Early-onset parkinsonism-intellectual disability syndrome

A rare X-linked syndromic intellectual disability characterized by infantile-onset non-progressive intellectual deficit (with psychomotor developmental delay, cognitive impairment and macrocephaly) and early-onset parkinsonism (before 45 years of age), in male patients.


Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

A rare, severe early-onset neurodegenerative encephalopathy characterized mainly by developmental delay (DD) / developmental regression (DR), epilepsy, cortical atrophy, secondary hypomyelination and thin corpus callosum. Additional features include secondary microcephaly, hypotonia, spasticity, optic atrophy and skeletal anomalies.

Summary:
Epidemiology
The prevalence is unknown. To date, approximately 39 cases have been reported in the literature.
Clinical description
Presentation is typically in the first year of life with severe developmental delay or regression and epilepsy, with progressive cerebral atrophy. Other neurologic problems include spasticity, hypotonia, optic atrophy, ataxia, thin corpus callosum, and secondary hypomyelination. Most of the patients also have secondary microcephaly, and postnatal growth retardation. Additional features include behavioral problems (aggressiveness, hyperactivity, and agitation), and skeletal anomalies (scoliosis, hip dislocation and plagiocephaly). There are no typical facial dysmorphisms. More recently, three additional patients with less severe phenotypes (including autism spectrum disorder and occasional generalized tonic-clonic seizures responding well to antiepileptic drugs) were described.
Etiology
This syndrome is caused by biallelic pathogenic variants in TBCD gene (17q25.3), encoding tubulin folding co-factor D (TBCD), one of five co-chaperones required for microtubule assembly dynamics. Pathogenic TBCD variants affect TBCD stability and function, resulting in disturbed microtubule dynamics. Recent studies suggest specific genotype-phenotype correlations, relating phenotypic expression to the level of dysfunction of the residual protein caused by the pathogenic variants.
Diagnostic methods
Molecular genetic testing approaches may include single-gene molecular genetic testing (Sanger sequencing) based on clinical findings and neuroimaging findings, as well as Next Generation Sequencing (NGS)-based multigene panel or a more comprehensive genomic testing (whole-exome sequencing or whole-genome sequencing).
Differential diagnosis
Differential diagnoses include most epileptic encephalopathies, such as Undetermined early-onset epileptic encephalopathy and Lennox-Gastaut syndrome and mitochondrial encephalopathies.
Antenatal diagnosis
Prenatal diagnosis can be offered if the disease-causing mutations have been identified.
Genetic counseling
The pattern of inheritance is autosomal recessive, meaning that an affected patient has two mutated alleles of TBCD gene. Genetic counseling should be offered to the parents of affected individuals. Each parent of an affected child is usually an asymptomatic carrier of one pathogenic TBCD variant. At each conception, the parents of an affected individual have a 25% risk of having an affected child, a 50% chance of having a child who is an asymptomatic carrier, and a 25% risk of having a child who is neither affected nor a carrier.
Management and treatment
Management should be multidisciplinary, usually addressing DD/DR and control of seizures. It can include physical, occupational and speech therapy. Epilepsy should be treated with antiepileptic drugs (such as sodium valproate and clonazepam) and ketogenic diet which, as well as pyridoxine, show limited success in controlling seizures.
Prognosis
Prognosis depends on the severity of the disease and the presence of seizures. In general, prognosis is poor, with severe to profound global psychomotor developmental delay and refractory epilepsy. Some patients evolve with respiratory failure and early death.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Marcia RODRIGUES | ITHACA* - Dr Marta P. SOARES | ITHACA*

                                * European Reference Network


Early-onset progressive encephalopathy with migrant continuous myoclonus

A rare disorder characterized by early-onset progressive encephalopathy with migrant, continuous myoclonus. Three cases have been reported. The focal continuous myoclonus appeared during the first months of life. Prolonged bilateral myoclonic seizures and generalized tonic-clonic seizures occurred later. Subsequently, a progressive encephalopathy with hypotonia and ataxia appeared. Cortical atrophy was revealed by computed tomography (CT) scan and magnetic resonance imaging (MRI). The aetiology is unknown.


Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome

A rare, genetic neurological disorder characterized by early-onset severe global developmental delay with regression, congenital or acquired microcephaly, hearing loss, truncal hypotonia, appendicular spasticity, and dystonia and/or myoclonus.

Summary:
Epidemiology
Currently only five affected individuals from four unrelated families (three consanguineous and one non-consanguineous) have been reported in the literature.
Clinical description
The clinical phenotypes of the affected individuals are similar: severe global development delay often with regression, epilepsy, congenital or postnatal microcephaly, hearing loss, dysphagia or reflux, scoliosis, truncal hypotonia, dystonia and/or myoclonus and spasticity. Eye and vision problems, such as optic atrophy and cortical visual impairment, neonatal hypertension, vocal cord paralysis, neurogenic bladder and hip subluxation have been described. In patients with no history of seizures at the time of diagnosis, electroencephalography can show paroxysmal discharges. Regarding neuroradiological features, the characteristic brain imaging findings are the following in various combinations: pons hypoplasia, partial or total agenesis of the corpus callosum, ventriculomegaly/hydrocephaly, marked cortical brain atrophy and simplified frontal gyri; cerebellar atrophy is present in two-thirds of patients. The basal ganglia is relatively spared.
Etiology
The syndrome is caused by homozygous variants or compound-heterozygous variants in the TRAPPC12 gene (2p25.3). TRAPPC12 is a component of the TRAPP multi-subunit tethering complex involved in intracellular vesicle trafficking and has also been reported to play a role in mitosis.
Diagnostic methods
Diagnosis is based on clinical examination, neurophysiological analysis, neuroradiological studies and cytogenetic and molecular studies (TRAPPC12 molecular analysis, NGS panel or whole-exome sequencing followed by Sanger sequencing).
Differential diagnosis
The differential diagnosis includes numerous genetic and metabolic diseases.
Antenatal diagnosis
Recurrent abortions and polyhydramnios are common in the mothers of the affected individuals. Prenatal signs are non-specific: agenesis of the corpus callosum, ventriculomegaly/hydrocephaly. Detection of the mutation by chorionic villus biopsy or amniocentesis should be discussed with the parents of an index case during subsequent pregnancies.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Management requires a lifelong multidisciplinary approach. Regular follow‐up by a pediatrician, neurologist, psychologist/psychiatrist will be very helpful. Periodical evaluations are required to find the most suitable medical services for the individual patient. Symptomatic medications can be used (antiepileptic and antispasticity drugs).
Prognosis
The course of the disease is progressive. Longitudinal data are insufficient to determine the life expectancy and the real amplitude of the phenotypic spectrum.

                            Last update:
                            May 2022

                            - Expert reviewer(s):
                            Dr Carlo FUSCO  - Dr Susanna RIZZI


Early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome

A rare genetic neurodegenerative disease characterized by neonatal to infantile onset of hypotonia, developmental delay, regression of motor skills with distal amyotrophy, ataxia, and spasticity, absent speech or dysarthria, and moderate to severe cognitive impairment. Optic atrophy may also be associated. Brain imaging shows cerebellar atrophy and thin corpus callosum, as well as brain iron accumulation in the pallidum and substantia nigra beginning during the second decade of life.


Early-onset progressive leukoencephalopathy-central nervous system calcification-deafness-visual impairment syndrome

A rare genetic neurological disorder characterized by early-onset progressive leukoencephalopathy, severe developmental delay, early-onset or congenital deafness (only few cases reported without hearing loss), and visual impairment. All patients manifest calcifications in brain and spinal cord. Cognitive impairment, seizures, hypotonia, spastic tetraplegia or quadriplegia are observed in the majority of the patients. Variable features may include microcephaly and anemia.


Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome

A rare, genetic, neurodegenerative disease characterized by normal early development followed by childhood onset optic atrophy with progressive vision loss and eventually blindness, followed by progressive neurological decline that typically includes cerebellar ataxia, nystagmus, dorsal column dysfunction (decreased vibration and position sense), spastic paraplegia and finally tetraparesis.


Early-onset seizures-distal limb anomalies-facial dysmorphism-global developmental delay syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable developmental delay, intellectual disability, early-onset seizures, and facial dysmorphism (including arched eyebrows, long palpebral fissures, prominent nasal bridge, large ears, thin upper lip, and high arched palate). Other reported features are microcephaly, hypotonia, growth retardation, congenital heart defects, and malformations of the fingers and toes, as well as additional neurologic manifestations (such as ataxia or spastic quadriplegia). Brain imaging may show hypoplastic corpus callosum, white matter abnormalities, or cortical atrophy.


Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome is a rare hereditary spastic ataxia disorder characterized by childhood onset of slowly progressive lower limb spastic paraparesis and cerebellar ataxia (with dysarthria, swallowing difficulties, motor degeneration), associated with sensorimotor neuropathy (including muscle weakness and distal amyotrophy in lower extremities) and progressive myoclonic epilepsy. Ocular signs (ptosis, oculomotor apraxia), dysmetria, dysdiadochokinesia, dystonic movements and myoclonus may also be associated.


Early-onset X-linked optic atrophy is a rare form of hereditary optic atrophy, seen in only 4 families to date, with an onset in early childhood, characterized by progressive loss of visual acuity, significant optic nerve pallor and occasionally additional neurological manifestations, with females being unaffected.


A rare genetic disease characterized by the association of epilepsy, ataxia, sensorineural hearing impairment, and renal tubulopathy. Patients present in infancy with generalized seizures, cerebellar dysfunction (including gait ataxia, intention tremor, and dysdiadochokinesis), and variable developmental delay and sensorineural hearing loss. Laboratory studies show persistent hypokalemic metabolic acidosis with hypomagnesemia. Additional reported neurologic features include brisk deep tendon reflexes, ankle clonus, extensor plantar responses, or nystagmus.


East Texas bleeding disorder is a rare, genetic, coagulation disorder characterized by easy bruising (without hemarthrosis or spontaneous hematomas), epistaxis, menorrhagia, and excessive bleeding after minor trauma and surgical procedures. Patients present a prolonged prothrombin time and/or activated partial thromboplastin time, normal levels of all coagulation factors, and normal protein C activity.


