A rare multisystemic disorder characterized by cone-rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy (DCM), and progressive hepatic and renal dysfunction.

Summary:
Epidemiology
Alström syndrome (AS) has a suggested prevalence of 1/1000,000 in Europe and North America. A much higher frequency was reported in some populations with a high level of consanguinity or those that are geographically isolated. More than 950 cases have been identified worldwide.
Clinical description
The clinical features, age of onset, and severity can vary greatly among and within families. Cone-rod retinal dystrophy usually develops within a few weeks after birth, with the first symptoms being nystagmus and extreme photodysphoria or light sensitivity. It is progressive and leads to blindness, usually by the second decade of life. Most patients develop mild-to-moderate slowly progressive bilateral sensorineural hearing loss. There is evidence of multi-organ fibrosis in AS. DCM manifests in approximately 2/3 of patients, either as infants or as adolescents. Patients are at risk of sudden congestive heart failure at any age. Obesity with hyperphagia, insulin resistance and hyperinsulinemia are early and consistent features. Liver dysfunction usually begins in childhood with steatosis (fatty liver). In some cases, cirrhosis, portal hypertension and liver failure can occur. Chronic respiratory illness (bronchitis/pneumonia), pulmonary hypertension, recurrent otitis media, and hypertriglyceridemia are frequent. Slowly progressive nephropathy can lead to end stage renal failure. Patients have distinctive facial characteristics ( thin hair, premature frontal balding, deep-set eyes with a rounded face and thick ears,). Most children have characteristic wide, thick, flat feet, and short stubby fingers and toes with no polydactyly or syndactyly. Hypogonadism in males/hyperandrogenism in females is also reported. Most patients have normal intelligence, although some reports have indicated delayed global development and intellectual disability. As some phenotypes develop slowly over time, non-classical presentations have also been reported.
Etiology
AS is caused by mutations in the ALMS1 gene (2p13.1). Its molecular function is currently unknown, although roles in ciliary function, cell cycle control, and intracellular transport have been suggested.
Diagnostic methods
Diagnosis is made on the basis of the clinical features observed (major/minor), and typically confirmed with genetic testing. Family history is considered a major criteria in the diagnosis of AS.
Differential diagnosis
Differential diagnoses include Bardet-Biedl syndrome, Biemond syndrome type 2, Wolfram syndrome, Cohen syndrome, familial isolated DCM and mitochondrial disorders.
Antenatal diagnosis
Prenatal testing can be offered if the ALMS1 mutations have been previously identified in a family member.
Genetic counseling
AS is transmitted autosomal recessively and genetic counseling is recommended.
Management and treatment
Management should include vigilant monitoring and treatment of the emerging clinical manifestations. Red-orange tinted prescription lenses can reduce photophobia. As blindness occurs in all cases, early educational planning to teach patients Braille, computing skills and adaptive living skills is essential. Bilateral digital hearing aids and cochlear implants can increase hearing capabilities. Heart failure is mainly treated with angiotensinogen-converting enzyme (ACE) inhibitors, beta-blockers, diuretics, and digoxin. Heart transplantation could be also considered. Diabetes can be managed with a low-fat, low sugar diet, exercise, metformin, glitazones, incretin analogues, and SGLT2 inhibitors (beneficial in 2/3 of cases). Beta-blockers, sclerotherapy of the esophageal veins, and banding usually treat portal hypertension. In unsuccessful cases a transjugular intrahepatic portosystemic shunt may be needed. In those with renal disease, ACE inhibitors can be considered. In several cases, renal transplantation has been successful. New medications are in clinical trials, and include PBI-4050 (phase 2 completed), a compound with anti-fibrotic and anti-inflammatory properties, and setmelanotide for the treatment of hyperphagia in rare forms of genetic obesity including AS.
Prognosis
Although the life span of AS patients can be shortened, early diagnosis and intervention can moderate the progression and improve the longevity and quality of life of patients.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Pietro MAFFEI


A rare, genetic, neurodevelopmental disorder characterized by early-onset of recurrent, transient episodes of hemiplegia (including quadriplegia), which typically disappear upon sleep.

Summary:
Epidemiology
Alternating hemiplagia of childhood (AHC) prevalence is estimated at 1/100,000 in children under 16 years old, although underdiagnosis is probable.
Clinical description
Patients usually present in infancy with episodic hemiplegia involving one or alternating sides of the body which typically disappear upon sleep. Episodes occur with variable frequency and may last a few minutes to several days. Isolated or associated episodes of bilateral hemiplegia may also be observed. Early signs of the disease are often noted, in some cases shortly after birth, associating paroxysmal involuntary movements (including tonic-dystonic movements) nystagmus, choreoathetosis, dyskinesia and autonomic abnormalities. Various triggers may precipitate symptoms, including exposure to heat or cold, emotional stress, fatigue, excessive light and sound stimuli, trauma, and bathing. Psychomotor delay, ranging from mild to severe, is common. Additional features include cerebellar signs, speech disorders and behavioral disturbances, such as mood changes, aggressiveness, impulsivity and attention deficit. A considerable number of AHC patients develop epilepsy and cardiac conduction abnormalities.
Etiology
Although the exact pathophysiological mechanism of AHC remains unclear, de novo heterozygous mutations in the ATP1A3 (19q13.2) gene, encoding a subunit of the Na+/K+ ATPase pump, have been implicated as causative for the majority of screened AHC cases. Over 60 different AHC mutations have been identified so far in the ATP1A3 gene as the most frequent mutations are D801N (43%), E815K (16%), and G947R (11%) Some cases with alternating hemiplegia and atypical features have been reported with mutations in the ATP1A2 (1q23.2),CACNA1A,ADCY5, TANGO2 and SLC1A3 genes.
Diagnostic methods
Diagnosis is based on characteristic clinical manifestations using Aicardi's diagnostic criteria. ATP1A3 gene testing would be recommended to support clinical diagnosis of AHC.
Differential diagnosis
Differential diagnoses includes infantile epilepsy syndrome, benign nocturnal alternating hemiplegia of childhood, as well as allelic disorders with overlapping clinical features, such as rapid-onset dystonia-parkinsonism, familial or sporadic hemiplegic migraine and Moyamoya disease. Neurological, metabolic and vascular syndromes with similar clinical features should also be excluded.
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is possible if a causative mutation has been previously identified in the family.
Genetic counseling
AHC is inherited in an autosomal dominant manner as most cases are sporadic. However, parental germline mosaicism has also been reported in couple of cases with familial recurrence. Therefore genetic counseling should be provided to parents with an affected child and should take into account the risk of recurrence in the family.
Management and treatment
There is no regulatory approved treatment for AHC. Flunarizine has been widely prescribed during the past 30 years to reduce the frequency, severity and duration of hemiplegic episodes. Other commonly used drugs are topiramate, benzodiazepines, chloral hydrate. Seizures and ECG abnormalities should be properly treated and monitored while triggers and irregular sleeping patterns should be avoided as much as possible.
Prognosis
Psychomotor outcome is highly variable as some patients may be wheelchair-bound while others are able to live independent lives in adulthood. Frequency and duration of acute manifestations generally decrease with age, however sudden deterioration can occur in the late course of the disease. Status epilepticus in alternating hemiplegia is linked to severe outcome.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Dr Tsveta SCHYNS-LIHARSKA


A rare parasitic disorder that occurs after ingestion of eggs of Echinococcus multilocularis and characterized by an initial asymptomatic incubation period of many years followed by a chronic course where the clinical manifestations include epigastric pain and jaundice.

Summary:
Epidemiology
E.multilocularis is endemic in the northern hemisphere and central Europe and the incidence in Europe is estimated to range between 1/10,000,000-1/330,000. Hot spots are in Western parts of China and Central Asia. People at high risk include dog-owners, including farmers, or others who have contact with wild foxes, or their stool.
Clinical description
The peak age group in Europe is 50-60 years. After an asymptomatic period of >10 years, the parasite invades mainly the liver forming slow-growing, minute vesicles comparable to a sponge. As the lesion gets larger, the central part may become necrotic, and appears as a pseudocyst. Calcifications can frequently be seen. The clinical manifestations include epigastric pain and jaundice which may be followed by fever, anemia and weight loss. Invasion of the bile ducts leads to cholangitis, portal hypertension, and biliary cirrhosis. The disease can progress to the cirrhotic stage after a long latent, asymptomatic period. Extrahepatic manifestation as primary disease is very rare (1%). 13% of cases present as multiorgan disease where the metacestode infiltrates the neighborhood of the liver, and/or sets metastasis involving the lungs, spleen, bones and/or brain. Lung or brain involvement is characterized by exertional dyspnea, dysarthria, hemiparesis and cranial nerve palsies.
Etiology
Alveolar echinococcosis (AE) occurs after ingestion of eggs of the parasite E.multilocularis. Wild carnivores, mainly foxes, are the most important definitive hosts but domestic dogs and cats may also serve as definite hosts by ingestion of infected wild rodents. Human are accidental intermediate hosts and are affected by the intermediate metacestode stage of the parasite.
Diagnostic methods
Diagnosis of AE is based on: typical organ lesions detected by imaging techniques such as ultrasound (large hepatic mass with juxtaposed areas of internal hyper- and hypoechogenicity, irregular margins, and scattered calcification, and/or a pseudocyst with a large area of central necrosis surrounded by an irregular ring-like region of hyperechogenicity representing fibrous tissue), CT (indistinct solid tumors with central necrotic areas, plaque like calcifications), and MRI; detection of specific serum antibodies by ELISA or by immunochromatographic test; specific staining of metacestode in histo-or immunohistopathology; and detection of E. multilocularis nucleic acid in a clinical specimen.
Differential diagnosis
Differential diagnosis includes benign or malignant neoplasms, focal hepatic lesions, and abscesses.
Management and treatment
The mainstay for AE treatment remains an interdisciplinary management guided by gastroenterologists, surgeons, radiologists and parasitologists. Radical surgery is indicated if lesion can be excised with safety margins. Long-term antiparasitic treatment with albendazole is mandatory. Preventive measures include avoidance of contact with fox feces, use of praziquantel-impregnated baits, regular treatment of dogs or cats with praziquantel, as well as hand washing and improved hygiene.
Prognosis
AE is one of the most dangerous zoonotic diseases in the world and if untreated prognosis is poor. Early diagnosis and treatment of AE, especially during the asymptomatic period, are important for reducing morbidity and mortality. Patients succumb to hepatic failure, invasion of contiguous structures, or, less frequently, involvement of the brain. Mortality rates have traditionally been high, ranging between 50% and 75%. However, in recent years major achievement has been reached by careful management of AE cases, and life-expectancy of patients is approaching that of the general population.

