Epidermolysis bullosa simplex with muscular dystrophy

A form of epidermolysis bullosa simplex (EBS) characterized by generalized blistering associated with muscular dystrophy.

Summary:
Epidemiology
Prevalence of epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) is unknown, but more than 40 cases have been reported to date.
Clinical description
Onset of blistering is usually as early as birth, whereas muscular dystrophy manifests between infancy and adulthood, with a median age of onset of 9.5 years. Blisters are often hemorrhagic and heal with mild atrophic scarring and rare milia formation. Associated findings comprise markedly dystrophic nails, and focal keratoderma of the palms and soles. Extracutaneous involvement is usually present, including enamel hypoplasia with premature tooth decay, blistering in the oral cavity, pharynx and, rarely, larynx and trachea with inspiratory stridor and breathing difficulties requiring tracheotomy. Slowly progressive weakness of the head and limb muscles appears between the first year and the fourth decade of life and may confine the patient to a wheelchair. Additional neurological symptoms (ptosis, oculobulbar muscle weakness and fatigability) indicative of a myasthenic syndrome have been described in some patients. Mucosal involvement including urethral mucosae is common. Cardiomyopathy may be associated and, in rare cases, pyloric atresia.
Etiology
EBS-MD is caused by mutations in the PLEC gene (8q24) encoding plectin. Plectin deficiency can be demonstrated in skin and muscle by analysis with specific antibodies.
Diagnostic methods
Diagnosis is based on the mode of transmission, histopathological findings, and clinical presentation. Immunofluorescence mapping demonstrates lack of immunoreactivity for plectin and a plane of cleavage deep within the basal pole of the basal keratinocytes. Transmission electron microscopy shows intraepidermal split formation with lamina densa and lucida, and hemidesmosomes on the floor of the blister. Genetic testing demonstrates biallelic loss-of-function pathogenic variants in PLEC coding for plectin.
Differential diagnosis
Differential diagnosis is of other types of EBS and disorders with congenital skin blistering.
Antenatal diagnosis
Prenatal diagnosis should be offered to affected families in which the pathogenic variant/s have been previously diagnosed.
Genetic counseling
The disorder is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
There is no specific treatment available, treatment is symptomatic with wound management and general support.
Prognosis
From a prognostic point of view, immunohistochemical recognition of EBS-MD in infancy is particularly important, since in some patients the associated muscular dystrophy may not become apparent until later in childhood or adulthood. EBS-MD may have a fatal outcome.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Pr Cristina HAS | ERN-Skin*

                                * European Reference Network


Epidermolysis bullosa simplex with pyloric atresia

A rare, inherited, epidermolysis bullosa simplex characterized by generalized severe blistering with widespread congenital absence of skin and pyloric atresia that is usually fatal in infancy. Antenatally, pyloric atresia can manifest with polyhydramnios. If patients survive, they experience life-long skin fragility and nail dystrophy. Additional extracutaneous findings include failure to thrive, anemia, sepsis, intraoral blistering, enamel hypoplasia, urethral stenosis and urologic complications.


A group of hereditary epidermolysis bullosa (HEB) disorders characterized by skin fragility resulting in intraepidermal blisters and erosions that occur either spontaneously or after physical trauma.