An acute arboviral infection caused by an alphavirus of the Togaviridae family transmitted by an infected mosquito, that is characterized by the onset of flulike symptoms including fever, chills, weakness, headache, vomiting, abdominal pain with diarrhea, myalgia, leucocytosis, and hematuria, rapidly progressing to diffuse central nervous system (CNS) involvement with confusion, somnolence, or even coma. Seizures, which may progress to status epilepticus and neurologic sequelae, cranial nerve palsies, and photophobia may occur. EEE is associated with a high rate of morbidity and mortality.


A rare reflex epilepsy characterized by in most cases complex partial seizures triggered by different components of eating, such as the sight of food, proprioceptive, olfactory or gustatory sensations, chewing, salivation, and gastric distension after food intake. The seizures may be idiopathic or associated with symptomatic localization-related epilepsies.


Ebola hemorrhagic fever (EHF), caused by Ebola virus, is a severe viral hemorrhagic disease characterized by initial fever and malaise followed by gastrointestinal symptoms, bleeding, shock, and multi-organ system failure.

Summary:
Epidemiology
EHF is seen in Central and West Africa. EHF is generally recognized only when there are outbreaks, usually of less than 100 cases, which are almost invariably fueled by nosocomial transmission in hospitals in resource-poor areas where proper infection control practices are not maintained. However, seroprevalence studies suggest unrecognized endemic transmission in some areas of Africa.
Clinical description
After an incubation period of about 8 days (range 3-21 days), patients typically present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain, and myalgia/arthralgia, followed rapidly by gastrointestinal symptoms (vomiting, diarrhea, abdominal pain) and, in some cases, a maculopapular skin rash. Severe cases develop bleeding (sub-conjunctival hemorrhage, epistaxis, bleeding from the mouth and rectum, oozing from venipuncture sites), neurologic involvement (disorientation, convulsions, coma), shock, and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often present and disseminated intravascular coagulation (DIC) commonly develops, best indicated by the presence of D-dimers.
Etiology
Over 25 different viruses cause viral hemorrhagic fever. Ebola virus is a member of the virus family Filoviridae, along with Marburg virus. Six different species of Ebola virus have been identified to date, although only four are pathogenic to humans, all of which are endemic only in sub-Saharan Africa. Accumulating evidence implicates fruit bats as the Ebola virus reservoir, with primary human infection occurring presumably from unwitting contact with bat excreta or saliva. Infection also occasionally occurs through contact with tissues of other wild primates, especially gorillas and chimpanzees, presumably also infected through bat exposure. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons.
Diagnostic methods
Common diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and RT-PCR. Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.
Differential diagnosis
EHF is difficult to distinguish from a host of other febrile illnesses, at least early in the course of disease. Other viral hemorrhagic fevers need to be excluded, especially Marburg hemorrhagic fever, as well as malaria, typhoid fever, leptospirosis, rickettsial disease (see these terms) and meningococcemia.
Management and treatment
Patients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns, and aprons) should be used to prevent nosocomial transmission. As there is presently no antiviral drug available for EHF, treatment is supportive, following the guidelines for treatment of severe septicemia. Persons who had unprotected contact with someone with EHF should be monitored.
Prognosis
Case fatality rates vary consistently with the specific infecting virus, ranging from zero to over 80%. Shock, bleeding, neurological manifestations, high viremia, AST > 150 IU/L, and pregnancy confer a poor prognosis. Although convalescence may last up to a year, survivors usually have no lasting sequelae.

                            Last update:
                            December 2012

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


A rare congenital cardiac anomaly characterized by downward (apical) displacement of the functional annulus, due to incomplete delamination of the septal and inferior leaflets of the tricuspid valve such that they are hinged within the right ventricle, rather than as expected at the atrioventricular junction. The anterosuperior leaflet is often abnormal (redundancy, fenestrations, tethering with abnormal subvalvar apparatus). The atrioventricular junction and the ''atrialized'' portion of the right ventricle are dilated, with variable degrees of thinning of the right ventricular wall.

Summary:
Epidemiology
The prevalence at birth is between 1/20,000-100,000. Ebstein malformation of the tricuspid valve accounts for less than 1% of all congenital heart defects. Both sexes are equally affected.
Clinical description
Clinical presentation is heterogeneous and depends on the severity of the lesion (extent of tethering of the antero-superior leaflet across the normal valvar orifice), and the degree of dysfunction of the right ventricle. Patients with minor forms of the disease remain asymptomatic or may present with an incidental murmur, exertional dyspnea, fatigue, or palpitations. Those with severe forms can present at various ages with arrhythmias, cyanosis, and sometimes cardiac failure. Those with the most severe malformations present as neonates, often with so-called ``wall-to-wall'' hearts. During adulthood, supraventricular tachycardia can also be observed, a proportion of patients also having Wolff-Parkinson-White syndrome. The malformation is often associated with other cardiac lesions, such as atrial or ventricular septal defects, patency of the arterial duct, pulmonary stenosis or atresia, or left ventricular non-compaction.
Etiology
Etiology is unknown. In some cases, maternal ingestion of lithium was associated with the disease. The incidence of heterozygous MYH7 (14q11.2) mutations is 6%, and more frequent if left ventricular non-compaction is associated.
Diagnostic methods
Diagnosis is based on cross-sectional or 3D echocardiography which also reveals the extent of valvular abnormalities (tethering and thinning) as well as the degree of regurgitation or stenosis. Presence of associated defects should also be assessed. Electrocardiogram can reveal right atrial hypertrophy, right bundle branch block, and supraventricular tachycardia. Radiography shows any cardiomegaly. Cardiac MRI shows the full extent of the valvar abnormalities, quantifies right ventricular volume, function and tricuspid regurgitation, and helps to plan surgery.
Differential diagnosis
The major differential diagnosis, particularly during fetal life, is dysplasia of the leaflets of the tricuspid valve. Both malformations can lead to severe tricuspid insufficiency. Gross thinning of the walls of the right ventricle should not be confused with Uhl anomaly. Severe forms of Ebstein malformation with an imperforate tricuspid valve must be distinguished from tricuspid atresia.
Antenatal diagnosis
Diagnosis is usually antenatal and based on severe tricuspid insufficiency with gross dilatation of the right atrium, which can cause fetal hydrops and fetal demise.
Genetic counseling
Familial cases associated with MYH7 are extremely rare; in these cases autosomal dominant transmission is reported.
Management and treatment
Medical treatment relies on inotropic agents (in case of cardiac failure) and antiarrhythmic drugs (in case of tachyarrhythmia). Definitive treatment is surgical and ideally consists of reconstructive surgery by the cone method. Provided that valvar anatomy is favorable, patients should be considered for surgery when they develop symptoms and/or worsening exercise capacity, cyanosis, paradoxical embolism, progressive right ventricle (RV) dilation or dysfunction, or arrhythmias. If the valve is too malformed, replacement with a bioprosthesis is the only option. Partial cavopulmonary connection can be used when RV function is impaired. Most arrhythmias can be treated percutaneously, and oval foramen can be closed percutaneously when responsible for cyanosis.
Prognosis
Patients with asymptomatic and mild forms have a normal life expectancy. However, symptoms usually develop progressively from adulthood onwards. Patients with severe forms of the disease, particularly those presenting during the fetal period or as neonates, have an increased risk of death due to biventricular failure, including at birth or during physical exercise. Supraventricular arrhythmias are frequent, particularly in adults, and can lead to sudden cardiac death.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Pr Lucile HOUYEL


Ectasia of the left atrial appendage is a rare cardiac malformation characterized by the enlargement of the left auricle without any other associated cardiac lesions. It can be asymptomatic (discovered fortuitously during routine chest imaging as an unusual cardiac shadow) or present clinically with supraventricular tachyarrhythmia, paroxysmal tachycardia, embolic events, respiratory distress, chest pain, angina pectoris or heart failure.


Ectasia of the right atrial appendage is a rare cardiac malformation characterized by the enlargement of the right auricle without any other associated cardiac lesions. It can be asymptomatic and diagnosed fortuitously, prenatally or during routine clinical examinations or it can present with heart murmur, palpitation, atrial arrhythmia, fatigue, dyspnea or respiratory distress.


The term ''ectodermal dysplasia'' defines a heterogeneous group of heritable disorders of the skin and its appendages characterized by the defective development of two or more ectodermal derivatives, including hair, teeth, nails, sweat glands and their modified structures (i.e. ceruminous, mammary and ciliary glands). The spectrum of clinical manifestations is wide and may include additional manifestations from other ectodermal, mesodermal and endodermal structures.

Summary:
Epidemiology
Overall prevalence of ectodermal dysplasia syndromes is unknown, but appears rare with a presumed cumulative incidence of approximately 1/1,429. More than 120 clinically and/or genetically distinct ectodermal dysplasias have been cataloged.
Clinical description
In ectodermal dysplasias, the skin usually appears dry with superficial scaling and proneness to dermatitis. Hair is often sparse (i.e. hypotrichosis) and slow-growing, with a tendency towards congenital or early-onset non-inflammatory alopecia. Teeth are slow-growing and defective in number (i.e. hypo-, oligo- and anodontia; see these terms); they are often dysplastic (i.e. peg shaped) and display enamel dysplasia. Nails manifest a wide range of features, comprising but not limited to dystrophic, thickened, and absent nails. Eccrine glands may be reduced in number or totally absent leading to hypohidrosis and anhidrosis, respectively. Hypoplastic breast and nipples and stenosis or agenesis of the lachrymal ducts are further manifestations of sweat gland involvement. A wide range of additional ectodermal features, such as achantosis nigricans (see this term), hyperkeratosis of the palm and soles, and skin hamartomas/neoplasms may be observed. Although many ectodermal dysplasias are disorders with manifestations limited to the skin, hair, teeth, nails and sweat glands, multiple features of ectodermal dysplasia are accompanying signs of many syndromic conditions with systemic involvement.
Etiology
Over 53 genes and 3 chromosome regions are responsible for the majority of ectodermal dysplasias as different phenotypes may result from mutations in a single gene.
Diagnostic methods
The present classification of ectodermal dysplasia syndrome is based on clinical features although a genetic classification, just as significant, has been proposed on the basis of gene function.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Marco CASTORI


Ectodermal dysplasia with natal teeth, Turnpenny type

A rare ectodermal dysplasia syndrome characterized by neonatal teeth, hypo- or oligodontia of the secondary dentition, flexural acanthosis nigricans, and sparse body and scalp hair (the latter being thin and slow-growing). There have been no further descriptions in the literature since 1995.