                            Last update:
                            June 2014


A rare soft tissue sarcoma characterized by a slowly growing, painless space-occupying lesion, composed of large, uniform, epithelioid cells arranged in solid nests and/or alveolar structures, separated by thin, sinusoidal vessels. The tumor mostly affects adolescents and young adults. Early metastasis, most commonly to the lung, bones, and brain, is a characteristic feature and relevant prognostic factor, together with age at presentation and tumor size, while histological features have no prognostic significance.


A rare, hereditary amyloidosis with primary renal involvement characterized by amyloid deposition in the kidney glomeruli and medulla, gastrointestinal tract, liver, spleen and slow disease progression. Symptoms and signs include nausea, vomiting, dyspepsia, gastritis, gastrointestinal hemorrhage, abdominal pain, hepatic rupture, sicca syndrome, purpura and petechiae, lymphadenopathy and renal dysfunction.


A rare, syndromic, inherited retinal disorder characterized by cone-rod type congenital amaurosis, severe retinal dystrophy leading to visual impairment and profound photophobia (without night blindness), and trichomegaly (bushy eyebrows with synophrys, excessive facial and body hair (including marked circumaleolar hypertrichosis). There have been no further descriptions in the literature since 1989.


A rare ectodermal dysplasia syndrome characterized by the association of hypocalcified and hypoplastic tooth enamel, distal finger and toenail onycholysis with subungueal hyperkeratosis, and functional hypohidrosis. Additional manifestations include seborrheic scalp dermatitis and rough, dry skin. Lacrymal punctae may be occasionally absent. There have been no further descriptions in the literature since 1975.


A rare odontogenic tumor characterized by aggressive clinical course and local destruction, occurring in mandible more often than in maxilla. The most common symptom is a rapidly progressing painful swelling, but it may present as a benign cystic lesion or as a large, rapidly growing mass with ulceration, bone resorption and teeth mobility, as well. The tumor may metastasize, most commonly to the cervical lymph nodes and the lungs.


A rare, benign, slow-growing odontologic tumor located in the mandible, and on occasion the maxilla, characterized by painless, variable-sized jaw swelling, which if left untreated may lead to a grotesque facial appearance. Occasionally, paresthesias, tooth displacement and adjacent root resorption may be associated. Local invasion is frequently observed, but malignant transformation and metastasis are not common.


A genetically heterogeneous autosomal recessive syndrome characterized by the triad of amelogenesis imperfect, infantile onset epilepsy, intellectual disability with or without regression and dementia.


A rare genetic odontal or periodontal disorder that represents a group of developmental conditions affecting the structure and clinical appearance of the enamel of all or nearly all the teeth in a more or less equal manner, and which may be associated with morphologic or biochemical changes elsewhere in the body.

Summary:
Epidemiology
The prevalence varies from 1:700 to 1:14,000, according to the populations studied.
Clinical description
The enamel may be hypoplastic, hypomineralised or both, and affected teeth may be discoloured, sensitive or prone to disintegration. Amelogenesis imperfecta (AI) exists in isolation or associated with other abnormalities as part of a syndrome.
Etiology
In families with an X-linked form, it has been shown that the disorder may result from mutations in the amelogenin gene, AMELX. The enamelin gene, ENAM, is implicated in the pathogenesis of the dominant forms of AI. Autosomal recessive AI has been reported in families with known consanguinity.
Diagnostic methods
Diagnosis is based on the family history, pedigree plotting and meticulous clinical observation. At present, genetic diagnosis is only available as a research tool.
Genetic counseling
It may be sporadic or show autosomal dominant, autosomal recessive or sex-linked inheritance.
Management and treatment
The condition presents social and functional problems and leads to discomfort, but it may be managed by early vigorous intervention, both preventively and restoratively, with treatment continued throughout childhood and into adult life. In infancy, the primary dentition may be protected by the use of preformed metal crowns on posterior teeth. Longer-term care involves either crowns or, more frequently these days, adhesive, plastic restorations.

                            Last update:
                            April 2007

                            - Expert reviewer(s):
                            Pr Michael ALDRED  - Pr Agnès BLOCH-ZUPAN  - Pr Peter CRAWFORD


A tropical disease mainly found in latin America and transmitted by triatomine insects (mostly Triatoma infestans and Rhodnius prolixus and Panstrongylus megistus) harboring the hemoflagellate protozoan parasite Trypanosoma cruzi. The disease is characterized by an acute phase which is either asymptomatic or manifest with fever, inflammation at the inoculation site (inoculation chancre or chagoma), unilateral palpebral edema called the Romaña sign (when the triatomine bite occurs near the eye), enlarged lymph nodes, and splenomegaly. The chronic phase is lifelong and development of chagasic cardiomyopathy (30%; complex arrhythmias, heart failure, and thromboembolic events), digestive (10%; megaoesophagus and megacolon), neurological (10%; stroke, peripheral neuropathy and autonomic dysfunction), or mixed alterations (10%) may be observed. These can all lead to high morbidity and mortality rates.


An inborn error of metabolism marked by a characteristic pattern of urinary N-acetyl amino acid excretion and neurologic symptoms.

Summary:
Epidemiology
Prevalence is unknown but less than 20 cases have been reported in the literature so far.
Clinical description
Most individuals with ACY1D identified so far are children who underwent selective screening tests for inborn errors of metabolism prompted mainly by delayed psychomotor development or by the occurrence of seizures. However, there is a considerable phenotypic variability between ACY1D individuals.
Etiology
ACY1D is caused by biallelic mutations in the ACY1 gene (3p21.2). ACY1 catalyzes the formation of free amino acids from N-acetylated precursors. The enzyme is strongly expressed in the human brain and is a potential modifier affecting the severity or manifestation of different neurologic diseases.
Diagnostic methods
Diagnosis is made by gas chromatography-mass spectrometry (GC-MS) analysis of urinary organic acids revealing increased levels of N-acetylated amino acids, including methionine, glutamine, alanine, leucine, glycine, valine, and isoleucine derivatives, or by NMR spectroscopy of urine. The diagnosis can be confirmed by identification of mutations in the ACY1 gene and by detection of reduced ACY1 enzyme activity in Epstein-Barr virus (EBV)-transformed lymphoblasts or in fibroblasts.
Genetic counseling
ACY1D is transmitted as an autosomal recessive trait.
Management and treatment
Management is symptomatic only.
Prognosis
Due to the small number of individuals known to have ACY1D and due to the young age of the reported patients, the clinical course cannot be fully predicted and the prognosis is unknown. Characterization of additional patients and long-term follow-up are indicated.

                            Last update:
                            August 2008

                            - Expert reviewer(s):
                            Pr Jörn Oliver SASS


A syndrome of developmental anomalies characterized by growth deficiency, facial dysmorphism and skull, limb and neural defects secondary to maternal exposure to aminopterin or methotrexate (MTX) during pregnancy.

Summary:
Epidemiology
At least 51 cases have been reported in the last decades; prevalence and incidence values are not available.
Clinical description
Fetuses and neonates present with short stature, skull anomalies (delayed calvarial ossification, craniosynostosis and cloverleaf skull), facial dysmorphism (hypertelorism, broad nasal bridge, prominent eyes, micrognathia, abnormal external ears), cleft palate, hydrocephalus, limb anomalies (shortness, ossification defects, talipes equinovarus, hypodactyly, syndactyly, hypoplastic toes, hypoplastic nails) and neural tube defects. In some cases, cardiac malformations such as tetralogy of Fallot, pulmonary atresia or ventricular septal defects have been reported. Occasional encephalic anomalies are absent corpus callosum, hypoplastic cerebellum and, more rarely, holoprosencephaly. Psychomotor development is usually normal, but cases with mild to severe intellectual deficit are reported.
Etiology
The syndrome is caused by exposure during the first trimester of pregnancy to aminopterin or MTX, two folate antagonists. Aminopterin is no longer used, but MTX is used as an abortifacient (especially in case of suspected ectopic pregnancy), in inflammatory diseases (Crohn's disease, psoriasis, rheumatoid arthritis) and in malignancies (at higher doses). The teratogenic effect was described very early, given the anti-mitotic activity. The malformation rate after in utero exposure to aminopterin or MTX is not known, but it is dose- and time-related. It has been suggested that the critical period for MTX-induced teratogenicity is from 6 to 8 weeks after conception. Paternal MTX exposure at the time of conception does not seem to raise any major concern for offspring, but therapy discontinuation 3-6 months before conception is usually advised.
Diagnostic methods
Diagnosis is based on clinical examination and a history of maternal/paternal exposure.
Differential diagnosis
Differential diagnosis includes various genetic diseases presenting with one of the following signs: anomalies of the developing calvaria, micrognathia with cleft palate (including Pierre Robin syndrome - see this term), limb reduction defects and hand/feet anomalies. An "aminopterin syndrome sine aminopterin (ASSA) syndrome" (see this term) has been described..
Antenatal diagnosis
Antenatal diagnosis can be oriented by 2nd-3rd trimester ultrasound if intrauterine growth retardation (IUGR), oligo-polyhydramnios and/or malformations are seen in an at-risk pregnancy.
Management and treatment
MTX and aminopterin should not be administered in pregnant women. A pregnancy could be considered, 3-6 months after MTX treatment has been stopped by women or men. Women with chronic diseases should be counseled to plan their pregnancies. In case of exposure during the 6 months preceding conception, folic acid supplementation (5 mg/day) is recommended in the preconception period (1-3 months) and for the whole first trimester of pregnancy. Folic acid supplementation (5 mg/day) is recommended throughout pregnancy for women exposed to aminopterin or MTX during pregnancy. Pregnancies exposed to aminopterin or MTX should be carefully monitored with second level ultrasounds and fetal heart ultrasound to control potential anomalies. Cardiac malformations can be corrected by surgery.
Prognosis
Prognosis depends on the extent and severity of malformations.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Matteo CASSINA  - Pr Maurizio CLEMENTI  - Dr Elena DI GIANANTONIO


A very rare syndrome characterized by extreme microcephaly and early death, within the first year.