Summary:
Epidemiology
Reported prevalence of epidermolysis bullosa simplex (EBS) ranges between 1/85,000-500,000 worldwide.
Clinical description
Onset is usually at or shortly after birth, although blistering in localized EBS may not develop until late childhood or early adulthood. Along with localized or generalized blistering and erosions, sometimes showing characteristic patterns (herpetiform grouping), cutaneous features may include nail shedding and dystrophy, and, rarely, milia formation. Scarring is mostly absent or minimal (mild atrophic wrinkling and dyspigmentation). Other findings may include congenital absence of the skin, and localized or diffuse keratoderma of the palms and soles. The commonest extracutaneous manifestation is blistering of the oral cavity. A variety of additional extracutaneous complications may occur and are age-dependent, with time of onset and cumulative risk of occurrence highly dependent on the EBS subtype (e.g. muscular dystrophy in PLEC-related EBS, cardiomyopathy in KLHL24-related EBS, nephropathy in CD151-related EBS). Blisters occur in the basal layer of the epidermis.
Etiology
EBS is a genetically heterogeneous group caused by pathogenic variants in specific genes depending on the subtype.
Diagnostic methods
Diagnosis is based on determination of the epidermal level within which blisters develop following minor skin traction. Recommended techniques are immunofluorescence antigen mapping (IFM) and transmission electron microscopy (TEM) performed on a skin biopsy sample. Subtypes are then defined on the basis of the mode of transmission, IFM and TEM, and clinical presentation. Cutaneous findings are not reliable diagnostic markers, in particular in neonates. Genetic testing should always be performed to determine the underlying genetic defect. Because of the genetic heterogeneity, analysis by next generation sequencing EB-gene panel is recommended.
Differential diagnosis
Diagnosis is usually straightforward with little need for extensive differential diagnosis. However, in the neonatal period, in utero herpes simplex infection may be considered, especially if there is no family history of blistering disease or if clinical findings are atypical for epidermolysis bullosa. The differential diagnosis in neonates and small children may include congenital aplasia cutis, neonatal pemphigus, neonatal herpes gestationis, staphylococcal scalded skin syndrome, as well as incontinentia pigmenti, epidermolytic ichthyosis, linear IgA dermatosis, bullous pemphigoid, and bullous impetigo.
Antenatal diagnosis
Prenatal diagnosis should be offered to families with severe EBS.
Genetic counseling
In autosomal dominant EBS subtypes, affected individuals have an affected parent from whom they inherited a pathogenic variant, but in a high percentage of cases, pathogenic variants occur de novo. Each child of an individual with EBS has a 50% risk of inheriting the pathogenic variant. In autosomal recessive EBS subtypes, the parents of an affected child are obligate heterozygotes for an EBS-related pathogenic variant. Each sib of an affected individual has a 25% risk of being affected, a 50% risk of being heterozygous , and a 25% risk of being unaffected and not heterozygous. Autosomal recessive EBS is common in countries with high rates of consanguineous marriages.
Management and treatment
Management is based on the avoidance of blistering by meticulous protective skin padding and appropriate life-style to avoid trauma, and prevention of secondary infection by careful wound care. Air-conditioning may help in preventing disease worsening in warm weather. Patients with EBS subtypes with the highest risk of specific extracutaneous complications need to be monitored closely and appropriate measures implemented to prevent the affected tissues from becoming severely injured. Topical inhibitors of IL-1 have proven some benefit in small clinical trials. No specific treatment is available for the extracutaneous manifestations of EBS.
Prognosis
Prognosis is highly dependent on the subtype. Most patients have a normal life expectancy but significant morbidity and even early death may occur in some subtypes.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Pr Cristina HAS | ERN-Skin*

                                * European Reference Network


A rare nevus characterized by single or multiple non-inflammatory verrucous skin lesions composed of keratinocytes, often present from birth, and distributed along the lines of Blaschko. Histologically, the lesions show features of epidermolytic hyperkeratosis with perinuclear vacuolization of keratinocytes of the upper epidermis with coarse keratohyaline granules. There is no extra-cutaneous involvement. Affected individuals are at risk of parenting a child with bullous ichthyosiform erythroderma.


A rare, non-syndromic, hereditary palmoplantar keratoderma characterized by diffuse, yellowish, thick hyperkeratosis of the palms and soles with a sharp demarcation at the volar border and an erythematous margin, and the epidermolytic pattern of changes on the skin biopsy, including perinuclear vacuolization, granular degeneration of keratinocytes in the spinous and granular layer, and tonofilament aggregates. Painful fissures and hyperhidrosis are frequently associated.