Ectodermal dysplasia, trichoodontoonychial type is a form of ectodermal dysplasia with hair, teeth and nail involvement characterized predominantly by hypodontia, hypotrichosis, delayed hair growth and brittle nails. Additionally, focal dermal hypoplasia, irregular hyperpigmentation, hypoplastic or absent nipples, amastia, hearing impairment, congenital hip dislocation and asthma have been associated. There have been no further descriptions in the literature since 1996.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, severe visual impairment due to ocular malformations (microphthalmos and microcornea with sclerocornea), short stature, hypotrichosis, dental anomalies, and dysmorphic facial features (such as a narrow nasal bridge with marked distal flaring and low-set, protruding ears). There have been no further descriptions in the literature since 1992.


Ectodermal dysplasia-hyperhidrosis-cutaneous syndactyly syndrome

A rare ectodermal dysplasia syndrome characterized by hypotrichosis, tooth enamel hypoplasia, hypoplastic nails, palmoplantar keratoderma, hyperhidrosis on hands, face, and scalp, bilateral partial cutaneous syndactyly, and dysmorphic facial features with large prominent ear pinnae, pointed nose, and thin upper lips. Association of cardiomegaly has also been reported.


Ectodermal dysplasia-intellectual disability-central nervous system malformation syndrome is a rare, multiple developmental anomalies syndrome characterized by the triad of ectodermal dysplasia (mostly hypohidrotic with dry skin and reduced sweating and sparse, fair scalp hair, eyebrows and eyelashes), severe intellectual disability and variable central nervous system anomalies (cerebellar hypoplasia, dilatation of ventricles, corpus callosum agenesis, Dandy-Walker malformation). Distinct craniofacial dysmorphism with macrocephaly, frontal bossing, midfacial hypoplasia and high arched or cleft palate, as well as cryptorchidism, feeding difficulties and hypotonia, are associated. There have been no further descriptions in the literature since 1998.


Ectodermal dysplasia-pili torti-cutaneous syndactyly syndrome

Ectodermal dysplasia-syndactyly syndrome is a rare, genetic ectodermal dysplasia syndrome characterized by sparse to absent scalp hair, eyebrows, and eyelashes (with pili torti when present), widely spaced, conical-shaped teeth with peg-shaped, conical crowns and enamel hypoplasia and palmoplantar hyperkeratosis, associated with partial cutaneous syndactyly in hands and feet.


Ectodermal dysplasia-sensorineural deafness syndrome is characterised by hidrotic ectodermal dysplasia, sensorineural hearing loss, and contracture of the fifth fingers. It has been described in brother and sister born to consanguineous parents. The girl also presented with thoracic scoliosis. The mode of inheritance is likely to be autosomal recessive.


Ectodermal dysplasia-skin fragility syndrome

Epidermolysis bullosa simplex due to plakophilin deficiency (EBS-PD) is a suprabasal subtype of epidermolysis bullosa simplex (EBS, see this term) characterized by generalized superficial erosions and less commonly blistering.

Summary:
Epidemiology
Prevalence is unknown but 11 cases have been reported to date.
Clinical description
Onset of the disease is usually at birth with skin blistering and generalized erythema which rapidly regresses. Skin erosions and crusting are associated with dystrophic nails, hypotrichosis or alopecia with absent or sparse eyelashes and eyebrows, palmoplantar keratoderma with painful fissuring, chronic cheilitis with perioral cracking. Occasionally hair may be woolly rather than reduced. Other variable cutaneous findings and symptoms include follicular hyperkeratosis, perianal erythema and erosions, inflammatory scaly plaques in the flexures, and pruritus. Extracutaneous involvement is usually present, typically with growth retardation, and, in some cases, with recurrent infections, chronic diarrhea, tongue fissuring, and blepharitis.
Etiology
EBS-PD is due to mutations in the PKP1 (1q32) gene encoding plakophilin-1.
Genetic counseling
Transmission is autosomal recessive.
Prognosis
The disease is frequently associated with significant morbidity, but life-expectancy does not seem to be affected.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


A rare, life-threatening, congenital non-syndromic heart malformation characterized by complete or partial location of the heart outside the thoracic cavity. The main ectopic positions are thoracic but anterior to the sternum, abdominal, thoracoabdominal, and cervical. Associated abnormalities include sternal, diaphragmatic, pericardial, and abdominal wall defects, as well as intracardiac malformations.


Ectopia lentis-chorioretinal dystrophy-myopia syndrome

A rare, genetic, ophthalmic disorder characterized by the association of lens (ectopia and cataracts) and retinal (generalized tapetoretinal dystrophy and retinal detachment) anomalies, and variable myopia. Microcephaly and intellectual disability has been reported in some patients.


Ectopic aldosterone-producing tumor is an extremely rare aldosterone-producing neoplasm composed of aberrant adrenocortical tissue located outside the adrenal glands (e.g. in retroperitoneum, perirenal or periaortic fatty tissue, thorax, spinal canal, testes, ovaries) typically characterized by symptoms related to increased aldosterone levels (such as sustained, treatment-resistant hypertension and hypokalemia) or symptoms caused by local tumor enlargement.


Ectrodactyly-polydactyly syndrome is a rare, genetic, congenital limb malformation disorder characterized by hypoplasia or absence of central digital rays of the hands and/or feet and the presence of one or more, unilateral or bilateral, supernumerary digits on postaxial rays, ranging from hypoplastic digits devoid of osseous structures to complete duplication of a digit. Cutaneous syndactyly, symphalangism and clinodactyly have also been reported. There have been no further descriptions in the literature since 1982.


A rare, autosomal dominant, eye disorder representing a constellation of inherited ocular findings, including early-onset or congenital cataracts, corneal stromal thinning, early-onset keratoconus, corneal endothelial dystrophy, and iris hypoplasia.


Edinburgh malformation syndrome is a rare, genetic, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by consistently abnormal facial appearance, true or apparent hydrocephalus, motor and cognitive developmental delay, failure to thrive (feeding difficulties, vomiting, chest infections) and death within a few months of birth. Carp mouth, hairiness of the forehead, neonatal hyperbilirubinemia and advanced bone age may also be associated. There have been no further descriptions in the literature since 1991.


EEC syndrome is a genetic developmental disorder characterized by ectrodactyly, ectodermal dysplasia, and orofacial clefts (cleft lip/palate).

Summary:
Epidemiology
The exact prevalence is not known. More than 300 cases have been described in the literature.
Clinical description
The three cardinal signs of the syndrome are ectrodactyly and syndactyly of the hands and feet, cleft lip with or without cleft palate (that can result in speech defects), and abnormalities in several ectodermal structures including skin (i.e. hypopigmentated and dry skin, hyperkeratosis, skin atrophy), hair (i.e. fine and sparse hair and eyebrows), teeth (small, absent or dysplastic teeth), nails (nail dystrophy) and exocrine glands (reductiobsence of sweat, sebaceous and salivary glands). The syndrome presents a wide intra- and interfamilial clinical variability: the presence of the cardinal signs together is not mandatory and each one of them can be expressed in varying degrees of severity. Other associated clinical features include abnormalities of the genitourinary system (i.e. renal agenesis, urethral atresia, hydronephrosis), conductive or sensorineural hearing loss, choanal atresia, mammary gland/nipple hypoplasia, ophthalmological findings (i.e. lacrimal duct defects, photophobia, corneal ulcerations, keratitis, blepharitis, entropion), gland abnormalities (i.e. hypoplastic thymus, hypopituitarism, growth hormone deficiency), and on exceptional occasions, presence of a white sponge nevus, delayed developmental milestones, and malignant lymphoma. Patients do not have intellectual deficit.
Etiology
In more than 90% of cases, EEC is due to missense mutations in the sequence of the TP63 gene (3q27) encoding the TP63 transcription factor that is essential for ectoderm and limb development. These cases correspond to the classical EEC syndrome (EEC type 3) and seem to present some degree of genotype-phenotype correlation. The other cases correspond to EEC syndrome type 1, which shows associated clinical features such as malformedauricles and middle and inner ear malformations, and was mapped to 7q21. EEC type 2 does not exist anymore. EEC syndrome is an autosomal dominant disorder with incomplete penetrance (between 93 and 98%) and variable expression.
Diagnostic methods
The diagnosis is based on clinical examination, X-rays of the limbs and jaw, and, according to the associated features, kidney ultrasound, ophthalmologic examinations, and skin biopsy. Genetic testing may confirm the diagnosis.
Antenatal diagnosis
Antenatal diagnosis is based on ultrasonography during the second trimester of pregnancy which may reveal the structural abnormalities. Molecular analysis by chorionic villi sampling or by amniocentesis helps in confirming the diagnosis for families for which the disease-causing mutation was identified.
Genetic counseling
Genetic counseling should be offered to affected families informing them of the 50% risk an affected person has of transmitting the disease-causing mutation. Due to germline mosaicism, unaffected parents of a child with EEC syndrome have a 4% risk of having another affected child.
Management and treatment
Management is multidisciplinary and requires evaluation by orthopedic, plastic and dental surgeons, ophthalmologists, dermatologists, and speech therapists. Surgery allows correction of orofacial and dental abnormalities and improves the function and appearance of the limbs. Ophthalmologic care (e.g. artificial tears in case of dry eyes) is necessary to avoid complications such as cataract and corneal scarring. Hot temperatures, heavy clothing, and exercise must be avoided in case of hypohidrosis.
Prognosis
Prognosis is good with a near to normal life expectancy. Hypohidrosis (reductiobsence of sweat glands) presents the most life-threatening complications, as it can cause seizures, coma and eventually death when not managed correctly.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Pr Didier LACOMBE


A rare ectodermal dysplasia syndrome characterized by the association of ectodermal dysplasia (with hypotrichosis affecting scalp hair, eyebrows, and eyelashes, and partial anodontia), ectrodactyly, and macular dystrophy (appearing as a central geographic atrophy of the retinal pigment epithelium and choriocapillary layer of the macular area with coarse hyperpigmentations and sparing of the larger choroidal vessels). Variable additional limb defects (including absence deformities, polydactyly, syndactyly, or camptodactyly) have also been described, the hands often being more severely affected than the feet.