Summary:
Epidemiology
It has been described only in the Old Order Amish of Lancaster County Pennsylvania. In this population, birth prevalence is about 1/500.
Clinical description
Microcephaly is a microcephalia vera (MV), evident at birth or through 22-week fetal ultrasound. Affected children have high urinary levels of alpha-ketoglutaric acid.
Etiology
All affected infants are homozygous for the same mutation of the SLC25A19 gene on chromosome 17 (17q25.3).
Genetic counseling
The condition follows an autosomal recessive pattern of inheritance.
Prognosis
Prognosis is very poor: the average life span of affected infants is between five and six months.

                            Last update:
                            December 2010


A type of nemaline myopathy (NM) only observed in several families of the Amish community.

Summary:
Clinical description
It has a neonatal onset and patients present with hypotonia associated to contractures, a severe pectus carinatum, and tremor that subsides after 2-3 months of age.
Etiology
TNNT1 (19q13.4) is the causative gene of the Amish NM.
Genetic counseling
Transmission follows an autosomal recessive pattern.
Prognosis
Life expectancy rarely exceeds 2 years as a consequence of severe respiratory insufficiency.

                            Last update:
                            October 2010

                            - Expert reviewer(s):
                            Dr Monique RYAN


Constriction rings syndrome is a congenital limb malformation disorder with an extremely variable clinical presentation characterized by the presence of partial to complete, congenital, fibrous, circumferential, constriction bands/rings on any part of the body, although a particular predilection for the upper or lower extremities is seen. Phenotypes range from only a mild skin indentation to complete amputation of parts of the fetus (e.g. digits, distal limb). Compression from the rings may lead to edema, skeletal anomalies (e.g. fractures, foot deformities) and, infrequently, neural compromise.


A parasitic disease caused by the protozoa, Entamoeba histolytica, mainly occurring in tropical regions after the ingestion of an amoebic cyst, and resulting in clinical manifestations that may range from an asymptomatic state to amoebic colitis (violent abdominal pain, a painful contracted feeling around the anal sphincter, blood and mucus in the stools but without the presence of fever), or amoebic liver abscesses (fever, chills, abdominal pain, weight loss, hepatomegaly) that can be fatal if not immediately treated. Extraintestinal involvement elsewhere (i.e. thoracic, hepatic) is extremely rare.


A rare parasitic disease caused by free-living amoebae belonging to the Acanthamoeba, Naegleria and Balamuthia genera, that are able to survive in an autonomous state in all natural environments and can also parasitize humans. In immunosuppressed individuals Acanthamoeba genus contamination leads to granulomatous amoebic encephalitis (also reported in association with species of the Balamuthia genus) together with other problems including cardiac, cutaneous and pulmonary manifestations, all of which influence the prognosis. In immunocompetent individuals, the Naegleria fowleri species is responsible for primary amoebic meningoencephalitis, the evolution of which is rapidly fatal.


A rare corneal infection due to the protozoan Acanthamoeba that generally occurs in contact lens wearers and that is characterized by severe ocular pain, blepharospasm, photophobia, eye tearing, blurred vision and foreign body sensation. It can lead to impaired visual acuity if not treated promptly.


A rare primary cutaneous amyloidosis characterized by macular or reticulate hyperpigmentation with symmetrically distributed guttate hypo- and hyperpigmented lesions which progress gradually over the years to involve almost the entire body (with relative sparing of the face, hands, feet and neck). Patients are usually asymptomatic, however mild pruritus may be associated. Amyloid deposition in the papillary dermis is observed on skin biopsy. Systemic amyloidosis is not present and association with generalized morphea, atypical Parkinsonism, spasticity, motor weakness or colon carcinoma is rare.


A vast group of rare systemic diseases characterized by the presence of insoluble fibrillar protein deposits in tissues. Amyloidoses are classified according to biochemical type of amyloid protein involved.

Summary:
Epidemiology
AL amyloidosis's estimated global incidence of 1/95,800 people, with males preponderance. Hereditary ATTR amyloidosis (or ATTRv) mid-global prevalence estimate is of 1/450,000 people (range 1/120,000-830,000). In Tuscany, the incidence of ATTR wild type (ATTRwt) and ATTRv is 1/37,500 and 1/370,000, respectively, with male preponderance. AA amyloidosis estimated incidence is 1-2/1,000,000, but is decreasing.
Clinical description
The most frequent forms are AL amyloidosis, involving all organs except the brain, ATTR amyloidosis, ATTRwt involving the heart and ATTRv involving nerves and heart, and AA amyloidosis involving mainly kidneys, thyroid and GI tract. Progression is usually severe, as affected organs' functions are progressively destroyed. Localized amyloidosis usually has a benign course.
Etiology
AL amyloidosis is caused by plasma cell clone producing misfolded immunoglobulin LC that deposits as fibrils in vital organs. ATTR amyloidosis is caused by transthyretin, produced mainly by the liver, the retina epithelial cells and choroid plexus. ATTRv is associated with >130 mutations in the transthyretin gene. In the elderly, particularly in men, ATTRwt causes cardiac amyloidosis. AA amyloidosis is caused by persistent high concentration of serum amyloid A (SAA) in chronic inflammatory diseases.
Diagnostic methods
Diagnosis can be facilitated by clinical red flags. Once the suspicion of amyloidosis is made, the first step is the search for the monoclonal protein. In the presence of a monoclonal protein, a biopsy of abdominal fat, or salivary glands, or target organs is necessary. Typing of amyloid deposits is mandatory, using mass spectrometry, or immunoelectron-microscopy and immunohistochemistry. In the absence of monoclonal protein, scintigraphy with bone tracers can diagnose cardiac ATTR.
Differential diagnosis
The various types of systemic amyloidosis have a similar clinical presentation, and can be misdiagnosed as each other with catastrophic therapeutic consequences. Misdiagnosis with common diseases, such as type 2 diabetes and congestive heart failure, can occur. ATTRv amyloidosis can be misdiagnosed with chronic inflammatory demyelinating polyneuropathy.
Antenatal diagnosis
Prenatal diagnosis is available for severe forms, mainly Portuguese amyloid neuropathies.
Genetic counseling
Genetic counseling is recommended in patients with hereditary forms of amyloidosis and in their at-risk relatives. Pre-symptomatic genetic testing can be offered in the context of genetic counseling. Clinical monitoring of asymptomatic TTR mutation carriers should start ten years before the predicted age of onset of the disease according to genotype.
Management and treatment
Effective therapies are now available for the three major types of amyloidosis. Frontline treatments vary greatly depending on the type of amyloidosis; careful diagnosis must be performed beforehand. For all types of amyloidosis, supportive therapy plays a fundamental role. Appropriate management of the cardiac, renal, liver, gastrointestinal, nutritional, and neurological manifestations requires concerted action with specialists.
Prognosis
The recent development of effective therapies has dramatically improved the outlook of patients with the most common systemic amyloidosis. For AL amyloidosis patients, the median survival is >6 years, with ∼1/3 of patients achieving long-term survival (>10 years) without sign of active disease. The same applies to ATTR amyloidosis. The median survival of patients presenting with polyneuropathy is ∼10 years, and ∼4-5 years for those presenting with cardiac involvement. Disease-modifying therapies recently introduced are expected to significantly improve outcomes. In AA amyloidosis, the prognosis depends on the nature of the underlying disease. Biologic therapies have dramatically improved the prognosis.

                            Last update:
                            April 2023

                            - Expert reviewer(s):
                            Pr Giampaolo MERLINI | RITA*

                                * European Reference Network


A rare, genetic motor neuron disease characterized by late childhood- or adolescent-onset of slowly progressive, severe, distal limb muscle weakness and wasting, in association with pyramidal signs, normal sensation, and absence of bulbar involvement, leading to degeneration of motor neurons in the brain and spinal cord.


A neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord.

Summary:
Epidemiology
Incidence (average around 1/50,000 per year) and prevalence (average around 1/20,000) are relatively uniform in Western countries, although foci of higher frequency have been reported in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male preponderance (male to female ratio of around 1.5:1).
Clinical description
Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, in which onset of symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solids or liquids. Limb symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases.
Etiology
Most ALS cases are sporadic but 5-10% of cases are familial, and of these 20% involve a mutation of the SOD1 gene (21q22.11), about 2-5% involve mutations of the TARDBP gene (1p36.22) encoding the TAR DNA-binding protein 43 (TDP-43) and 1-2% involve mutations of the VCP gene (9p13.3) coding for the Valosin Containing Protein. Two percent of apparently sporadic cases involve SOD1 mutations, and TARDBP mutations have also been identified in sporadic cases.
Diagnostic methods
The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. multifocal motor neuropathy, Kennedy's disease (seethese terms) and cervical spondylotic myelopathy) by appropriate investigations. The pathological hallmarks comprise loss of motor neurons with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurons and TDP-43 immunoreactive inclusions in degenerating lower motor neurons. Signs of upper motor neuron and lower motor neuron damage not explained by any other disease process are suggestive of ALS.
Management and treatment
The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Nigel LEIGH  - Dr Lokesh WIJESEKERA


A rare intestinal condition characterized by an abnormal communication between the lower rectum and the perianal skin, which usually develops after an acute perianal abscess. A fistulous traject may be established on either side of the anus (never in the midline) and mucous or fecal discharge can appear. The skin around the external orifice can be irritated. Males are more often affected than females.


