with treatment is however excellent.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Sonia BERRIH-AKNIN  - Pr Bruno EYMARD


A rapidly progressive type of nemaline myopathy (NM) characterized by a very late onset.

Summary:
Epidemiology
The annual incidence of NM has been estimated at 1/50,000 live births. Adult-onset NM represents <5% of total cases.
Clinical description
Adult onset NM occurs sporadically between 20 and 50 years of age. It presents with a generalized weakness, myalgia and rapid progression. Several cases have been associated with cardiomyopathy, dropped head syndrome and respiratory involvement. Muscle biopsy can reveal inflammatory changes. Monoclonal gammopathy and paresthesiae may be a marker of poor prognosis.
Etiology
This form of NM is due to mutations in the ACTA1 (1q42.13), NEB (2q22), TPM2 (9p13.3) or TPM3 (1q21.2) genes.
Genetic counseling
Adult onset NM is usually sporadic and no familial history of neuromuscular diseases is found.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Monique RYAN


A rare inflammatory multisystem disorder characterized clinically by four cardinal signs: fever of unknown origin, arthralgia or arthritis, hyperleucocytosis, and typical skin rash.

Summary:
Epidemiology
Prevalence and incidence data are difficult to determine given the broad, non-specific clinical presentation of adult-onset Still disease (AOSD). The estimated prevalence of AOSD is more than 1/100,000 population. There is a slightly higher number of affected women than affected men.
Clinical description
AOSD primarily affects young adults, although older patients have been reported. The presenting features are variable and may include high fever (>39°C) with daily spikes, sore throat or pharyngitis, arthralgia or arthritis (>65% of patients), transient maculopapular rash, and more rarely myalgia, lymphadenopathy, hepatosplenomegaly, and serositis. Arthritis may involve any joint and can migrate in early disease and then stabilize with time. Arthralgia is usually correlated with fever spikes. Rash mostly consists of transient, small, discrete, salmon-pink, non-pruritic macules or maculopapules that often occur concomitantly with fever and generally spare the face, palms and soles of the feet. Pleuritis or pericarditis are commonly found. Patients may lose weight and have a generally poor overall health status. Three different disease courses have been described: self-limited, systemic course with a single flare and complete remission within 2 to 4 weeks, intermittent course with recurrence of systemic or articular flares after remission of 2 weeks to 2years, and a primarily articular chronic course (with erosions in a 1/3 patients). Some affected individuals have a history of systemic juvenile idiopathic arthritis.
Etiology
The etiology of AOSD and its underlying pathogenetic mechanisms are not known. No risk factors for the disease have been identified so far, but environmental factors are suspected. Several infectious conditions have been reported to be associated with onset of the disease (e.g. Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, Coxsackie virus, hepatitis A, B, and C viruses, and Mycoplasma pneumoniae).
Diagnostic methods
The non-specific clinical features of AOSD make diagnosis difficult. No serological marker is currently available. AOSD is a diagnosis of exclusion. Two sets of classification criteria, Yamaguchi and Fautrel, exist. Major diagnostic criteria include arthralgia for more than 2 weeks, intermittent high fever for more than 1 week, characteristic rash, and white blood cell count above 10,000. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, abnormal liver function tests, and negative rheumatoid factor and ANA. Elevated ferritin is often found and may assist in diagnosis, especially if it is associated with a low level of glycosylated ferritin.
Differential diagnosis
Many other inflammatory, neoplastic, and infectious conditions with a similar presentation must be ruled out in order to diagnose AOSD. Differential diagnoses include infections (endocarditis, occult infections, secondary syphilis, viral rash), malignancies (lymphoma) or autoimmune diseases (such as polyarteritis nodosa, vasculitis, or polymyositis).
Genetic counseling
AOSD is a sporadic non-inheritable disease and genetic counseling is therefore not needed.
Management and treatment
The aim is to achieve complete remission and prevent joint damage through treatment. Treatment-free remission is possible but the risk of relapse remains present throughout life Multidisciplinary rounds in contact with a reference center are highly recommended. The mainstay of first-line treatment is prednisone, and most guidelines tend to recommend an early association with biologic therapies (anti-IL1 agents (anakinra, canakinumab), and anti-IL-6 agents (tocilizumab)), in order to allow a rapid tapering of prednisone and hence prevent steroid-induced complications. Methotrexate and tumor necrosis factor blockers may be used in chronic articular forms, but have limited efficacy in systemic forms. Regular clinical and biological monitoring (initially tight) is necessary.
Prognosis
The overall prognosis is generally good, but acute life-threatening manifestations may occur in rare cases. The most classical complication is macrophage activation syndrome but blood coagulation disorders, fulminant hepatitis, cardiac and pulmonary complications may occur. Some patients with chronic disease and major joint involvement may have significantly altered quality of life, but this tends to disappear thanks to a better and earlier management with biologics.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Bruno FAUTREL  - Dr Stéphane MITROVIC


A rare, hereditary amyloidosis with primary renal involvement characterized by fibrinogen A-alpha-chain amyloid deposition predominantly in the kidney glomeruli and clinically presenting with hypertension, uremia, nephrotic syndrome slowly progressing to end-stage renal disease. Extra-renal involvement is possible, due to neurological, cardiac, visceral and vascular amyloid deposition.