A heterogeneous group of diseases characterized by fragility of the soft connective tissues resulting in widespread skin, ligament, joint, blood vessel and/or internal organ manifestations. Clinical spectrum is highly variable, ranging from mild skin and joint hyperlaxity to severe physical disability and life-threatening vascular complications. Overlap with osteogenesis imperfecta may be observed resulting in an EDS/osteogenesis imperfecta overlap phenotype. Diseases in this group include classical Ehlers-Danlos syndrome (EDS), musculocontractural EDS, hypermobile EDS, vascular EDS, arthrochalasia EDS, dermatosparaxis EDS, periodontal EDS, X-linked EDS, brittle cornea syndrome, classical-like EDS type 1 and type 2, cardiac-valvular EDS, spondylodysplastic EDS, myopathic EDS, and kyphoscoliotic EDS.


A rare systemic disease characterized by the association of the features of Ehlers-Danlos syndrome with those of osteogenesis imperfecta. Predominant clinical manifestations include generalized joint hypermobility and dislocations, skin hyperextensibility and/or translucency, easy bruising, and invariable association with mild signs of osteogenesis imperfecta, including short stature, blue sclera, and osteopenia or fractures.


A group of acute febrile tick-borne diseases characterized by an overlapping clinical picture that includes fever, headache, myalgias, arthralgias, skin eruptions, gastrointestinal symptoms and neurological manifestations. Diseases in this group include human monocytotropic ehrlichiosis (HME), human granulocytotropic anaplasmosis (HGA), and human ehrlichiosis ewingii (HEE).


A rare, genetic, primary bone dysplasia syndrome characterized by multiple epiphyseal dysplasia, severely delayed ossification (mainly of the epiphyses, pubic symphysis, hands and feet), abnormal modeling of the bones in hands and feet, abnormal pelvis cartilage persistence, and mild growth retardation. Calcium, phosphate and vitamin D serum levels are typically within normal range, while parathyroid hormone serum levels are normal to slighly elevated. Oligodontia has been rarely associated.


A rare respiratory disease associated with unoperated congenital heart disease and characterized by congenital heart malformations with reversed or bi-directional shunting through an intra-cardiac or intervascular (usually aorto-pulmonary) communication with the development of PAH.

Summary:
Epidemiology
The disease is thought to be rare and affects both males and females equally. The incidence of the syndrome is decreasing in the developed world as the vast majority of causative cardiac lesions are now readily treatable. Incidence may still be higher in the less developed regions of the world as perinatal survival is higher but surgical treatment remains unaffordable for many.
Clinical description
The disease generally develops in children before puberty, but may develop in adolescence or early adulthood. Infants born with a large ventricular septal defect, an atrio-ventricular septal defect, or a persistently patent arterial duct are most susceptible. Pulmonary hypertension can also be associated with atrial septal defects but it is more controversial as to whether this is more accurately a form of idiopathic pulmonary hypertension (possibly accelerated by the shunt) than directly due to the atrial shunt. Clinical manifestations include exertional dyspnea, fatigue, lethargy, central cyanosis, chest pain, palpitations, atrial and ventricular arrhythmias. Right heart failure (with hepatomegaly, jugular venous distention and peripheral edema), is a very late complication. Dizziness and syncope due to low cardiac output is much rarer in Eisenmenger's syndrome than in PAH without intracardiac shunts. Clubbing and hemoptysis may occur. Precordial signs of ES are loud (often palpable) second heart sound and right ventricular heave. A pulmonary ejection click may be heard; Murmurs are variable and include those of pulmonary and tricuspid regurgitation. Complications include infective endocarditis, hyperviscosity, iron deficiency, bleeding disorders, hyperuricemia, stroke and cerebral abscess. Patients are at extremely high risk of death or major complications during pregnancy and the puerperium.
Etiology
The disease results from communication between right and left sides of the circulation, permitting oxygenated blood to recirculate at high pressure within the pulmonary vasculature. This increase blood pressure +/- increased flow promotes endothelial dysfunction and proliferation; which leads to vascular remodeling, and pulmonary hypertension. Reversal of shunt and development of cyanosis is regarded as Eisenmenger syndrome.
Diagnostic methods
Diagnosis is based on the clinical features, pulse oximetry findings, an abnormal electrocardiogram (right axis deviation, right ventricular hypertrophy and right atrial enlargement), echocardiography (underlying lesion, site of shunt and estimating pulmonary arterial pressure) and imaging (MRI and CT). Right-heart catheterization (saturation, hemodynamics and pulmonary vasoreactivity study if appropriate) is usual to establish the diagnosis and may be clinically useful in planning treatment / assessing efficacy. Routine lab testing (total blood count, liver function test, urea, creatinine, electrolytes, uric acid and iron status) is sought to detect emerging complications.
Differential diagnosis
Differential diagnoses include idiopathic pulmonary hypertension, tetralogy of Fallot, tricuspid atresia, transposition of the great arteries, persistent newborn pulmonary hypertension, pulmonary infection and respiratory failure.
Management and treatment
The disease can be avoided if appropriate repair of the underlying heart defect is undertaken prior to the establishment of irreversible changes to the pulmonary vascular bed. Management includes maintaining fluid balance, prophylaxis against infective endocarditis, iron supplementation and avoiding precipitating factors (pregnancy, isometric exercise, high altitude). Targeted pharmacological therapies are recommended for symptomatic patients; prostacyclin analogues (treprostinil), endothelin antagonists (bosentan, macitantan), nitric oxide, phosphodiesterase inhibitor (sildenafil). Heart and lung transplantation (or lung transplantation with intracardiac repair) is an option for patients with a poor prognosis who fail to respond to medical therapy.
Prognosis
Life expectancy depends on the type and severity of the underlying defect and right ventricular function, and ranges from 20 to 50 years. In patients with the syndrome the maternal mortality rate exceeds 50%. The chances of preterm delivery and low birth weight are extremely high and the likelihood of livebirth drops dramatically with lower maternal oxygen saturation levels (to below 10% in some series) if maternal resting oxygen saturations are less than 85%.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Frances BU'LOCK


An extremely rare, acquired, dermis elastic tissue disorder characterized by localized increased skin laxity associated with delayed skin recoil, typically occurring on the elbows, knees and/or neck. Histologically, focal abundace of elastic tissue in the dermis with pleomorphic and fragmented elastic fibers, without calcification, is observed.


Elastofibroma dorsi is a rare, acquired, dermis elastic tissue disorder characterized by a benign, slowly progressive, often bilateral, non-encapsulated lesion, usually presenting as an ill-defined mass under the inferior angle of the scapula (but other locations have been reported), which adheres to the deep layers and presents no local signs of inflammation. It is commonly asymptomatic and discovered inadvertently, but symptoms may include pain and discomfort or stiffness when using the shoulder. The presence of a firm mass masked by the scapula during retropulsion of the shoulder and becoming prominent when the shoulder is displaced toward the front is a frequent sign. Neuromuscular involvement of the upper limb may occur in rare cases.


A rare, genetic or acquired, dermis elastic tissue disorder characterized by asymptomatic, solitary or multiple, firm, skin-colored to yellowish papules or nodules of variable size that are disseminated or grouped in clusters and typically located on the trunk, buttocks, thighs or face, among others. Histologically, focal increase of thickened, tortuous elastic fibers in the reticular dermis, without signs of degeneration, is reported. Isolated cases, as well as cases associated with osteopoikilosis (Buschke-Ollendorf syndrome), may be observed.


A rare acquired dermis elastic tissue disorder with increased elastic tissue characterized by focal dermal elastosis and transepidermal elimination of abnormal elastic fibers, presenting as small keratotic papules or plaques arranged in groups in serpiginous or annular patterns on the neck, face, and arms, while other areas are less frequently affected. Although spontaneous regression is possible, the lesions often persist over longer periods of time. The condition typically occurs during childhood or early adulthood and is more frequent in men than in women.


A rare chondral and ectodermal dysplasia characterized by short ribs, polydactyly, growth retardation, and ectodermal and heart defects.

Summary:
Epidemiology
It is a rare disease with approximately 150 cases reported worldwide. The exact prevalence is unknown, but the syndrome seems more common among the Amish community.
Clinical description
Prenatal abnormalities (that may be detected by ultrasound examination) include narrow thorax, shortening of long bones, hexadactyly and cardiac defects. After birth, cardinal features are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth. Heart defects, especially abnormalities of atrial septation, occur in about 60% of cases. Cognitive and motor development is normal.
Etiology
Mutations of the EVC and EVC2 genes, located in a head to head configuration on chromosome 4p16, have been identified as causative.
Differential diagnosis
EVC belongs to the short rib-polydactyly group (SRP) and these SRPs, especially type III (Verma-Naumoff syndrome), are discussed in the prenatal differential diagnosis. Postnatally, the essential differential diagnoses include Jeune dystrophy, McKusick-Kaufman syndrome and Weyers syndrome.
Genetic counseling
This rare condition is inherited as an autosomal recessive trait with variable expression.
Management and treatment
The management of EVC is multidisciplinary. Management during the neonatal period is mostly symptomatic, involving treatment of the respiratory distress due to narrow chest and heart failure. Orthopedic follow-up is required to manage the bones deformities. Professional dental care should be considered for management of the oral manifestations.
Prognosis
Prognosis is linked to the respiratory difficulties in the first months of life due to thoracic narrowness and possible heart defects. Prognosis of the final body height is difficult to predict.

                            Last update:
                            June 2007

                            - Expert reviewer(s):
                            Dr Geneviève BAUJAT  - Dr Martine LE MERRER


A constitutional genomic disorder due to the presence of a supernumerary derivative 22 chromosome and characterized by severe intellectual disability, characteristic facial dysmorphism (micrognathia, hooded eyelids, upslanting downslanting parebral fissures, deep set eyes, low hanging columnella and long philtrum), congenital heart defects and kidney abnormalities.


A neuromuscular disease that is characterized by muscular weakness and atrophy, with early joint contractures and cardiomyopathy.