A rare, high-grade, malignant glial tumor, histologically characterized by abundance of pleomorphic astrocytes and multiple mitotic figures, often associated with diffuse infiltration of the surrounding tissue, considerable edema and mass effect and involvement of the contralateral brain. Depending on the primary localization of the tumor, patients can present with signs of raised intracranial pressure (headache, vomiting, papilledema), seizures, progressive neurological deficits, and/or behavioral changes. The tumor is most commonly localized in the frontal and temporal lobes, brain stem and spinal cord.


A rare, malignant type of ependymoma that most often arises in the supratentorial region of the brain of children and young adults and that manifests with variable symptoms including headaches, nausea, vision impairment, memory loss and difficulty walking.


A rare mixed neuronal-glial tumor characterized by a mostly supratentorial space-occupying lesion often involving the temporal lobe, although it may occur anywhere in the central nervous system. The tumor shows anaplastic features in its glial component and is considered WHO grade III, which may, albeit inconsistently, indicate more aggressive behavior and less favorable prognosis. Clinical symptoms vary according to the location, the most common manifestation being seizures.


A rare and aggressive peripheral T-cell non-Hodgkin lymphoma, belonging to the group of CD30-positive lymphoproliferative disorders, which affects lymph nodes and extranodal sites. It is comprised of two sub-types, based on the expression of a protein called anaplastic lymphoma kinase (ALK): ALK positive and ALK negative ALCL.

Summary:
Epidemiology
ALCL accounts for approximately 3% of adult non-Hodgkin lymphomas and 10% to 20% of childhood lymphomas. Its prevalence is unknown. The ALK positive subtype usually affects children and young adults. The ALK negative subtype is more commonly found in older patients over the age of 40.
Clinical description
ALCL is characterized by peripheral, mediastinal, or abdominal lymph node involvement. It manifests with the development of painless and enlarged lymph nodes, especially in the neck or armpit (axillary lymph nodes). General symptoms include loss of appetite and fatigue as well as fever, weight loss, and night sweats (B symptoms). Mediastinal involvement manifests as cough, dypsnea and/or edema. ALCL can also extend to extranodal sites such as the bones, bone marrow, subcutaneous tissue, lungs, spleen and liver.
Etiology
Etiology is unknown. In the ALK positive sub-type, the anaplastic lymphoma receptor tyrosine kinase ALK gene (2p23) is overexpressed due to a t(2;5)(p23;q35) translocation.
Diagnostic methods
Diagnosis is based on physical examination, medical history and is confirmed by histopathological and immunohistochemical evaluation of a lymph node biopsy. The biopsy shows a cohesive growth pattern, usually with lymph node-sinus involvement, with anaplastic cytology (atypical large cells with abundant cytoplasm, prominent nucleoli, and horseshoe-like or reniform nuclei), constant membrane expression of the CD30 antigen, EMA (epithelial membrane antigen) expression in the majority of cases, and CD3, CD5 or CD2 expression (mostly in ALK negative cases). ALK protein is detected by immunohistochemistry in the ALK positive sub-type. Additional tests include blood and bone marrow analysis, as well as imagery (X rays, computed tomography, PET scans and MRI) for bone disease.
Differential diagnosis
Differential diagnosis includes Hodgkin lymphoma and peripheral T cell lymphomas (see these terms), which may express CD30.
Management and treatment
Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like regimens, constitutes the first-line of treatment. It may only be combined with radiotherapy in stage I/II disease. Pediatric patients have distinct protocols similar to protocols used for B-cell lymphomas, with other drugs such methotrexate, etoposide, and cytarabine being used. High-dose chemotherapy followed by autologous stem cell transplantation can also be performed, usually in cases of relapse or as first line treatment in cases with an adverse prognosis. Antibody-drug conjugate therapy (brentuximab velotin) may be given when at least one chemotherapy regimen is unsuccesful.
Prognosis
With treatment, ALK-positive patients (5-year survival of 70-80%) have a better prognosis than ALK-negative patients (5-year survival of 33-49%). Relapse confers a poorer prognosis.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Dr Pauline BRICE


A rare and aggressive glial tumor of the central nervous system, that usually presents in adults with seizures, is most often located in the cerebral hemispheres and that is associated with a very poor prognosis.


A rare glial tumor characterized by a grade III oligodendroglial tumour with focal or diffuse anaplastic features. It typically occurs in the supratentorial white matter. Histologically, the cells are enlarged and epithelioid with pleomorphic and increased size nuclei, a vesicular chromatin pattern and prominent nucleoli. Most patients present with seizures.


A disorder that represents the ultimate dedifferentiation step of thyroid tumorigenesis and is one of the most severe cancers in humans.

Summary:
Epidemiology
It accounts for less than 2% of thyroid cancers and affects older patients in their sixth to eighth decade.
Clinical description
Usual clinical presentation is a rapidly growing thyroid mass invading surrounding structures with compressive symptoms. Cervical lymph nodes enlargement and distant metastases occur frequently.
Diagnostic methods
Though cytological results obtained by fine needle aspiration may be suggestive of diagnosis, tissue biopsy for immunohistochemichal study can be necessary to exclude lymphoma and to validate aggressive therapies.
Management and treatment
Patients developing anaplastic thyroid cancer must be referred urgently in cancer centers to plan multimodality therapeutic approach depending on their performance status. The treatment regimen combines surgery when feasible, hyperfractionated and accelerated external beam radiotherapy and doxorubicin based chemotherapy. Such treatment can provide control of locoregional disease but does not impact on overall survival in patients with distant metastases. Therapeutic research is investigating redifferenciation strategies and targeted therapies to inhibit EGF receptors and neoplastic angiogenesis. Primary prevention of this lethal disease may consist of adequate treatment of differentiated thyroid cancers and goiters in the elderly.
Prognosis
The prognosis is dismal with a mean survival of four to nine months after diagnosis. Long survivors are patients with emerging disease presenting a resectable tumor and receiving adjuvant radiotherapy and/or chemotherapy.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Dr Christine DO CAO  - Pr Jean-Louis WEMEAU


A histological variant of medulloblastoma, an embryonic malignancy, associated with extremely low survival rates and a high risk of metastatic disease and manifesting with symptoms of increased intracranial pressure such as vomiting, headache, listlessness, papilledema and diplopia.


A rare spondyloepimetaphyseal dysplasia characterized by severe short-limb short stature beginning prenatally, joint hypermobility, dental abnormalities, dysmorphic facial features (including hypertelorism, midface hypoplasia, macroglossia, and prognathism), and other skeletal anomalies (such as atlantoaxial subluxation causing compression of the spinal cord, kyphoscoliosis, hip dislocation, or rocker-bottom feet). Mild intellectual disability may also be present.


A rare disorder characterized by periodic muscle paralysis, prolongation of the QT interval with a variety of ventricular arrhythmias (leading to predisposition to sudden cardiac death) and characteristic physical features: short stature, scoliosis, low-set ears, hypertelorism, broad nasal root, micrognathia, clinodactyly, brachydactyly and syndactyly.


A rare difference of sex development (DSD) characterized by the presence of female external genitalia, ambiguous genitalia or variable defects in virilization in a 46,XY individual with absent or partial responsiveness to age-appropriate levels of androgens. It comprises two clinical subgroups: complete AIS (CAIS) and partial AIS (PAIS).


A rare, genetic, neuro-endocrino-cutaneous disorder characterized by highly variable degrees of alopecia, moderate to severe intellectual disability, progressive, late-onset motor deterioration and combined anterior pituitary hormone deficiency, manifesting with central hypogonadotropic hypogonadism, delayed or absent puberty, growth hormone deficiency (resulting in short stature), progressive central adrenal insufficiency and a hypoplastic anterior pituitary gland. Additional features include hypodontia, flexural reticulate hyperpigmentation, gynecomastia, microcephaly and kyphoscoliosis.


A rare congenital heart malformation of one or more of the aortic sinuses, consisting of a dilation that when unruptured is usually asymptomatic but when ruptured presents with progressive exertional dyspnea, fatigue, chest pain and that can lead to congestive heart failure if left untreated.


A rare, genetic, systemic disease characterized by the presence of arterial aneurysms, tortuosity and dissection throughout the arterial tree, associated with early-onset osteoarthritis (predominantly affecting the spine, hands and/or wrists, and knees) and mild craniofacial dysmorphism (incl. long face, high forehead, flat supraorbital ridges, hypertelorism, malar hypoplasia and, anomalies of the palate and uvula), as well as mild skeletal and cutaneous anomalies. Joint abnormalities, such as osteochondritis dissecans and intervertebral disc degeneration, are frequently associated. Additional cardiovascular anomalies may include mitral valve defects, congenital heart malformations, ventricular hypertrophy and atrial fibrillation.


A rare bone tumor characterized by a benign, cystic lesion consisting of blood-filled cavities divided by fibrous septa containing fibroblasts, multinucleated osteoclast-type giant cells, and reactive woven bone. The tumor may arise de novo or secondarily, complicating other benign or malignant bone tumors. It most commonly arises during the first two decades of life and often affects the epiphyses of long bones and posterior elements of vertebral bodies. Patients typically present with pain and swelling, or neurological symptoms due to compression of nerve roots or the spinal cord by vertebral tumors.


A form of acromelic dysplasia characterized by the distinctive radiological sign of angel-shaped middle phalanges, a typical metacarpophalangeal pattern profile (mainly affecting first metacarpals and middle phalanges of second, third and fifth digits, which all appear short), epiphyseal changes in the hips and, in some, abnormal dentition and delayed bone age.