A rare bacterial infectious disease caused by the tick-borne bacterium Rickettsia africae, characterized by acute onset of fever accompanied by myalgia, localized lymphadenitis, and a papulovesicular rash. In most cases at least one, sometimes multiple, inoculation eschars are observed. Clustering of cases is frequent.


A rare parasitic disease characterized by infection with the protozoans Trypanosoma brucei rhodesiense (East African trypanosomiasis) or T. brucei gambiense (West African trypanosomiasis), usually due to the bite of an infected tsetse fly. The first, hemolymphatic stage presents with fever, headaches, fatigue, lymphadenopathy, and aching muscles and joints. In East African trypanosomiasis, the fly bite may develop into a red sore or chancre. This form then progresses to CNS invasion with somnolence and other neurologic and psychiatric symptoms within a few weeks, while West African trypanosomiasis slowly progresses within about 3 years. Both forms are fatal if left untreated.


A rare syndromic agammaglobulinemia characterized by profound B-cell depletion (with normal T-cell numbers) resulting in agammaglobulinemia, associated with severe developmental delay, microcephaly, craniosynostosis, cleft palate, narrowing of the choanae, blepharophimosis, and severe dermatitis. Additional reported features include distal joint contractures, renal/genitourinary anomalies, and mild cerebral atrophy, among others.


A rare, systemic amyloidosis characterized by a triad of ophthalmologic, neurologic and dermatologic findings due to the deposition of gelsolin amyloid fibrils in these tissues. Clinical manifestations include corneal lattice dystrophy, cranial neuropathy, especially affecting the facial nerve, bulbar signs, cutis laxa, increased skin fragility, and less commonly peripheral neuropathy and renal failure.


A rare congenital anomaly of the great veins characterized by unilateral or bilateral complete absence of the superior vena cava (SVC). Unilateral agenesis is mainly asymptomatic (most of the time diagnosed incidentally) and patients usually have otherwise normal heart structure. Bilateral agenesis, however, is frequently associated with other congenital cardiac anomalies and/or conduction abnormalities (such as tetralogy of Fallot, atrial septal defect) and typically present symptoms of SVC syndrome.


An extremely rare and highly aggressive neoplasm, usually manifesting in the third to fourth decade of life, affecting males and females equally, and characterized by the onset of high fever, weight loss, jaundice, skin infiltration, lymphadenopathy, hepatosplenomegaly, and severe anemia. It has a fulminant and rapidly fatal disease course with the progressive appearance of multiorgan failure and disseminated intravascular coagulation.


A rare, aggressive form of advanced systemic mastocytosis (advSM) characterized by massive infiltration of mast cells (MC) in different tissues and presence of extracutaneous organ dysfunction, but without evidence of mast cell leukemia or another hematologic neoplasm.