Summary:
Epidemiology
Emery-Dreifuss muscular dystrophy (EDMD) prevalence is estimated at 1 in 400,000.
Clinical description
The clinical triad is comprised of joint contractures of the Achilles, elbow and posterior neck tendons (beginning during early childhood and worsening to result in limited joint movement). It presents slowly progressive muscle weakness and atrophy (initially and generally with a humeroperoneal distribution but later becoming more diffuse). Cardiac anomalies (conduction defects, rhythm disturbances and dilated cardiomyopathy) that usually manifest at the turn of the 2nd to the 3rd decade of life and may lead to sudden death (sometimes the presenting feature of the disease) and ischemic accidents due to embolism. Disease course and severity vary between families and between patients from the same family.
Etiology
Several causative genes have been identified encoding ubiquitous proteins including emerin (EMD; Xq28 and FHL1; Xq26.3) for X-linked EDMD and lamin A/C (LMNA; 1q21.2) for EDMD with autosomal transmission. Exceptionally, variants in LUMA (TMEM43), Nesprine1 (SYNE1) and Nesprine2 (SYNE2) were reported in EDMD-like patients with autosomal transmission. Emerin, lamin A/C, Nesprine1, Nesprine2 and LUMA are nuclear envelope proteins. Around 45% of patients do not carry mutations in these genes suggesting other causative genes that remain to be identified.
Diagnostic methods
Diagnosis relies on recognition of the clinical triad (although the cardiac manifestations may be absent at onset). Muscular imagining may reveal isolated involvement of the soleus, suggestive of the initial stages of disease. For X-linked forms linked to the EMD gene, immunodetection of emerin in various tissues reveals an absence or reduction of the protein. The diagnosis can be confirmed by detection of EMD mutations. For autosomal forms and X-linked forms linked to FHL1, direct molecular analysis of LMNA, FHL1 , SYNE1, SYNE2 and TMEM43 genes is the only approach for confirming the diagnosis.
Differential diagnosis
The main differential diagnoses include other forms of myopathy with joint contractures, with or without cardiac involvement (Bethlem myopathy, SEPN1 and FKRP-related myopathies); the desmin-related myopathies; proximal myotonic myopathy; and certain forms of LGMD with cardiac involvement.
Antenatal diagnosis
Prenatal diagnosis is possible when the causative mutation is known.
Genetic counseling
Several modes of transmission have been reported: X-linked and autosomal dominant or recessive. Genetic counselling depends on the mode of transmission and on whether the mutation has been identified or not.
Management and treatment
Management should include orthopaedic measures (orthopaedic apparatus, surgery for the Achilles tendon contractures and scoliosis). Treatment of the cardiac disease: anti-arrhythmic agents including beta-blockers, diuretics, ACE inhibitors, cardiac devices (pacemaker, implantable cardiac defibrillator) when required, heart transplantation in case of end-stage heart failure, and treatment of the respiratory complications (intermittent nasal ventilation, tracheostomy).
Prognosis
Prognosis depends on the severity of muscle weakness, joint contractures, and of the cardiac and respiratory involvement. Patients with severe forms of the disease may lose the capacity to walk or require intermittent nasal ventilation.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Dr Rabah BEN YAOU  - Dr Gisèle BONNE  - Dr France LETURCQ


A rare congenital limb malformation syndrome characterized by facial dysmorphism (high forehead, depressed nasal bridge, long philtrum, flat malar region, high arched palate), short stature and deformities of the hands and feet (small hands/feet, flexion contractures of the first three metacarpophalangeal joints, extension contractures of the thumbs at the interphalangeal joints, clawed toes, mild pes cavus). Additional features include neonatal hypotonia, thin and shiny skin of the hands/feet, ridged nails, dry and coarse hair, mild weakness of the orbicularis oculi muscles and occasional ventricular extrasystoles. Intellectual disability may be present. There have been no further descriptions in the literature since 1970.


EMILIN-1-related connective tissue disease

A rare hereditary disease with peripheral neuropathy characterized by distal sensorimotor or motor neuropathy of the lower limbs with muscle weakness and atrophy. Some patients show overt connective tissue disease with signs and symptoms like increased skin elasticity and easy bruising (but no atrophic scarring), decreased clotting, aortic aneurysms, joint hypermobility, and recurrent tendon ruptures.


A extremely rare, genetic malformation syndrome characterized by hypoplastic amelogenesis imperfecta (hypoplastic dental enamel) and nephrocalcinosis (precipitation of calcium salts in renal tissue). Oral manifestations include yellow and misshaped teeth, delayed tooth eruption, and intrapulpal calcifications. Nephrocalcinosis is often asymptomatic but can progress during late childhood or early adulthood to impaired renal function, recurrent urinary infections, renal tubular acidosis, and rarely to end-stage renal failure.


A rare brain inflammatory disease characterized by acute or subacute encephalitis with involvement of the midbrain and basal ganglia occurring in children as well as adults. Initial symptoms are pharyngitis and fever, followed by progressive lethargy, sleep disturbances, extrapyramidal symptoms (parkinsonism, chorea, dystonia), neuropsychiatric manifestations (obsessive-compulsive behavior, mutism, catatonia), and ocular features (oculogyric crises). Autoantibodies against human basal ganglia are often positive. Survivors may develop post-encephalitic syndromes, most prominently parkinsonism.


A rare, genetic skin disease characterized by the ocular, cutaneous, and central nervous system anomalies. Typical clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas, leading sometimes to seizures, spasticity, and intellectual disability. Nevus psiloliparus, focal dermal hypo- or aplasia, eyelid skin tags, colobomas, abnormal intracranial vessels, hemispheric atrophy, porencephalic cyst, and hydrocephalus have also been associated.


Encephalopathy due to mitochondrial and peroxisomal fission defect

A rare mitochondrial disease characterized by a variable phenotype comprising delayed psychomotor development or neurodevelopmental regression, hypotonia, seizures, microcephaly, optic atrophy, pyramidal signs, and peripheral neuropathy, among others. Age of onset and disease severity are also variable with some cases taking a fatal course in early infancy. Serum lactate levels may be elevated. Reported brain imaging findings include abnormal signals in the basal ganglia, cerebral and/or cerebellar atrophy, and white matter abnormalities.


A lysosomal storage disease belonging to the group of sphingolipidoses.

Summary:
Epidemiology
It is very rare with less than 10 cases reported in the literature so far.
Clinical description
Clinically, it is a severe neurovisceral disease manifesting immediately after birth and following a rapidly progressive fatal course (death between 1 and 4 months in the cases documented so far). The neurological signs and symptoms include hypotonia, massive myoclonic bursts, abnormal ocular movements and dystonia. Grand mal seizures and seizures triggered by tactile stimuli have been described. Patients also develop hepatosplenomegaly. Death usually occurs from respiratory failure following repeated pulmonary infections.
Etiology
The disease is caused by mutations in the PSAP gene (10q21) leading to absence or non-functionality of the prosaposin protein. Prosaposin is the common precursor for proteins required for the in vivo lysosomal degradation of several sphingolipids, and has other important but still poorly understood functions. Under normal conditions, proteolytic processing of prosaposin produces four smaller "sphingolipid activator proteins'' called saposins (or Sap) A, B C and D. An isolated deficiency of each of these factors leads to rare variant genetic forms of Krabbe disease (Sap A), metachromatic leukodystrophy (Sap B), Gaucher disease (Sap C) and, putatively, Farber disease (Sap D; see these terms). In prosaposin deficiency, there is a combined deficiency of all four factors.
Diagnostic methods
The final diagnosis is established by identification of the PSAP mutation(s), but the study of sphingolipids in urine sediment (showing a massive combined excretion of globotriaosylceramide (Gb3), sulfatides and other sphingolipids) is a good orientation test. Low galactosylceramidase in leukocytes has also been reported. Bone marrow/liver biopsies usually show the presence of Gaucher-like macrophages.
Antenatal diagnosis
Prenatal diagnosis is feasible by mutation analysis on uncultured (or cultured) chorionic villi, or amniotic fluid cells.
Genetic counseling
The mode of inheritance is autosomal recessive.
Management and treatment
No specific treatment is available.
Prognosis
Encephalopathy due to prosaposin deficiency is a very severe metabolic disorder with a poor prognosis.

                            Last update:
                            December 2009

                            - Expert reviewer(s):
                            Dr Marie-Thérèse VANIER


Encephalopathy due to sulfite oxidase deficiency is a rare neurometabolic disorder characterized by seizures, progressive encephalopathy and lens dislocation.

Summary:
Epidemiology
The prevalence is unknown but is very rare. At least 100 patients with sulfite oxidase deficiency have been reported with approximately 75% of cases being related to molybdenum cofactor (MoCo) deficiency.
Clinical description
Symptoms usually occur within the first week after birth with feeding difficulties, vomiting and seizures which are difficult to control. The majority of patients exhibit facial dysmorphism (prominent forehead, narrow bifrontal diameter, sunken eyes, elongated palpebral fissures, puffy cheeks, small nose and long philtrum and thick lips). The course is progressive, with spasticity, severe intellectual deficit, and microcephaly seen in survivors. Lens dislocation usually occurs late in infancy but has been observed as early as two months of age. A late onset form with a milder phenotype has also been described.
Etiology
Isolated sulfite oxidase deficiency is caused by a mutation in the SUOX gene (12q13.13) (see this term). The SUOX gene encodes the enzyme sulfite oxidase which catalyzes sulfite to sulfate, a process essential for the catabolism of sulfur-containing amino acids. MoCo deficiency secondary to mutations in either the MOCS1 (6p21.2) or MOCS2 (5q11) genes also causes sulfite oxidase deficiency (see this term). These genes encode two of the biosynthetic MoCo pathway enzymes. Impaired synthesis of MoCo leads to the combined deficiencies in sulfite oxidase, xanthine dehydrogenase, mitochondrial amidoxime reducing component (mARC) and aldehyde oxidase (the four human molybdoenzymes). The GPHN (14q23.3) gene has also been identified as the cause in one case of MoCo deficiency (see this term).
Diagnostic methods
A sulfite test strip in a fresh urine sample is a simple screening test but false positive and negative results can occur. Hypouricemia is seen in the MoCo deficiency form of the disease. A third test involves detection of low levels of plasma homocysteine. Diagnosis is confirmed by a skin fibroblast culture showing the absence of sulphite oxidase and/or MoCo activity in cultured fibroblasts. Magnetic resonance imaging shows diffuse cystic lesions within the white matter, basal ganglia and thalamus along with ulegyric changes in the cerebral cortex and cerebellar hypoplasia.
Differential diagnosis
Isolated sulfite oxidase deficiency is clinically indistinguishable from MoCo deficiency (see these terms). Hypoxic-ischemic encephalopathy (see this term) and neonatal hyperekplexia should be eliminated. Feeding difficulties can mimic amino acid intolerances.
Antenatal diagnosis
Antenatal diagnosis is possible by measuring the enzyme activity in chorionic villus samples or s-sulfocysteine levels in amniotic fluid, or by DNA analysis.
Genetic counseling
The disease follows an autosomal recessive pattern of inheritance and genetic counseling is possible.
Management and treatment
There is no cure for sulfite oxidase deficiency. Antiepileptic drugs in various combinations are used for control of seizures. Administration of diets low in sulfur containing amino acids along with sulfate supplementation have been attempted with positive biochemical responses but with no lasting neurological improvement. MoCo type A defective individuals have benefited from precursor Z (cPMP), a precursor to MoCo. Although it cannot reverse the cerebral injury that has already occurred, seizures are stopped and neurotoxicity and further cerebral damage is prevented. Genetic therapy with a MOCS1 expression cassette being carried by AAV vectors is now being studied as a future treatment.
Prognosis
The prognosis of the disease is poor. For those who survive infancy, new treatments have led to improvement in some patients.