Summary:
Epidemiology
The prevalence is unknown. ASPED is a rare disease with less than 20 cases reported in the literature to date, however, it is likely underdiagnosed.
Clinical description
Clinical manifestations in ASPED are not only restricted to the hands, and the original description reported various combinations of angel-shaped middle phalanges, hip dysplasia and dental anomalies (hypodontia). Patient stature ranges from short to normal. Hip dysplasia gives rise to premature or severe osteoarthritis causing severe intermittent hip pain. Non-specific brachydactyly and hyperextensible interphalangeal joints have been reported, as well as delayed bone age. Delayed dentition, abnormally placed teeth, premature loss of teeth, abnormal enamel, and malocclusion have also been described in some.
Etiology
ASPED is caused by mutations in the growth differentiation factor 5 (GDF5) gene, located on chromosome 20q11.2, encoding CDMP1 (cartilage derived morphogenetic protein). CDMP1 belongs to the TGF beta super family and plays a role in bone growth and joint morphogenesis.
Diagnostic methods
Diagnostic methods include skeletal x-rays, showing the typical radiological features of ASPED, along with GDF5  molecular analysis, which confirms diagnosis. Angel-shaped middle phalanges are usually an isolated bone anomaly, and are shaped like ''Christmas tree angels'', with the wings formed by the diaphyseal cuff of bone surrounding the phalanx, the skirt by a cone-shaped epiphysis, and the head by the distal pseudoepiphysis. Angel-shaped phalanges can be difficult to find in adults. However, they can be associated with dental anomalies, hip dysplasia and short stature.
Differential diagnosis
The main clinical differential diagnosis is Brachydactyly type C (see this term), which is also associated with a GDF5 mutation, suggesting that both syndromes may be part of the same clinical spectrum.
Antenatal diagnosis
As ASPED is not a serious condition, prenatal diagnosis is not offered.
Genetic counseling
ASPED is transmitted as an autosomal dominant condition and genetic counseling is possible. Clinical variability and low penetrance have been reported.
Management and treatment
Treatment may involve orthopedic management (i.e. hip arthroplasty), and plastic surgery (when thumb involvement is very severe or if syndactyly is associated). In patients with severe hip involvement, walking aids may be required. Dental anomalies may require orthodontic management.
Prognosis
ASPED does not affect life-expectancy and the prognosis is good. Quality of life is reduced in those with untreated and severe coxarthrosis.

                            Last update:
                            December 2014

                            - Expert reviewer(s):
                            Dr Muriel HOLDER-ESPINASSE


A neurogenetic disorder characterized by severe intellectual deficit and distinct facial dysmorphic features.

Summary:
Epidemiology
Prevalence of AS is estimated to be 1/10,000 to 1/20,000 worldwide.
Clinical description
Patients with AS appear normal at birth. In the first 6 months of the neonatal period, feeding difficulties and hypotonia may occur, followed by developmental delay between 6 months and 2 years of age. Generally from 1 year of age, the typical features of AS develop: severe intellectual deficit, absent speech, outbursts of laughter with hand flapping, microcephaly, macrostomia, maxillary hypoplasia, prognathia and neurological problems with a puppet-like gait, ataxia and epileptic seizures with specific electroencephalogram (EEG) abnormalities (triphasic delta activity with a maximum over the frontal regions). Other signs that have been described include a happy demeanor, hyperactivity without aggression, short attention span, excitability and sleeping problems with decreased need to sleep, increased sensitivity to heat, attraction to and fascination with water. With advancing age, the typical features of the disease become less marked because of facial coarsening, thoracic scoliosis and mobility problems. Thoracic scoliosis is reported in 40% of AS patients (mostly females). Seizures remain present in adult patients, but hyperactivity, short attention span and sleeping problems improve. In patients with deletion of the 15q11 region, iris and choroidal hypopigmentation are common.
Etiology
Different genetic mechanisms may cause Angelman syndrome, such as deletion of the 15q11.2-q13 critical region (60-75%), paternal uniparental disomy (2-5%), imprinting defect (2-5%) and mutation in the UBE3A gene (10%). In a group representing 5-26% of patients, the genetic defect remains unidentified.
Diagnostic methods
Diagnosis is based on clinical and EEG findings, and can be confirmed in most cases by cytogenetic and molecular testing. The typical EEG pattern can be helpful for diagnosis.
Differential diagnosis
Differential diagnosis includes hypsarrhythmia in West syndrome or the petit mal variant pattern in Lennox-Gastaut syndrome (see these terms). Other differential diagnoses include Rett syndrome, Mowat-Wilson syndrome, X-linked alpha-thalassemia-intellectual deficit syndrome (ATR-X), and 22q13 deletion syndrome (see these terms).
Genetic counseling
Genetic counseling is advised as the recurrence risk varies between 0 and 50%, depending on the underlying genetic mechanism.
Management and treatment
Management includes physical, occupational and speech therapy including nonverbal methods of communication. As patients commonly develop seizures at a very young age, anticonvulsant medication is required. Sedative medication can be given in patients with severe sleep disorders. Visual function should also be monitored.
Prognosis
In adulthood, patients become less active and have a tendency towards obesity. Mobility decreases with joint contractures leading to difficulties in walking and some patients become wheelchair bound. Life expectancy appears to be normal although autonomy is never reached.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Griet VAN BUGGENHOUT


An extremely rare slow-growing glial neoplasm of the central nervous system, usually arising in a superficial location in the cerebrum, affecting all ages and both sexes, and characterized by intractable seizures and headaches, with most cases being cured by surgical incision alone and therefore having a good prognosis.


A rare T-cell non-Hodgkin lymphoma characterized by infiltration of lymph nodes by neoplastic cells of T follicular helper cell origin with a polymorphous inflammatory background including markedly increased follicular dendritic cells and EBV-positive B-cells, as well as prominent proliferation of high endothelial venules. The spleen, liver, skin, and bone marrow are also frequently involved. Patients typically present with generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, and polyclonal hypergammaglobulinemia. Pruritic skin rash, arthritis, pleural effusion, and ascites may also be observed. The condition is aggressive with generally poor prognosis.


A benign congenital skin disease characterised by progressive dilation of the subepidermal skin vessels manifesting as purple punctate lesions usually appearing on the lower limbs and buttocks and following the lines of Blaschko.

Summary:
Epidemiology
The disease occurs almost exclusively in females.
Etiology
A mutation in the Xp11.3-Xq12 region has been identified in one of the reported families. However, in this family the AS was associated with oesophageal papillomatosis leading to the suggestion that this case of familial AS represents a mild form of focal dermal hypoplasia (see this term).
Genetic counseling
The majority of cases are sporadic. Only a few familial cases have been reported in the literature so far and transmission may be autosomal dominant or X-linked.

                            Last update:
                            October 2008


A rare soft tissue tumor characterized by a slow-growing, usually painless, subcutaneous nodule, predominantly located in the extremities, less frequently the trunk or head and neck region. Histopathologically, the lesion is well-circumscribed, lobulated, and composed of epitheloid, ovoid, or spindle cells arranged in a nodular and often syncytial pattern, with pseudoangiomatoid spaces and a peripheral fibrous pseudocapsule with a prominent lymphoplasmacytic cuff. The tumor is most common in the first two decades of life and usually follows an indolent course, although local recurrence may occur, while metastasis is rare.


A congenital vascular bone syndrome (CVBS) characterized by the presence of a vascular malformation in a limb, mainly of the arteriovenous type, which results in overgrowth of the affected limb.


A rare, congenital, vascular anomaly syndrome characterized by venous or, on occasion, arterial malformations which lead to soft tissue hypertrophy and bone hypoplasia. Affected limb is generally shortened, highly deformed, painful and edematous and associates bone and muscle hypotrophy. Single parts, or multiple small parts, of limbs are typically affected but more extensive involvement, including complete extremity, shoulder girdle and axilla, has been reported.


A rare vascular tumor characterized by a malignant space-occupying lesion composed of cells variably recapitulating features of normal endothelium. It mostly develops as a cutaneous tumor and is much less frequently located in the deep soft tissue. Clinical presentation is an enlarging mass, sometimes with symptoms like coagulopathy, anemia, persistent hematoma, or bruisability. Some tumors are associated with pre-existing conditions, e. g. Klippel-Trenaunay syndrome, Maffucci syndrome, or following radiation, among others. Older age, retroperitoneal location, large size, and high mitotic activity are predictors for poor outcome.


A foodborne zoonotic disease, endemic to Southeast Asia and the Pacific Islands, caused by the rat lungworm Angiostrongylus cantonensis and that is acquired by the ingestion of the infective larvae on vegetables or in raw or undercooked snails, slugs, land crabs, freshwater shrimps, frogs and lizards. The main feature is eosinophilic meningitis, with clinical manifestations including fever, headache, malaise, fatigue, vomiting, rhinorrhea, blurred vision, diplopia, cough, stiff neck, enteritis, constipation and paraesthesia due to the movement of the worms from the intestines to the lungs, central nervous system and eyes. In severe cases without treatment, coma and death can occur.


A rare nevus disorder characterized by the presence of epidermal nevi consisting of depigmented hypertrichosis manifesting with long, soft, white hair which grows from dilated follicles and follows Blaschko's lines, typically located on the scalp, neck, face, trunk and/or limbs. Association with hyperpigmented, hyperkeratotic linear epidermal nevi, macrocephaly, body asymmetry, sacral pit and koilonychia, as well as skeletal, ocular, and neurological abnormalities, has also been reported.


Anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome

This syndrome is characterized by severe immunodeficiency, osteopetrosis, lymphedema and anhidrotic ectodermal dysplasia.

Summary:
Epidemiology
It has been described in a few unrelated male patients born to mothers with mild incontinentia pigmenti.
Clinical description
The first two reported children died before three years of age from multiple infections with Gram-positive cocci, Gram-negative bacilli, mycobacteria, and fungi.
Etiology
The syndrome is classified as a X-linked osteopetrosis and is caused by mutations in the IKBKG (NEMO) gene (Xq28).