Epignathus is a very rare and life threatening intraoral teratoma, usually arising from the maxilla, mandible, palate or base of skull and invading the cranium, nasopharynx or oral cavity. Epignathus is more commonly seen in females, and presents with various manifestations (depending on the tumor size) including obstructive polyhydramnios in the prenatal period and dyspnea, cyanosis, cough, difficulty in sucking and swallowing, and rarely vomiting (due to swallowing difficulties) postnatally. When large, they can lead to airway obstruction, asphyxia and death in the neonatal period.


A rare, idiopathic, generalized form of reflex epilepsy characterized by childhood onset, unique seizure manifestations, striking light sensitivity, and possible occurrence of generalized tonic-clonic seizures.

Summary:
Epidemiology
Prevalence is unknown but Jeavons syndrome appears to represent around 7-8% of all idiophatic generalized epilepsies (IGEs). The syndrome is slightly more frequent in females than in males.
Clinical description
Onset occurs in childhood, with a peak at 6-8 years of age. Eyelid myoclonia is the principle clinical feature and may or may not be associated with brief (less than 6s) absences. Eye closure in the presence of uninterrupted light is the major triggering factor. Eyelid myoclonic status epilepticus is reported in up to one fifth of the patients and self-induction, although rare, has been described. Generalized tonic-clonic seizures occur in most patients, but the frequency of the seizures is low. Mental development is usually normal but mild to moderate intellectual deficit has been reported in some cases.
Etiology
The etiology is unknown but Jeavons syndrome appears to be genetically determined: the majority of reported patients have a family history of IGE and a few cases of affected twins have been reported.
Diagnostic methods
Eyelid myoclonia is a highly distinctive seizure type and is strongly suggestive of Jeavons syndrome. Video-electroencephalography (video-EEG) is the only procedure required for diagnosis and reveals eye closure-related generalized paroxysmal activity. Thus, in patients with eyelid myoclonia with or without absences, associated with photosensitivity and EEG discharges triggered by eye closure, the diagnosis of Jeavons syndrome is straightforward.
Differential diagnosis
However, other forms of idiopathic, cryptogenic, and symptomatic epilepsy featuring eyelid myoclonia or eye closure sensitivity (juvenile myoclonic epilepsy, juvenile absence epilepsy, and idiopathic photosensitive occipital lobe epilepsy; see these terms) may also be considered in the differential diagnosis. Misdiagnosis of eyelid myoclonia as a facial tic has also been reported.
Management and treatment
The seizures in Jeavons syndrome usually respond well to antiepileptic treatment, with antimyoclonic drugs (valproate, benzodiazepines, levetiracetam, and zonisamide) showing the highest level of efficacy and generally allowing good seizure control. However, polytherapy is often needed and some cases may be drug-resistant.
Prognosis
The overall prognosis is good, although Jeavons syndrome is usually a lifelong condition.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Pasquale STRIANO


A rare childhood-onset epilepsy characterized by sudden onset, short lasting absence associated with rhythmical myoclonia of head and shoulders.