                            Last update:
                            January 2012

                            - Expert reviewer(s):
                            Dr Parayil Sankaran BINDU


Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome is a rare mitochondrial disease due to a defect in coenzyme Q10 biosynthesis that manifests with a broad spectrum of signs and symptoms which may include: neonatal lactic acidosis, global developmental delay, tonus disorder, seizures, reduced spontaneous movements, ventricular hypertrophy, bradycardia, renal tubular dysfunction with massive lactic acid excretion in urine, severe biochemical defect of respiratory chain complexes II/III when assayed together and deficiency of coenzyme Q10 in skeletal muscle. Cerebral and cerebellar atrophy can be seen on magnetic resonance imaging and multiple choroid plexus cysts and symmetrical hyperechoic signal alterations in basal ganglia have been observed on ultrasound.


Encircling double aortic arch is a very rare congenital anomaly of the great arteries characterized by the presence of two aortic arches (right and left) which encircle and compress the trachea and esophagus, resulting in various respiratory and gastrointestinal symptoms (e.g. harsh breathing, stridor, dyspnea, cyanotic and choking episodes, chronic cough, recurrent respiratory tract infections, dysphagia and reflux). Esophageal atresia and tracheoesophageal fistula have also been reported. It usually occurs isolated, but, on occasion, may be associated with other congenital heart anomalies and chromosomal aberations.


A rare cardiac disease characterized by thickening of the endocardium due to deposition of collagen and elastic fibers and leading to dilated cardiomyopathy-like phenotypes more often than to restrictive forms. It predominantly occurs in infants and children and may be observed as an isolated disorder or in association with congenital heart conditions.


Endocrine-cerebro-osteodysplasia (ECO) syndrome is characterized by various anomalies of the endocrine, cerebral, and skeletal systems resulting in neonatal mortality.

Summary:
Epidemiology
To date, six cases from consanguineous parents have been described.
Clinical description
Endocrine anomalies include hypoplasia of the adrenal and pituitary glands. Skeletal anomalies include micromelia, syndactyly, brachydactyly and ulnar deviation of hands. Facial anomalies, such as midface hypoplasia, micrognathia, and a flat and wide nasal bridge, are also observed.
Etiology
The disease is caused by mutations in the ICK gene, encoding an intestinal cell kinase.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            October 2009


A rare malignant epithelial tumor of ovary characterized by confluent or cribriform proliferations of round, oval, or tubular glands, typically lined by stratified non-mucin-containing epithelium with well-defined luminal margins. Squamous differentiation, secretory changes, oxyphilic variants, sex cord-stromal type patterns, or sertoliform endometrioid carcinomas may occur. Patients most commonly present in the sixth decade of life, either with a pelvic mass with or without pain, or without any symptoms. The tumor may be bilateral and is frequently associated with endometriosis and/or endometrial carcinoma.


A rare ophthalmic disorder characterized by inflammation involving the vitreous and/or aqueous humors, usually due to bacterial or fungal infection. It may arise endogenously from hematogenous spread of the infectious agent, or exogenously after direct inoculation, and can take an acute or chronic course. Clinical signs and symptoms include progressive vitritis, hypopyon, reduced or blurred vision, red eye, pain, and lid swelling. The condition may be complicated by panophthalmitis, corneal infiltration and perforation, affection of orbital structures, and phthisis bulbi.


A rare sclerozing bone disorder characterized by generalized skeletal densification, particularly of the cranial vault and tubular long bones, which is not associated to an increased risk of fracture.

Summary:
Epidemiology
The syndrome has been described in less than 10 families.
Clinical description
Craniofacial anomalies develop during adolescence and include a prominent forehead, wide and deep mandibles, wide nasal root, taurus palatinus and increased gonial angle.
Etiology
The syndrome is due to a mutation in the LRP5 gene that leads to increased bone formation.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            November 2009


Endosteal sclerosis-cerebellar hypoplasia syndrome is characterized by congenital cerebellar hypoplasia, endosteal sclerosis, hypotonia, ataxia, mild to moderate developmental delay, short stature, hip dislocation, and tooth eruption disturbances. It has been described in four patients. Less common manifestations are microcephaly, strabismus, nystagmus, optic atrophy, and dysarthria. It is appears to be transmitted as an autosomal recessive trait.


A rare disorder characterized by intrauterine growth retardation and intermittent locking of the finger joints. It has been described in two individuals: a mother and her daughter. The mode of transmission is autosomal dominant.


Enlarged parietal foramina (EPF) is a developmental defect, characterized by variable intramembranous ossification defects of the parietal bones, which is either asymptomatic, symptomatic (headaches, nausea, vomiting, intellectual disability) or associated with other pathologies.

Summary:
Epidemiology
Prevalence is estimated to be 1/15,000-1/50,000.
Clinical description
EPF is a congenital disorder characterized by symmetrical, paired persistent foramina (openings) in the parietal bones (diameter >5 mm), located close to the intersection of the sagittal and lambdoid sutures. In infants, EPF presents as a persistent enlargement extending forward from the posterior fontanelle, caused by a single large central parietal bone defect, termed cranium bifidum. The latter tends to resolve in early childhood leaving two distinct, large parietal foramina through the ossification of a midline bridge. EPF is usually asymptomatic, but may be associated with headaches, nausea, vomiting, intense local pain and intellectual disability. EPF can also be accompanied by meningeal, cortical, and vascular malformations of the posterior fossa (that may predispose to epilepsy), and Duane retraction syndrome (see this term). Craniofacial anomalies including cleft palate, myelomeningocele and isolated encephalocele are rarely associated (see these terms). Clavicular hypoplasia may lead to confusion with cleidocranial dysplasia (see this term).
Etiology
EPF is caused by insufficient ossification around the parietal notch. In most cases this results from heterozygous loss of function mutations in human homeobox genes, MSX2 (5q35.2) and ALX4 (11p11.2), which encode transcription factors involved in skeletal development. A possible third locus on 4q21-q23 has also been reported in a large Chinese pedigree. EPF may also be seen in aminopterin/methotrexate embryofetopathy (see this term), which is caused by exposure to folic acid antagonists during the first trimester of preganancy.
Diagnostic methods
Diagnosis of EPF is based on family history and on clinical examination. Radiographically, EPF presents as symmetric radiolucencies. Computed tomography (CT) imaging with 3D reconstructions can delineate the osseous defect and magnetic resonance (MR) imaging may demonstrate associated intracranial changes. If EPF is associated with anomalies of the cerebral vasculature, additional vascular imaging like CT, MR, or digital subtraction angiography may be warranted. Diagnosis is confirmed by screening for the pathogenic mutation.
Differential diagnosis
Differential diagnosis includes Potocki-Shaffer syndrome; distal monosomy 15q; cleidocranial dysplasia; acromelic frontonasal dysplasia; craniosynostosis-anal anomalies-porokeratosis; and frontonasal dysplasia with alopecia and genital anomaly (see these terms).
Antenatal diagnosis
Preimplantation genetic testing, or prenatal diagnosis during pregnancy from 10 weeks gestation, is available for families with a known genetic defect.
Genetic counseling
Transmission is autosomal dominant with high but incomplete penetrance.
Management and treatment
Treatment for EPF is generally conservative, since the natural history of the defect is to close progressively with age. Protective helmets can be considered in young, active children with particularly large defects, but surgery is not usually recommended. Imaging to assess for any accompanying venous anomalies is imperative prior to any surgical intervention.
Prognosis
There is no known correlation between the size of the defect and the likelihood of having an associated brain abnormality. A spontaneous closure of the defect with growth of the infant has been observed, but it is frequently incomplete.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Dr Tracy LESTER  - Pr Andrew WILKIE


A very rare genetic gastroenterological disease characterized by severe malabsorptive diarrhea (requiring parenteral nutrition and disappearing at fasting) due to a lack of intestinal enteroendocrine cells. It is associated with early-onset (within the first weeks of life) dehydration, metabolic acidosis and diabetes mellitus (that can develop until late childhood). Patient may display various degrees of pancreatic insufficiency that does not explain diarrhea, as it is not reduced with pancreatic enzyme supplementation. Central hypogonadism (developing in the second decade), as well as an association with celiac disease have been reported.


A rare T-cell non-Hodgkin lymphoma characterized by a neoplasm of intraepithelial T-cells mostly occurring in the jejunum or ileum in patients with celiac disease. The lesion may be multifocal and form ulcerating nodules, plaques, strictures, or an exophytic mass. The mesentery and mesenteric lymph nodes are commonly involved. Patients typically present with abdominal pain, malabsorption or diarrhea, anorexia, weight loss, fatigue, nausea, vomiting, and sometimes intestinal perforation or hemorrhage. Prognosis is generally poor.