                            Last update:
                            March 2009


A rare syndrome described in three members of a family (a boy, his father, and his paternal grandmother) that is characterized by the association of aniridia with patella aplasia or hypoplasia. The grandmother also had bilateral cataracts and glaucoma. There have been no further descriptions in the literature since 1975.


Aniridia-cerebellar ataxia-intellectual disability syndrome

A rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia with non-progressive cerebellar ataxia, and intellectual disability.

Summary:
Epidemiology
To date, less than 30 patients have been reported in the literature.
Clinical description
Aniridia is visible at birth as fixed dilated pupils and is associated with photobia. It can be accompanied with additional ocular findings such as foveal, patchy iris and/or optic nerve hypoplasia, retinal hypopigmentation, and/or pigmentary macular changes leading to reduced visual acuity. Cataract and corneal opacities are never observed. Non-progressive cerebellar ataxia is associated with delayed developmental milestones and hypotonia (visible from the first year of life), gait and balance disorders with incoordination, intention tremor, and scanning speech. Intellectual disability is variable. Mild facial dysmorphic features may be observed such as high forehead, hypertelorism, epicanthic folds, depressed nasal bridge with anteverted nostrils, and thin upper lip. The cases referred to as atypical Gillespie syndrome correspond to those showing a more complex phenotype, associating additional ocular findings and a mild dysmorphic face.
Etiology
The etiology is unknown. Some atypical cases have been linked to mutations in the PAX6 gene (11p13), encoding a transcriptional regulator expressed in ocular, cerebral, olfactory, and pancreatic tissues. One case has also been reported to be due to a de novo translocation of chromosome X and 11 t(X;11) (p22.32;p12), but with no involvement of the PAX6 gene.
Diagnostic methods
A presumptive diagnosis can be made in the first months of life: on slit lamp examination, the pupil border of the iris typically shows a scalloped, 'festooned' edge with iris strands extending onto the anterior lens surface at regular intervals. In many cases, neuroimaging studies (CT scan, MRI) show cerebellar hypoplasia or atrophy, especially of the vermis, with occasional white matter changes, and diffuse atrophy of the cerebral hemispheres, brainstem and frontal cortex.
Differential diagnosis
Differential diagnosis includes Marinesco-Sjögren syndrome (see this term) in which congenital cataract is present, as well as cerebellar ataxia, intellectual disability, and aniridia (see this term).
Genetic counseling
Sporadic and familial cases have been observed. Although some reported families are compatible with autosomal dominant inheritance, Gillespie syndrome is more likely to be an autosomal recessive condition.
Management and treatment
Management includes regular ophthalmologic evaluation with prescription of optical aids, physical, speech and occupational therapy for muscular re-education.
Prognosis
There are no reports on the natural history of the disease. Prognosis depends on the proper management and anticipation of ocular and mental symptoms and disabilities.

                            Last update:
                            December 2014

                            - Expert reviewer(s):
                            Pr Francesc PALAU


An extremely rare autosomal dominant developmental defect of the eye described in several members of one family that is characterized by the association of moderate intellectual disability with aniridia, lens dislocation, optic nerve hypoplasia and cataracts. There have been no further descriptions in the literature since 1974.


Aniridia-ptosis-intellectual disability-familial obesity syndrome

An extremely rare syndrome described in three members of a family (a mother and her two children) that is characterized by the association of various ocular abnormalities (partial or complete aniridia, ptosis, pendular nystagmus, corneal pannus, , persistent pupillary membrane, lenticular opacities, foveal hypoplasia, and low visual acuity) with various systemic anomalies including intellectual disability and obesity in the two children, and alopecia, cardiac abnormalities, and frequent spontaneous abortion in the mother. There have been no further descriptions in the literature since 1986.


Aniridia-renal agenesis-psychomotor retardation syndrome

An extremely rare syndrome reported in two siblings of non consanguineous parents that is characterized by the association of ocular abnormalities (partial aniridia, congenital glaucoma, telecanthus) with frontal bossing, hypertelorism, unilateral renal agenesis and mild psychomotor delay. There have been no further descriptions in the literature since 1974.


A fish-borne zoonosis caused by the ingestion of third stage larvae of nematodes belonging to the genus Anisakis, present in fish or cephalopods. Following its penetration in the human gastrointestinal tract, the parasite can cause gastrointestinal classified as acute (manifesting as abdominal pain, diarrhea, nausea and vomiting), chronic, or ectopic reactions or allergic manifestations (urticaria, angioedema, anaphylactic shock).

Summary:
Epidemiology
To date, more than 20,000 cases of anisakiasis have been reported worldwide, over 90% from Japan (2,000-3,000 cases reported annually), and the rest from the five continents: Asia (Korea), Europe (the Netherlands, Germany, France, United Kingdom, Spain, Italy), America (the United States, Canada, and South American countries), and New Zealand.
Clinical description
Anisakiasis can take a number of forms, depending on the location and lesions caused by the larvae. In the luminal anisakiasis, larvae remain in the gastrointestinal tract without penetrating the tissues, causing an asymptomatic infection that may be discovered when the worms are expelled (1 day-2 weeks after ingestion) by coughing, vomiting or defecating. In invasive anisakiasis, larvae penetrate the gastrointestinal mucosa (more rarely the throat). The acute gastric form is characterized by nausea, vomiting, abdominal pain, and diarrhea, within 1-7 hours of the ingestion of contaminated food. If misdiagnosed, it can become chronic, with intermittent abdominal pain, nausea and vomiting lasting from weeks to several years. Symptoms of the acute intestinal form are analogous to those of the gastric one, and manifest 5-7 days after consumption. The chronic intestinal symptoms include weight loss, mild cramping, abdominal pain, and diarrhea, lasting for months or years. The migration of the larvae to the peritoneal cavity or to solid or hollow organs (larva migrans) may cause symptoms related to the involved tissue. In some cases anisakiasis is accompanied by an allergic response, such as urticaria, angioedema and anaphylactic shock. Asthma, conjunctivitis and dermatitis may also be observed as occupational exposure of fish processing employees to Anisakis allergens.
Etiology
Anisakiasis is caused by the ingestion of third stage larvae of Anisakid nematodes of the genus Anisakis, present in viscera or muscle of fish or cephalopods which are eaten raw, insufficiently cooked, smoked or marinated. Commonly reported species are Anisakis simplex  (sensu stricto) and Anisakis pegreffii, although the first has a higher rate of penetration in the fish muscle than the second one. Humans are accidental hosts in the life cycle, and the parasites almost never develop further within the human gastrointestinal tract. Some cases of human infection have been reported with worms from a number of species within the Anisakidae (Contracaecum, Pseudoterranova) or Raphidascarididae (Hysterothylacium, negligible) families.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Paolo MERELLA


ANK3-related intellectual disability-sleep disturbance syndrome

A rare, genetic, syndromic intellectual disability disorder characterized by variable degrees of intellectual disability, behavioral problems (including attention deficit and hyperactivity disorder, autism spectrum disorder, and aggressiveness), an altered sleeping pattern, and delayed speech and language development associated with disruption of ankyrin-3 (ANK3 gene). Additional features observed may include muscular hypotonia and spasticity. Epilepsy, chronic hunger, and dysmorphic facial features have been reported.


Ankyloblepharon filiforme adnatum-cleft palate syndrome

A rare, syndromic, developmental defect of the eye malformation characterized by unilateral or bilateral, single or multiple, filiforme bands of elastic tissue which connect the eyelid margins at the grey line, associated with cleft lip and palate. Eye examination is otherwise normal.


Ankyloblepharon filiforme adnatum-imperforate anus syndrome

A rare developmental defect during embryogenesis malformation syndrome characterized by bands of extensile tissue connecting the margins of the upper and lower eyelids, in association with anal atresia. Patients may additionally present cleft palate, hydrocephalus and meningomyelocele. There have been no further descriptions in the literature since 1993.


An ectodermal dysplasia syndrome with defining features of ankyloblepharon filiforme adnatum (AFA), ectodermal abnormalities and a cleft lip and/or palate.

Summary:
Epidemiology
Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC syndrome) prevalence is unknown.
Clinical description
A history of skin erosions, especially of the scalp neonatally is typical. Congenital erythroderma occurs in 78%. Skin erosions often persist intermittently for many years, evolving into alopecia and cutaneous scarring of the skin. Wound healing appears to be delayed. Other prevalent skin manifestations include hyperpigmentation and/or hypopigmentation, often reticulated, and palmar and plantar changes with effaced dermatoglyphics. Nail changes are universal and variable and include hyperconvexity, pseudoptyergium and frayed distal margin with nail plate resorption. Hypotrichosis is common and hair is thin, brittle, wiry and uncombable. Mild hypohidrosis is always present. Nearly all cases have clefting abnormalities, ranging from submusous cleft palate, to soft and/or hard cleft palate, cleft lip or a combination. Other oroauditory findings include recurrent otitis media, canal stenosis and over 90% have a conductive hearing loss associated with a delay of speech development. AFA affects most neonates (70%) but is not always evident as these may autolyse or be lysed by a healthcare provider applying ophthalmic antibiotic ointment at birth. Eyes often are deficient of lacrimal puncta. In childhood, other facial features become more apparent and include broad nasal root, hypoplastic alae nasi, short philtrum, thin vermillion border, maxillary hypoplasia and small mandible. Over time, cone-shaped teeth and hypodontia become evident. Other anomalies are limb changes with syndactyly of fingers and toes most common, hypospadias (males 78%) and trismus (less frequently described). Failure to thrive, growth delay and gastrointestinal issues are also common.
Etiology
AEC is an autosomal dominant condition caused by pathogenic (usually missense) changes in the Tumor suppressor gene TP63. Over 4/5th of the reported pathogenic variants occur in the sterile alpha motif (SAM) domain, and about 1/5th occur in the transactivation inhibitory (TI) domain of TP63.
Diagnostic methods
Clinical features can be diagnostic. Light or scanning microscopy of the hair in combination with genetic testing may ascertain diagnosis.
Differential diagnosis
Differential diagnosis may include epidermolysis bullosa simplex, disorders of cornification, CHAND syndrome and hypohidrotic ectodermal dysplasia. Allelic disorders include Acro-dermal-ungual-lacrimal-tooth (ADULT) syndrome, ectrodactyly-ectodermal dysplasia clefting (EEC) syndrome, limb-mammary syndrome and split hand/foot malformation type 4. AEC is generally distinguished from these other disorders by clinical features (particularly scalp erosions) as well as the location of the TP63 change. The Rapp-Hodgkin syndrome is not a separate disease entity, but is now considered part of the disease spectrum of AEC syndrome.
Antenatal diagnosis
In case of family history, prenatal diagnosis is possible by genetic testing of amniocentesis or chorionic villus sampling.
Genetic counseling
AEC syndrome follows an autosomal dominant inheritance pattern. About 70% of cases are caused by a de novo change in TP63. In case of family history, genetic counseling is recommended. Genetic counseling should be proposed to individuals having the pathogenic variants, informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
AFA and cleft palate may require surgical intervention, as well as dental abnormalities requiring prosthetics. Efforts to prevent secondary infections in skin erosions comprise gentle wound care and dilute bleach soaks. Secondary infections should be cultured and treated appropriately. Extra care should be taken to avoid complications in infants with severe skin erosions. Extensive grafting procedures are not recommended. Hearing loss, growth and gastrointestinal problems should be monitored regularly. Gastrostomy is common. Psychological consequences of ectodermal defects should be addressed.
Prognosis
Overall prognosis is good with most having normal life expectancy. Unfortunately infants with extensive skin erosions are at risk of premature death due to complications including sepsis and fluid/electrolyte abnormalities. Quality of life and psychosocial functioning is often mildly but variably impacted.