Summary:
Epidemiology
It represents less than 10% of all SM cases and the global prevalence is estimated in the order of between 1/250,000-400,000.
Clinical description
Aggressive systemic mastocytosis (ASM) may occur at any age, occurring predominantly in adults and very rarely in pediatric patients. Presentation is with organ dysfunction related to mast cell invasion (C-findings) and the intense release of mediators including syncope, recurrent flushing, diarrhea, pain, organomegaly. C-findings include bone marrow (BM) dysfunction, palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension, skeletal involvement with large osteolytic lesions and/or pathological fractures, palpable splenomegaly with hypersplenism and malabsorption with ascites. Patients do not show signs of non-mast cell hematological disease. Cutaneous involvement is slightly less frequent than in indolent SM. The most serious complications include potentially fatal anaphylactic shock and transformation to mast cell leukemia (MCL). Disease progression can be either slow or rapid. In patients with rapid progression, serum tryptase levels increase rapidly, multi-organ damage occurs (or worsens) within a short time, and rapid progression to MCL is frequent. Due to the latter, ASM with >5% MC in BM smears is termed ASM in transformation.
Etiology
The etiology is not well understood but there is evidence of an activating mutation of KIT, usually D816V, in the mast cells and sometimes in non-MC hematopoietic lineages. Additional and recurrent somatic mutations of other genes have been reported in ASM; the genes most frequently affected includeTET2, SRSF2, ASXL1, RUNX1, JAK2, N/KRAS, and CBL and, less frequently,EZH2, IDH2, ETV6, U2AF, or SF3B1. These defects contribute to aggressiveness of the disease, particularly in multi-mutated patients.
Diagnostic methods
Diagnosis of SM is established using the WHO (World Health Organization) consensus criteria. The disease is then categorized according to the presence of B- and C-findings. The characteristics of ASM includes BM smear with <20% MC, and one or more C-findings. In rapidly progressive cases, the percentage of MC in the BM smears is of major prognostic significance and is usually elevated substantially (>5%).
Differential diagnosis
Differential diagnoses include all causes of cytopenias (myelofibrosis, myelodysplasia and other hematological malignancies) and other abnormal types of mutation in JAK2, that are excluded by the detection of bone marrow infiltration by neoplastic mast cells with an activation mutation of KIT.
Management and treatment
Treatment is constant with non-targeted or targeted cytoreductive therapy. Non-targeted therapies include interferon-(IFNalpha), which may be effective in a subset of patients, and cladribine (2CdA) which provides high, and sometimes long lasting, response rates. Allogeneic stem cell transplantation (allo-SCT) is rarely used and reserved for fit patients with a suitable donor. However, when applicable, allo-SCT provides frequently good response rates and complete remission. Targeted therapy is with KIT tyrosine kinase inhibitors (KIT TKIs) Midostaurin which inhibits the D816V mutant (approved in Europe and the USA), is regarded as the standard first-line therapy in ASM. Whilst it is efficacious, it does not induce complete hematologic remissions. Midostaurin may also be useful for patients who need debulking prior to allo-SCT or those who fail treatment with 2CdA or IFNalpha. Other TKIs included imatinib mesylate or masitinib and may be indicated for the few patients without the KITD816V mutation. Symptomatic treatment is mainly with antihistamines (anti-H1 and anti-H2). The use of iodinated contrast agents should be limited.
Prognosis
The prognosis is usually poor with a median survival of 2 to 4 years. Due to rapid progression to MCL, ASM patients with a MC count in the BM smears >5% have a worse outcome with reduced survival and progression-free survival compared to patients with <5%. Furthermore, the presence of mutations in other critical target genes, in particular SRSF2, ASXL1, RUNX1, is associated with progression and poor outcome.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr Michel AROCK


An extremely rare and fatal association syndrome, characterized by absence of the mandible, cerebral malformations with facial anomalies related to a defect in cleavage in the embryonic brain (e.g. synophthalmia, malformed and low-set ears fused in midline (otocephaly), agenesis of the olfactory bulbs, microstomia, hypoglossia/aglossia) and situs inversus partialis or totalis.


A rare, systemic amyloidosis characterized by the aggregation and deposition of amyloid fibrils composed of monoclonal immunoglobulin heavy-chain fragments, usually produced by a plasma cell neoplasm. Amyloid fibrils deposit in various organs, most commonly in the kidneys. It typically affects older patients and clinical presentation includes signs and symptoms of renal dysfunction, sometimes leading to nephrotic syndrome and end stage renal disease. Cardiac, liver and nerves involvement has also been described.


AHDC1-related intellectual disability-obstructive sleep apnea-mild dysmorphism syndrome

A rare, syndromic intellectual disability characterized by hypotonia, developmetal delay, absent or severly delayed speech development, intellectual disability, obstructive sleep apnea, mild dysmorphic facial features and behavioral abnormalities. Epilepsy, ataxia and nystagmus have also been reported.


A rare and severe inborn metabolic disease characterized clinically by the association of severe-to-profound neurodevelopmental impairment, severe visual impairment, ante-postnatal growth impairment, severe scoliosis and, frequently, early-onset epilepsy.