A rare inflammatory rheumatic disease in a child younger than 16 years characterized by arthritis and/or enthesitis and/or acute anterior uveitis. The most commonly affected joints at diagnosis are the knees, ankles, and hips. The small joints of the feet and toes are also often involved.

Summary:
Epidemiology
The incidence of juvenile idiopathic arthritis (JIA) in Caucasians is 8.3/100,000. Enthesitis-related juvenile idiopathic arthritis accounts for 10%-20% of these cases. Males account for approximately 60% of cases.
Clinical description
JIA describes a clinically heterogeneous group of diseases, characterized by arthritis beginning before the age of 16 years, involving one or more joints, and lasting for at least 6 weeks. The enthesitis-related category describes a clinically heterogeneous group of children including some who have predominately enthesitis, enthesitis and arthritis, or axial involvement (sacro iliac or dorsal or lumbosacral pain), or inflammatory bowel disease-associated arthropathy. Onset typically occurs in late childhood or adolescence with a peak age of onset between 10 and 12 years. In the first 6 months of disease, oligoarticular disease is most common.
Etiology
The etiology is unknown.
Diagnostic methods
Diagnosis is established by the presence of enthesitis and arthritis, or by the presence of arthritis and at least two of the following: sacroiliac pain and/or spinal inflammation, acute anterior uveitis, presence of the HLA-B27 antigen, a family history of uveitis, and spondylarthropathy, or sacroiliitis with inflammatory bowel disease in a first-degree relative. Arthritis and enthesitis are typically diagnosed by clinical findings of localized pain, tenderness, and swelling; when clinical findings are difficult to assess, echography or MRI could help. Exclusion criteria include the presence of psoriasis in the patient or a family history of psoriasis in a first-degree relative, detection of Rheumatoid Factor IgM in two tests taken at a 3-month interval, and the presence of systemic arthritis in the patient.
Differential diagnosis
Differential diagnosis should include other types of juvenile idiopathic arthritis, infectious arthritis, other inflammatory diseases, and hemato-oncologic diseases that may lead to arthritis (in particular connective tissue diseases and acute leukemia).
Management and treatment
Treatment typically revolves around monotherapy or combination therapy of nonsteroidal anti-inflammatory drugs (NSAIDs), and biologic anti-TNF agents such as etanercept and adalimumab. Use of biological DMARDs (disease modifying anti-rheumatic drugs) are only recommended in severe, refractory cases. NSAID monotherapy may be appropriate for children with low disease activity and without features of poor prognosis, although continuation of this approach for longer than 2 months may require routine laboratory studies to monitor for hepatic and renal toxicity. In order to manage pain associated with enthesitis in the foot, padded heel inserts may be recommended.
Prognosis
Progression to axial disease can occur in children with enthesitis-related JIA. In the majority of cases, the disease progressively evolves into spondylarthritis. By 5 years after disease onset, 92% of children with spondylarthritis develop sacroiliitis. Tarsitis, and hip arthritis within the first 6 months, are associated with worse prognosis. In comparison with other JIA categories, enthesitis-related JIA is associated with worse function, quality of life, and pain. Disease remission is often obtain with biological DMARDs when NSAIDs are insufficient; without treatment, remission occurs in less than 20% of children 5 years after diagnosis.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Dr Chantal DESLANDRE


A rare otorhinolaryngologic disease characterized by an indolent submucosal mass of variable size and extent, most commonly arising in the anterior nasal cavity, involving the nasal septum and lateral nasal wall, and potentially extending into the adjacent sinuses. Occurrence in the larynx and lower respiratory tract or the orbit is rare. Histological examination shows concentric angiocentric stromal fibrosis (onionskin fibrosis) and prominent eosinophils. Increased numbers of IgG4-positive plasma cells in the lesion may also be observed, in addition to elevated serum IgG4. Patients typically present with long-standing obstructive symptoms.


A rare gastroenterologic disease characterized by extensive eosinophilic infiltration of the colon in the absence of any known cause of secondary intestinal eosinophilia. Patients present with abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding, malabsorption, and/or weight loss. Symptoms do not correlate with the extent of the disease, which can be segmental or pancolonic. Blood testing may show peripheral eosinophilia. The condition has a bimodal age distribution, with a first peak in neonates and a second peak in young adulthood.


A rare idiopathic inflammatory myopathy that is characterized by inflammation and thickening of the fascia, usually associated with peripheral eosinophilia. It presents during adulthood with symmetrical and painful swelling of mainly the extremities that progressively become indurated. Fatigue, disabling cutaneous fibrosis, myositis and arthritis may also be observed.


A rare benign gastrointestinal disease characterized by the presence of abnormal and nonspecific gastro-intestinal (GI) manifestations, associated with an eosinophilic infiltration of the GI tract, which can affect several segments and involve several layers within the GI wall.

Summary:
Epidemiology
Prevalence and incidence are unknown. To date, more than 280 cases have been reported, mainly in Caucasians and with a slight male preponderance.
Clinical description
EGE can occur at any age, but it is most commonly observed between the ages of 30 and 50 years. It can affect any area of the digestive tract, with the stomach and duodenum being the most commonly affected sites. The clinical presentation is variable and depends on the region of the digestive tract involved and the depth of eosinophilic involvement. Three sub-types have been defined according to the digestive tract layer involved. Mucosal EGE (the most common sub-type) is characterized by abdominal pain, diarrhea (with or without hemorrhage), dyspepsia, nausea, vomiting, weight loss and symptoms of protein losing enteropathy (e.g. swelling and edema). In children and adolescents, growth retardation, failure to thrive, and anemia may also be observed. Muscular EGE is often associated with hypertrophy and hyperplasia of the muscular layers, leading to symptoms of intestinal stenosis/obstruction (e.g. vomiting, nausea). Less often, symptoms of intussusception can be observed (severe abdominal pain with cramps). Serosal EGE is characterized by bloating, exudative ascites and peripheral eosinophilia. Other features have also been observed such as cholingitis, pancreatitis, and acute appendicitis.
Etiology
The pathogenesis of EGE is poorly understood but it is thought that EGE is mediated by a hypersensitivity reaction. Various stimuli, including food allergens, drugs (azathioprine, gold salts, trimethoprim-sulphonamide) and immunological disorders, may trigger eosinophilic infiltration of the GI tract, followed by degranulation with cytokine release and cellular damage.
Diagnostic methods
Laboratory examinations demonstrate peripheral blood eosinophilia and elevated serum IgE concentrations (20-80% of cases). Other findings include steatorrhea, hypoalbuminemia, iron deficiency anemia, and prolonged prothrombin time. Endoscopy shows erythematous, friable, sometimes nodular and ulcerated mucosa. Histopathological examination of gastric and duodenal biopsies confirms the diagnosis by usually showing eosinophilic infiltrates (> 20-30 eosinophils per high-power field) in the absence of other known causes of eosinophilia. Eosinophilic degranulation or cryptitis are also diagnostic.
Differential diagnosis
Differential diagnosis includes eosinophilic esophagitis, Crohn disease, periarteritis nodosa, Churg-Strauss syndrome, idiopathic hypereosinophilic syndrome, congenital chronic diarrhea with protein-losing enteropathy, celiac disease, lymphoma (see these terms) and gastric cancer.
Management and treatment
In some early-onset pediatric cases, EGE has resolved by suppressing milk from diet. Complete resolution has also been achieved in children by exclusive feeding with an amino acid-based elemental formula or by following a hypoallergenic diet. In moderate to severe cases, treatment is based on oral corticotherapy. Low dose maintenance corticotherapy is needed in case of relapse and to keep the disease under control. Mast cell stabilizers and antihistamines have been successfully used in some cases.
Prognosis
With treatment, prognosis is good with full resolution of symptoms in spite of a possible relapsing course. Complications have been reported in rare cases, mainly in the serosal sub-type, such as intestinal obstruction and perforation that may require surgery and may affect the quality of life.

                            Last update:
                            April 2014


Eosinophilic granulomatosis with polyangiitis

A rare systemic vasculitis of small vessels characterized by asthma, blood and tissue eosinophilia and vasculitis manifestations.

Summary:
Epidemiology
The prevalence ranges from 1/70,000-100,000 in Europe.
Clinical description
Onset of eosinophilic granulomatosis with polyangiitis (EGPA) usually occurs in adulthood but may occur anywhere between 15 and 70 years of age. EGPA may involve multiple organ systems. The onset of EGPA is often associated, in patients with preexisting asthma, with worsening of the asthma. Eosinophilic asthma and angiitis are the two hallmarks of the disease. EGPA has been divided into three distinct phases, which may or may not be sequential. The prodromal phase is characterized by asthma with or without allergic rhinitis. The second phase is marked by peripheral blood eosinophilia and eosinophilic tissue infiltration producing a picture similar to those of simple pulmonary eosinophilia (Loeffler syndrome), chronic eosinophilic pneumonia, or eosinophilic gastroenteritis. The third phase, i.e. vasculitic phase, usually develops within 3 years of onset and may involve any of the following organs: heart (myocarditis, pericarditis, failure), peripheral nervous system (mononeuritis multiplex in 78% of patients), paranasal sinuses, muscles, skin and less frequently kidney. Skin involvement (nodules, utricarial rash) occurs in two thirds of patients. Fever, flu-like symptoms, and weight loss are also observed. Anti-myeloperoxidase (MPO)-anti neutrophil cytoplasmic antibodies (ANCA) are found in 30 to 40% of patients and identify patients with a different clinical phenotype (e.g a higher prevalence of renal disease).
Etiology
Etiology of EGPA is unknown.
Diagnostic methods
Classification criteria of EGPA include, in the presence of evidence of vasculitis, four of the following six features: asthma, eosinophilia, neuropathy, pulmonary infiltrates, paranasal sinus abnormalities and eosinophilic vasculitis. Eosinophilia above 10% is the hallmark laboratory finding in patients with EGPA and may be as high as 75% of the peripheral blood cell count. Findings in chest X-ray (infiltrates, pneumonitis) are extremely common in EGPA. Tissue biopsies show eosinophilia, necrotizing vasculitis of small to medium vessels and, sometimes, small necrotizing granulomatous inflammation.
Differential diagnosis
Differential diagnoses of EGPA include granulomatosis with polyangiitis, hypereosinophilic syndrome, microscopic polyangiitis, polyarteritis nodosa, drug reactions, bronchocentric granulomatosis, fungal and parasitic infections, and malignancy.
Management and treatment
The treatment of patients with mild disease involves glucocorticoids (GC) monotherapy. Other immunosuppressive regimens, such as those using cyclophosphamide (CP), azathioprine or methotrexate, are used for patients with an aggressive disease. Other treatments, including rituximab or interferon-alpha, has been used in patients refractory to GC plus CP. Treatment with the anti-interleukin-5 antibody mepolizumab now represents a very effective treatment of GC-dependent eosinophilic asthma; however, its efficacy to treat vasculitis manifestations remains to be evaluated.
Prognosis
Cardiac involvement used to be the leading cause of death related to EGPA, followed by cerebral hemorrhage and stroke. GC-related toxicity is also a frequent cause of morbidity and mortality. Despite treatment, neurological sequelae rarely resolve completely.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER


A tumor of neurectodermal origin arising from ependymal cells that line the ventricles and central canal of the spinal cord, that can occur in both children and adults, and that is characterized by wide a range of clinical manifestations depending on the location of the tumor, such as intracranial hypertension for tumors originating in the posterior fossa, behavioural changes and pyramidal signs for supratentorial tumors, and dysesthesia for tumors of the spinal cord. They can be classified as myxopapillary ependymoma, subependymoma, ependymoma (low grade tumors) or anaplastic ependymoma (grade III tumors).