                            Last update:
                            August 2019

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


Ankylosing vertebral hyperostosis with tylosis

A rare dysostosis with predominant vertebral involvement characterized by paraspinal ligament ossification (most pronounced in the lower thoracic region), osteophytosis, marginal sacroiliac joint sclerosis, and punctate hyperkeratosis on the soles and palms. Patients may be asymptomatic or present mild to moderate back pain. There have been no further descriptions in the literature since 1969.


A hookworm infection caused primarily by the species Ancylostoma duodenale  or Necator americanus, usually acquired through penetration of the skin, (often asymptomatic but that can also manifest with an allergic reaction at the site of skin penetration), followed by the migration of larva through the bloodstream to the lungs (causing asymptomatic pneumonitis, eosinophilia) and finally reaching and colonizing the small intestines where they cause blood extravasation leading to diarrhea, abdominal pain, and when untreated, melena, iron-deficiency anemia and protein malnutrition.


A rare variant of cutaneous lichen planus characterized by both annular and atrophic LP features in the same lesion.

Summary:
Epidemiology
Fewer than ten cases have been reported in the literature.
Clinical description
Small violaceous papules develop on the trunk and extremities and are characterized by an atrophic centre and a raised hyperpigmented border. Patients are generally middle-aged and have no past history of cutaneous lesions. Histopathologically, the peripheral border has the typical features of lichen planus, while the centre of the lesion shows loss of rete ridges. There is loss of elastic fibres within the papillary dermis, both centrally and peripherally.
Etiology
Etiology is unknown.

                            Last update:
                            May 2015

                            - Expert reviewer(s):
                            Dr Stephanie ARNOLD  - Dr Susan COOPER


A rare clinical variant of epidermolytic ichthyosis (EI) characterized by the presence of a blistering phenotype at birth and the development from early infancy of annular polycyclic erythematous scales on the trunk and extremities.

Summary:
Epidemiology
It has been reported in less than 10 families.
Clinical description
At birth, clinical features are similar to those of classical EI with erythroderma, blistering and superficial skin erosions at sites of minor trauma. In contrast to EI, an improvement of clinical symptoms occurs during early infancy after which patients develop outbursts of annular polycyclic erythematous scales on the trunk and extremities. Skin is normal between the outbursts. These skin abnormalities persist for several weeks to several months with only benign localized disease observed in adulthood. Patients also present palmoplantar hyperkeratosis.
Etiology
The disease is caused by mutations in the KRT1 (12q11-q13) and KRT10 (17q21-q23) genes, encoding keratins 1 and 10 respectively. These mutations impair keratin filament formation and weaken the structural stability of the keratinocyte cytoskeleton.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER


A rare variant of cutaneous lichen planus characterized by the development of annular lesions.

Summary:
Epidemiology
The exact prevalence is unknown.
Clinical description
Annular lesions occur in 10% of all cases of lichen planus, they usually occur in association with more classic lesions. Annular LP is characterized by the development of annular violaceous or hyperpigmented plaques, with no central atrophy and slightly raised, non-scaly borders. Genital and oral lesions have been reported, along with lesions affecting the axillae, trunk, and extremities.
Etiology
Etiology is unknown.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Stephanie ARNOLD  - Dr Susan COOPER


A distinct form of duodenal atresia in which the head of the pancreas forms a ring around the second portion of the duodenum.

Summary:
Epidemiology
The annual incidence is estimated at around 1/50,000 births, representing 10% of all cases of duodenal stenosis.
Clinical description
During the neonatal period, the clinical picture is dominated by epigastric distension with vomiting, which is nonbilious as the obstruction is usually supra-vaterian (above the junction of the biliary ducts). As in other forms of duodenal atresia, malformations of the cranial intestine are also frequently present in patients with annular pancreas. Cardiac anomalies may also be present and are more frequent in the context of notochord induction anomalies or deficiency. Chromosomal abnormalities are present in one-third of cases of annular pancreas, with trisomy 21 (followed by trisomy 18 and 13; see these terms) being the most frequently detected anomaly.
Etiology
Annular pancreas is an embryopathy resulting from an anomaly occurring early (towards the fourth week) in development. It is a distinct form of duodenal atresia, rather than a pancreatic anomaly, and should not be confused with other congenital malformations of the pancreas or pancreaticobiliary ducts (such as anomalies of the pancreaticobiliary junction) for which the diagnosis cannot be made until childhood or adulthood.
Diagnostic methods
Diagnosis of annular pancreas is often made before birth through ultrasound findings showing duodenal dilation and through difficulties in observing peri-duodenal pancreatic development. In cases where the diagnosis is not made prenatally, it is made in the neonatal period on the basis of the clinical picture and imagining studies (abdominal radiography and ultrasound).
Differential diagnosis
The differential diagnosis should include other forms of duodenal stenosis.
Antenatal diagnosis
Prenatal diagnosis allows management to be planned in a specialized center immediately after birth.
Management and treatment
Investigations using a gastric tube allow drainage of the digestive tract prior to the site of obstruction. Treatment is surgical and is performed in the neonatal period.
Prognosis
The prognosis for annular pancreas is very favorable, but the overall prognosis depends on the presence of associated malformations.

                            Last update:
                            January 2019

                            - Expert reviewer(s):
                            Pr Frédéric BARGY


Anoctamin-5-related limb-girdle muscular dystrophy R12

A form of limb-girdle muscular dystrophy most often characterized by an adult onset (but ranging from 11 to 51 years) of mainly proximal lower limb weakness, with difficulties standing on tiptoes being one of the initial signs. Proximal upper limb and distal lower limb weakness is also common, as well as atrophy of the quadriceps (most commonly), biceps brachii, and lower leg muscles. Calf hypertrophy has also been reported in some cases. LGMD2L progresses slowly, with most patients remaining ambulatory until late adulthood.


An extreme developmental dental anomaly characterized by the complete absence of all teeth.

Summary:
Epidemiology
The prevalence is unknown but it is extremely rare and usually only occurs as part of an associated syndrome such as X-linked hypohidrotic ectodermal dysplasia (X-linked HED; see this term).
Etiology
Genes found to be responsible for HED include EDA and EDAR and EDARADD.
Diagnostic methods
Clinical examination along with a panoramic radiograph (and intra-oral X-rays if needed) is performed when teeth eruption is delayed and teeth are then thought to be missing. In normal conditions all primary teeth and crypts of permanent first molars are visible on radiography at birth and permanent teeth crowns (except third molars) at 6 years of age. A diagnosis of anodontia is given when all teeth are missing.
Management and treatment
Treatment involves full fixed dentures or, in suitable candidates, dental implants. Early mandibular implants therapy is indicated in these severe phenotypes of anodontia. A marked alveolar bone hypotrophy is generally associated with anodontia and requires CT exams of the mandible and 3D reconstructions for implants surgical planning. Maxillary rehabilitation based on osteointegrated implants and prosthodontics is indicated at the end of the skeletal growth. Bone grafts such as onlay autogenous grafts and maxillary sinus floor augmentation procedures are often necessary. Before completion of growth a removable maxillary denture should be used.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN  - Dr François CLAUSS


Anomalous aortic origin of coronary artery

A rare group of coronary artery congenital malformation disorders characterized by an anomalous origin and course of the left or right coronary artery, which originates from the contralateral aortic sinus of Valsalva and has an anomalous trajectory which may be: pre-pulmonary (with no hemodynamic consequences), retroaortic (with a course posterior to the aortic root and no hemodynamic consequences), interarterial (located between the aorta and the pulmonary artery and associated with a poorer prognosis), subpulmonary (with an intraconal or intraseptal course), or retrocardiac (located in the posterior atrioventricular sulcus). Clinical manifestations depend on the specific anomalous origin and course which is present, with patients being frequently asymptomatic, although nonspecific chest pain, palpitations, dizziness, dyspnea or syncope, usually following physical exertion, may be associated. Sudden death, due to compression/occlusion of the coronary artery and usually associated with, or immediately following, vigorous physical exercise, may be occasionally observed.