Summary:
Epidemiology
To date only 4 affected individuals from 3 independent families have been reported worldwide.
Clinical description
There are no specific fetal abnormalities. However, during pregnancy, intrauterine growth retardation and low amniotic fluid are noted frequently. The newborns usually display a marked global hypotonia and global developmental delay is usually noticeable during the first year. Affected children are able to learn some skills but most of them will remain unable to walk and speak. No structural brain abnormalities are noted. Epilepsy of variable type and severity is frequent and usually noticeable during the first year of life. Visual issues are also usually noticeable during the first year of life, characterized mainly by severe hypermetropia and chorio-retinal atrophy. Some individuals can see close objects whereas others are blind. Severe scoliosis usually appears during childhood. Growth remains delayed to approximately -2 to -4 standard deviations, with normal cranial circumference. Affected individuals share common inconspicuous facial features (short and upturned nose, brushy eyebrows, and long eyelashes). Other clinical features that may be related to the disease include chronic hepatic cytolysis with recurrent acute aggravations and hepatomegaly , aortic coarctation of the newborn, and nephrocalcinosis. A less severe phenotype is possible.
Etiology
AICA-ribosiduria is caused by germline defects in the ATIC gene (2q35). The pathogenesis seems to involve a cytotoxic effect of abnormally accumulated substrates of ATIC enzyme: AICAR and AICA-riboside. No genotype-phenotype relationship has been identified.
Diagnostic methods
The diagnostic is not usually suspected on clinical grounds, although theoretically recognizable. It is more realistically suspected after exome-, genome-, or gene-panel- sequencing, in the presence of two pathogenic loss of function variations in the gene ATIC, with a bi-allelic pattern. The diagnosis can also be suspected in the presence of a positive urine Bratton-Marshall test suggesting an accumulation AICA-riboside. The diagnosis may be definitively confirmed by HPLC (High Performance Liquid Chromatography) analysis.
Differential diagnosis
There is no true differential diagnosis. However, each of the core features has numerous differential diagnoses.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variants have been previously identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive. For the parents of an affected child, the risk of recurrence for each future pregnancy is 25%. Genetic counseling is highly recommended for affected families.
Management and treatment
Management is multidisciplinary. There is no preventive, curative, or specific treatment to date. Epilepsy should be sought, and when present should be treated by an experienced neuropediatrician according to the standard protocols. It may become pharmacoresistant. The patient should be referred to an experienced ophthalmologist. Hypermetropia can be treated according to standard procedures; however, chorio-retinal atrophy has no specific treatment. The presence of scoliosis should be assessed and treated aggressively if present. Neurodevelopment should be supported through an early intervention program. Growth retardation is not usually subject to specific measures.
Prognosis
To date all individuals affected by AICA-ribosiduria require extensive support. Life expectancy is unknown (oldest individual is 20 years of age).

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Dr Francis RAMOND


A rare neurodevelopmental disorder characterized by the classic triad of agenesis of the corpus callosum (total or partial), central chorioretinal lacunae and infantile spasms that affects almost exclusively females.

Summary:
Epidemiology
About 200 individuals with Aicardi syndrome have been reported in North America and Europe, but the true prevalence is unknown. Single cases in males with 47, XXY chromosome constitution have been reported.
Clinical description
Individuals typically present within the first few months of life with infantile spasms and low muscle tone. In addition to the classic triad (agenesis of the corpus callosum, central chorioretinal lacunae and infantile spasms), other characteristics have been identified. All individuals manifest additional developmental brain abnormalities, with most presenting periventricular nodular heterotopias, brain cysts and polymicrogyria or pachygyria. While infantile spasms are the most common initial seizure type, most evolve into a complex pattern of partial and generalized seizures that are typically very difficult to control. In addition to chorioretinal lacunae, microphthalmia, retinal and optic nerve colobomas can be seen. Facial features, including prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows have been described. Scoliosis is present in up to one third of affected individuals. Gastrointestinal disorders such as reflux, discomfort and constipation are nearly universal. Less common findings include cutaneous vascular malformations and pigmentary skin lesions. Vascular tumors have been reported in a few individuals.
Etiology
It is believed that Aicardi syndrome is a sporadic disorder caused by heterozygous pathogenic variants in an X-linked gene in females, with early embryonic lethality in hemizygous males; however, a candidate region on the X chromosome has not yet been identified due to the sporadic nature of the condition. Some groups have reported potential causative genes in single individuals but these have not been confirmed in larger studies.
Diagnostic methods
Diagnosis is based on clinical features, brain imaging and skeletal findings. There is no blood test or other clinical diagnostic test to confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes microcephaly-chorioretinopathy with or without lymphedema (in this disorder, the lacunae are peripheral and the microcephaly is significant ; girls with Aicardi syndrome typically do not have microcephaly), oculocerebrocutaneous syndrome, neuronal migration disorders and numerous syndromes that present with one or more of the features characteristic for Aicardi syndrome.
Antenatal diagnosis
Prenatal diagnosis may be suspected based upon fetal brain imaging.
Genetic counseling
Aicardi syndrome appears to be a de novo, X-linked dominant disorder with lethality in males. There are no confirmed cases of familial recurrence.
Management and treatment
Long-term follow-up by a pediatric neurologist is necessary for management of seizures. Seizures are often refractory to multiple medication regimens and no single medication works for all; some have reported improvement with vagal nerve stimulators. Physical, occupational, speech and vision therapy should begin at diagnosis. Appropriate musculoskeletal support and treatment for prevention of scoliosis-related complications is indicated. Immunizations, infection control measures and therapy for pulmonary toilet are important to reduce the risk of pneumonia, a major cause of mortality.
Prognosis
Difficult-to-control seizures and significant neurodevelopmental disorders are the primary challenge for individuals with Aicardi syndrome. Most are not able to sit independently, walk or speak. The 5-, 10- and 20-year survival rates are 90%, 80% and 50%, respectively. Pulmonary infections, presumed secondary to hypotonia, are the most common cause of death.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr V. Reid SUTTON