Ependymoma is the most frequent intramedullary tumor in adults (but accounts for only 10-12% of pediatric central nervous system tumors), and can be benign or anaplastic. Ependymoma arise from the ependymal cells of the cerebral ventricles, corticle rests and central canal of the spinal cord, and manifest with variable symptoms such headache, vomiting, seizures, focal neurological signs and loss of vision and can cause obstructive hydrocephalus in some cases.


EPHB4-related lymphatic-related hydrops fetalis

A rare primary lymphedema characterized by a highly variable lymphatic phenotype ranging from severe lymphatic-related hydrops fetalis, which may cause perinatal demise or fully resolve to become completely asymptomatic, to a mild presentation in older patients with persistent varicose veins, peripheral edema, and impaired lymph drainage in the lower limbs. Atrial septal defect has been described in association and may be the only anomaly in some patients.


A rare eyelid malposition disorder characterized by a horizontal fold consisting of redundant skin and underlying pretarsal orbicularis muscle overriding the eyelid margin and causing inward rotation of the eyelashes with potential irritation of the ocular surface. Patients may be asymptomatic or experience foreign body sensation, constant watering, itching, and redness of the eyes. Complications include repeated infections and corneal erosion. The condition is usually bilateral and more commonly affects the lower eyelids.


Epibulbar lipodermoid-preauricular appendage-polythelia syndrome

Epibulbar lipodermoid  preauricular appendages  polythelia is a branchial arch syndrome described in seven sibs of one Danish family and characterized by supernumerary nipples (polythelia), preauricular appendages and often binocular epibulbar lipodermoids or unilateral subconjunctival lipodermoids.


A Rickettsial disease characterized by malaise and vague symptoms before the onset of high fever, headache, severe myalgias and less commonly petechial rash on the trunk and limbs, nausea, vomiting, coughing and pneumonia. Most patients also have some central nervous system disturbances, such as meningeal irritation, confusion, drowsiness, seizures, coma, and hearing loss.


Epidermal nevus syndrome (ENS) is a rare congenitally acquired syndrome, characterized by the presence of epidermal nevi in association with various developmental abnormalities of the skin, eyes, nervous, skeletal, cardiovascular and urogenital systems.

Summary:
Clinical description
Epidermal nevi are developmental disorders characterized by hyperplasia of epidermal structures in a circumscribed area of the skin. Most are present at birth, occur sporadically and affect both sexes. All well-defined ENS are lethal gene syndromes, except nevus comedonicus syndrome. About 50% of the patients have neurological abnormalities that include mental retardation and epilepsy, spastic paresis, cerebral vascular malformations, cortical atrophy, lateral ventricle enlargement. About one third of the patients may have ocular abnormalities such as colobomas of the eyelid, iris and retina, conjuctival lipodermoids and choristomas, cortical blindness, micro-, macro- or anophthalmia, corneal opacities and cataracts. Skeletal abnormalities and many other non-cutaneous abnormalities may be present.
Management and treatment
No ideal medical therapy for the cutaneous lesions of ENS exists. The skin lesions may be amenable to surgery. The inflammatory linear verrucous epidermal nevus (ILVEN) sometimes responds to Erbium-YAG laser or vitamin D analogues. Salicylic acid, topical and systemic retinoids, emollients, shave dermabrasion and cryotherapy have been tried. The concomitant skeletal and ocular defects can be surgically repaired. Epilepsy should be treated appropriately.

                            Last update:
                            April 2004

                            - Expert reviewer(s):
                            Dr Michael KAKEPIS  - Pr Nikolaos STAVRIANEAS


A rare, chronic, incurable, sub epithelial autoimmune bullous disease characterized by the presence of tissue bound autoantibodies against type VII collagen within the basement membrane zone of the dermal-epidermal junction of stratified squamous epithelia. The patient's serum may also have anti-type VII collagen autoantibodies. The clinical presentation is varied, and may involve the skin, oral mucosa and the upper third of the esophagus. The classical presentation is reminiscent of hereditary dystrophic epidermolysis bullosa (EB) with skin fragility, blisters and erosions and skin scarring. Other non-classical clinical presentations include an inflammatory bullous pemphigoid-like eruption, a mucous membrane pemphigoid-like eruption, and an IgA bullous dermatosis-like disease.

Summary:
Epidemiology
The prevalence is unknown, but the incidence is estimated at 1/96,200 new cases per year.
Clinical description
Epidermolysis bullosa acquisita (EBA) is an acquired disease with onset typically in middle-aged adults but can rarely occur in childhood. The disease manifests in several possible ways. The classical presentation is reminiscent of hereditary dystrophic EB with skin fragility, blisters and erosions and skin scarring. There is marked skin fragility with skin blisters and erosions over trauma-prone areas of the skin that results in skin scarring. This form is relatively non-inflammatory. Mucous membrane lesions and nail dystrophy are common. A second possible clinical presentation is an inflammatory bullous eruption reminiscent of the autoimmune bullous disease, bullous pemphigoid. These bullae are on inflammatory plaques and may be flexural rather than over trauma-prone areas. A third possible clinical presentation is mucosal-centered with blisters, erosions and scarring of the conjunctival and oral mucosae, but may also involve the larynx and urethra. A fourth possible presentation is an IgA anti-type VII collagen mediated disease reminiscent of IgA bullous dermatosis and dermatitis herpetiformis. Diseases frequently associated with EBA include inflammatory bowel diseases (Crohn's disease and ulcerative colitis) and systemic lupus erythematosus.
Etiology
EBA is caused by IgG autoantibodies generated against type VII collagen in the skin located at the dermal-epidermal junction. Type VII collagen is the major component of anchoring fibril structures located at the dermal-epidermal junction just beneath the lamina densa. These structures hold the epidermal and dermal layers of skin together. The autoantibodies against type VII collagen perturbs the function of anchoring fibrils and the adherence between these two main layers of skin is compromised and prone to blistering.
Diagnostic methods
Diagnosis is made by histology and direct immunofluorescence (DIF) of skin biopsies, salt-split skin DIF, indirect immunofluorescence (IIF) of patient's serum, salt-split skin IIF, immunoblotting of patient serum against type VII collagen, detection of anti-type VII collagen autoantibodies by ELISA and/or immune-electron microscopy of a skin biopsy.
Differential diagnosis
The differential diagnosis should include other subepidermal, autoimmune bullous diseases.
Management and treatment
In EBA patients without inflammatory bowel disease, oral colchicine is the first-line treatment. Dapsone may be helpful in some patients. Oral cyclosporine A controls the disease, but its nephrotoxic side-effects limit its use. In the classical form of EBA, other types of immunosuppressive therapy (such as systemic steroids, azathioprine, mycophenylate mofetil,) are often ineffective, but may be useful in the inflammatory varieties of EBA. Although further trials are necessary, encouraging results have been obtained with other approaches such as intravenous immunoglobulin therapy, extracorporeal photochemotherapy and, more recently, rituximab therapy.
Prognosis
EBA is a chronic, incurable disease that leads to dystrophic scarring and milia. During the disease course, the inflammatory forms may evolve to resemble the classical form and vice-versa. Although not fatal, the progressive scarring and involvement of the oral and ocular mucosae can be functionally disabling.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr David WOODLEY


Epidermolysis bullosa simplex due to BP230 deficiency

A rare, inherited, epidermolysis bullosa simplex characterized by mild, predominantly acral, trauma-induced skin fragility, resulting in blisters. Blisters mostly affect the feet, including the dorsal side.


Epidermolysis bullosa simplex due to exophilin 5 deficiency

A rare, inherited, epidermolysis bullosa simplex characterized by mild, generalized trauma-induced scale crusts and intermittent blistering, sometimes combined with erosions, recovering with slight scarring and post-inflammatory hyperpigmentation. Clinical symptoms improve with age.


Epidermolysis bullosa simplex with anodontia/hypodontia

A rare epidermolysis bullosa simplex characterized by the association of the typical trauma-induced blisters with additional features including hearing impairment, alopecia, hypo- or anodontia, and nail dystrophy. Occurrence of vitiliginous skin areas unrelated to the sites of the blisters has also been described.


Epidermolysis bullosa simplex with circinate migratory erythema

A rare, inherited, epidermolysis bullosa simplex characterized by belt-like areas of erythema with multiple vesicles and small blisters at the advancing edge of erythema. The lesions occur on the limbs and trunk and heal with brown pigmentation but no scarring. Extracutaneous involvement is absent. Onset of the disease is usually at birth.


Epidermolysis bullosa simplex with mottled pigmentation

A rare, inherited, epidermolysis bullosa simplex characterized by neonatal or infantile onset of generalized blistering with mottled or reticulate brown pigmentation developing later. Blistering is often accompanied by mild nail dystrophy and focal palmoplantar keratoderma, and rarely by milia and mostly affects the limbs and trunk.