Anomalous aortic origin of the left coronary artery

A rare coronary artery congenital malformation characterized by an anomalous origin and course of the left coronary artery, which originates from the right aortic sinus of Valsalva and has an abnormal proximal course, which may be intramural, prepulmonic, subpulmonic, retroaortic, retrocardiac or wrapped around the apex. Patients are frequently asymptomatic, although chest pain, dyspnea, palpitations, dizziness, syncope, and sudden cardiac arrest/death (typically following intense physical exertion) may be observed. This malformation is associated with a high risk of sudden cardiac death so surgical revascularization is recommended even in cases with no associated evidence of myocardial ischemia.


Anomalous aortic origin of the right coronary artery

A rare coronary artery congenital malformation characterized by an anomalous origin and course of the right coronary artery, which originates from the left aortic sinus of Valsalva and has an abnormal proximal course, which may be intramural, prepulmonic, subpulmonic, retroaortic, retrocardiac or wrapped around the apex. Patients are frequently asymptomatic, although chest pain, dyspnea, palpitations, dizziness, syncope, and sudden cardiac arrest/death (typically following intense physical exertion) may be observed. This malformation is associated with a lower risk of sudden cardiac death therefore surgical revascularization is recommended only when signs and/or symptoms of ischemia are present.


Anomalous origin of coronary artery from the pulmonary artery

A rare coronary artery congenital malformation characterized by an anomalous origin of the left (ALCAPA) or right (ARCAPA) coronary artery from the pulmonary artery, with variable clinical presentation, ranging from asymptomatic to early heart failure and death depending on the degree of development of collateral circulation between the left and right coronary artery systems, as well as the pressure level of the pulmonary artery. Infants typically present with feeding difficulties, failure to thrive, dyspnea, irritability, hyperhidrosis, heart murmurs, tachypnea, tachycardia and/or chest pain while adults usually associate dyspnea, chest pain, syncope, and intolerance to physical exercise. Sudden death may occur due to congestive heart failure, myocardial infarction, valvular insufficiencies or ventricular arrhythmias. The majority of cases reported are of an ALCAPA, while ARCAPA is rarely observed.


A group of rare congenital coronary artery malformations comprising abnormal number of coronary ostia, malposition of a coronary ostium, and stenosis or atresia of a coronary ostium. Patients may remain asymptomatic or present with variable signs and symptoms, depending on the nature and severity of the malformation, including failure to thrive, dyspnea, syncope, angina pectoris, ventricular tachycardia, and myocardial ischemia.


Anomaly of the mitral subvalvular apparatus

A group of rare congenital mitral malformations characterized by anomalies of the chordae tendineae and papillary muscles. This comprises anomalous mitral arcade or hammock valve (due to thickened and extremely short chordae tendineae), straddling valve (abnormal attachment of the chordae tendineae to both ventricles), and parachute valve (unifocal attachment of the chordae tendineae to a single or fused papillary muscle), resulting in an incompetent valve with regurgitation and/or stenosis and impaired left ventricular inflow, potentially leading to heart failure. In most cases, other cardiac anomalies are found in association.


Anomaly of the tricuspid subvalvular apparatus

A group of rare congenital tricuspid malformations characterized by anomalies of the chordae tendineae and papillary muscles, including aberrant chordae tendineae, straddling valve (abnormal attachment of the chordae tendineae to both ventricles), and parachute valve (unifocal attachment of the chordae tendineae to a single or fused papillary muscle), resulting in an incompetent valve with regurgitation and/or stenosis and impaired right ventricular inflow, potentially leading to heart failure. In most cases, other cardiac anomalies are found in association.


A rare ectodermal dysplasia syndrome characterized by anonychia congenita totalis or rudimentary nails, macular hyper- and/or hypopigmentation (particularly affecting groins, axillae and breasts), coarse scalp hair (that becomes markedly thinned in early adult life), dry palmoplantar skin with distorted epidermal ridges and sore, cracked soles, and hypohidrosis. There have been no further descriptions in the literature since 1975.


A multiple congenital anomaly disorder characterized by anonychia congenita totalis and microcephaly, and normal intelligence along with some minor anomalies including single transverse palmar creases, fifth-finger clinodactyly and widely-spaced teeth.


A very rare multiple congenital anomaly syndrome characterized by the presence of anophthalmia or severe microphthalmia, cleft lip/palate, facial cleft and sacral neural tube defects, along with various additional anomalies including congenital glaucoma, iris coloboma, primary hyperplastic vitreous, hypertelorism, low-set ears, clinodactyly, choanal atresia/stenosis, dysgenesis of sacrum, tethering of spinal cord, syringomyelia, hypoplasia of corpus callosum, cerebral ventriculomegaly and endocrine abnormalities. An autosomal recessive inheritance has been suggested.


A rare multiple congenital anomalies syndrome, reported in the offsprings of a consanguineous couple and characterized by multiple congenital skeletal (dolichocephaly, skull asymmetry, camptodactyly, clubfoot), muscular (muscle hypoplasia), ocular (anophthalmia, buphthalmos, retinal detachment, aniridia (see this term)) and cardiac (prolapse of tricuspid valves, mitral and tricuspid insufficiency) abnormalities. An autosomal recessive inheritance with variable expressivity was suspected. There have been no further descriptions in the literature since 1992.


A syndrome that belongs to the group of syndromic microphthalmias and is characterized by the association of uni- or bilateral anophthalmia or microphthalmia, and esophageal atresia with or without trachoesophageal fistula.

Summary:
Epidemiology
Prevalence is unknown but less than 30 cases (male and female) have been described in the literature so far.
Clinical description
Genital anomalies (hypospadias, micropenis, and/or cryptorchidism) were reported in most of the male patients. Several other associated anomalies have been described including developmental anomalies of the central nervous system, cardiac defects, vertebral anomalies, growth failure, sensorineural hearing loss, anterior pituitary hypoplasia and hypogonadotropic hypogonadism. Intellectual development was normal in some cases, but mild to significant psychomotor delay has also been reported.
Etiology
Inheritance is autosomal dominant and the syndrome is caused by heterozygous mutations or deletions in the SOX2 gene (3q26.3-q27).

                            Last update:
                            February 2010


A congenital malformation of the external ear and the most extreme form of microtia characterized by the complete absence of the external ear and auditory canal, conductive hearing loss, attention deficit disorders and delayed language development.


A rare, genetic, dermis disorder characterized by bilateral, fairly symmetrical, antecubital webbing extending from distal third of humerus to proximal third of forearm, associated with musculoskeletal abnormalities (i.e. absent long head of triceps, bilateral posterior dislocation of the radial head and hypoplasia of the olecranon processes) and absent skin creases over the terminal interphalangeal joints of fingers, clinically manifesting with moderate to severe elbow extension and supination limitation.


Anterior cutaneous nerve entrapment syndrome

A chronic neuropathic pain syndrome of the abdominal wall caused by entrapment of anterior cutaneous branches of 7 to 12th intercostal nerves along the lateral border of the anterior rectus abdominis fascia causing severe pain and tenderness of the involved dermatome.

Summary:
Epidemiology
Around 20% of patients with chronic abdominal pain have abdominal wall pain, which is often caused by ACNES. The prevalence in patients alleged to have functional abdominal pain is estimated to be 3-4%. One out of 50 patients consulting an emergency department for abdominal pain suffers from ACNES. The incidence in general population is probably 1: 4000 to 5000. ACNES, hence may be not so rare as is thought.
Clinical description
ACNES most commonly affects young women (75%) but can occur at any age, also in children. History of trauma, pregnancy and delivery or abdominal surgery is sometimes present. Patients present with sharp stabbing pain emanating from the anterior abdominal wall. Presentation can be acute or chronic. Patients can usually localize the source of pain to the spot where the nerve is entrapped (lateral margin of rectus abdominis muscle), palpation of which triggers a lancinating pain along the distribution of the involved nerve. The most frequent involved pain location is in the right lower quadrant (50%), however, all other quadrants can be involved. Pain is always in the same area and is aggravated by exercise. Most patients also have concomitant various pseudo-visceral complains, anorexia, nausea, bloating, altered defecation, (pseudo visceral complaints). Asking the patient to tense his/her abdominal wall will elicit the pain (positive Carnett's test).
Etiology
ACNES is caused by the entrapment of the cutaneous end branches of the intercostal nerve in the muscular foramen as they pass through the rectus abdominis, which probably leads to ischemic neuropathy. Etiology is unclear, but there seems to be a causative relation with any kind of abdominal surgery, pregnancy and sometimes trauma. However, in more than half of the patients there is a sudden onset of pain, without any specific event.
Diagnostic methods
Imaging and laboratory tests are indicated to rule out potential visceral causes of abdominal pain. The diagnosis is clinical. Physical examination reveals altered skin sensibility in the painful area with one specific painful spot and reproducibility of pain by pinching the affected skin area. Subfascial injection of local anesthetic around the entrapped nerve (the trigger point) serves as both diagnostic and can be therapeutic in about 30% of patients.
Differential diagnosis
Differential diagnoses include hernias, tumors, tears and endometriosis of abdominal wall, radiculopathy (diabetic, traumatic, herpetic), herniated vertebral disc, rib and vertebral column abnormalities.
Management and treatment
Most pain killers have no effect on this type of neuropathic pain. Treatment is by injection of the anterior cutaneous nerve with a local anesthetic at the point at which it pierces the fascia by free hand or under ultrasound guidance. Neuropathic pain killers like pregabaline or amitryptilline may be helpful. In patients in whom pain persists after several injections, surgical exploration and neurectomy is indicated. This strategy of injections followed by neurectomy is curative in 80% of patients.
Prognosis
Diagnostic delay is common; untreated ACNES can lead to functional disability and reduced quality of life resulting in high medical health care costs, highlighting the importance of the awareness of ACNES among medical professionals.

                            Last update:
                            June 2015

                            - Expert reviewer(s):
                            Dr R.M.H. [Rudi] ROUMEN


Anterior maxillary protrusion-strabismus-intellectual disability syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of severe intellectual disability, strabismus, and anterior maxillary protrusion with vertical maxillary excess, open bite, and prominent crowded teeth. Mild cochlear hearing loss has been reported in addition.