Summary:
Epidemiology
Exact incidence of this rare epilepsy syndrome is unknown. Both sexes are affected, with a male predominance (70%).
Clinical description
Seizure onset is between 1 to 12 years of age (peak 7 years) and characterized by absences associated with rhythmical jerks of head/shoulders. Other seizure types (generalized tonic-clonic, atonic seizures and typical absences) occur in the majority of patients. At presentation, approximately half the children are developmentally and neurologically normal; a spectrum of learning disability is eventually seen in 70% of cases.
Etiology
Currently, the etiology is unidentified in the majority of cases. In 30% of cases, a genetic cause can be found with possible polygenic etiologies. SLC2A1 variants (1p34.2), causing GLUT1 deficiency, are one of the most common monogenic etiologies of myoclonic absences. There is one case report of a translocation resulting in a truncation in the SYNGAP1 gene causing epilepsy with myoclonic absences. A family history (usually of generalized seizures) is present in 20% of cases. Rarely, there is a family history of febrile seizures.
Diagnostic methods
Micro-array and dedicated epilepsy panels can show pathogenic mutations. On electroencephalogram (EEG), generalized spike-and-wave discharges and polyspike-and-wave discharges may occur. Background is otherwise normal. Ictal EEG: regular 3-Hz generalized spike-and-wave accompanies myoclonic absences. Electromyography recordings from the upper arm show a constant relationship between the bilateral myoclonic jerks and spike-and-waves. High resolution magnetic resonance imaging is required to exclude structural brain abnormality although neuroimaging is usually normal. However, mild non-specific diffuse atrophy is seen in some cases.
Differential diagnosis
Differential diagnosis includes Lennox-Gastaut syndrome (atypical absences may occur with rhythmic myoclonic jerking but EEG background is typically abnormal), myoclonic seizures due to structural brain abnormality, childhood absence epilepsy with a common EEG pattern but the description of the seizure is different, progressive myoclonic epilepsies, and myoclonic atonic epilepsy.
Antenatal diagnosis
Not relevant.
Genetic counseling
In case of a monogenic etiology or a chromosomal anomaly, genetic counseling can be provided.
Management and treatment
Seizures are often difficult to treat and may continue into adulthood. Anti-seizure drugs for absence seizures can be used: sodium valproate, ethosuximide, zonisamide, topiramate, or levetiracetam.
Prognosis
Seizures are usually difficult to control. Later on, in adolescence and adulthood, other (generalized) seizures may develop in almost half of patients. Sometimes an evolution towards juvenile myoclonic epilepsy is seen. Cognitive function seems to be preserved in children in whom myoclonic absences are controlled.

                            Last update:
                            December 2021

                            - Expert reviewer(s):
                            Pr Lieven LAGAE | EpiCARE* - Pr Rima NABBOUT | EpiCARE* - Pr Sylvie NGUYEN | EpiCARE*

                                * European Reference Network


A rare multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, seizures, microcephaly, delayed bone maturation, and skeletal abnormalities (such as scoliosis or pectus excavatum, among others). Dysmorphic features include coarse face, hirsutism, thick eyebrows, broad nasal septum, short philtrum, large mouth, and prominent ears. There have been no further descriptions in the literature since 1996.


A rare, genetic, epilepsy syndrome characterized by epilepsy, palpebral conjunctival telangiectasias, borderline to moderate intellectual disability, diminished serum IgA levels, shortened fifth fingers and dysmorphic facial features (including frontal hirsutism, synophrys, anteverted nostrils, prominent ears, long philtrum, irregular teeth implantation, micrognathia). No new cases have been described in the literature since 1978.


Epileptic encephalopathy with global cerebral demyelination is a rare mitochondrial substrate carrier disorder characterized by severe muscular hypotonia, seizures (with or without episodic apnea) beginning in the first year of life, and arrested psychomotor development (affecting mainly motor skills). Severe spasticity with hyperreflexia has also been reported. Global cerebral hypomyelination is a characteristic imaging feature of this disease.


Epiphyseal dysplasia-hearing loss-dysmorphism syndrome is a rare multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, intellectual disability, short stature, sensorineural hearing impairment, facial dysmorphism (incl. epicanthus, broad, depressed nasal bridge, broad, fleshy nasal tip, mildly anteverted nares, deep nasolabial folds, broad mouth with thin upper lip) and skeletal anomalies (incl. abnormally placed thumbs, brachydactyly, scoliosis, dysplastic carpal bones). Patients also present severe behavior disturbances (aggression, hyperactivity), as well as hypopigmented skin lesions and hypoplastic digital patterns. There have been no further descriptions in the literature since 1992.


Epiphyseal stippling-osteoclastic hyperplasia syndrome

A rare primary bone dysplasia characterized by extensive epiphyseal, tarsal, spinal, and sometimes metacarpal and/or phalangeal stippling, severe generalized osteopenia, vertebral clefting, platyspondyly, bowing and shortening of the long bones, and variable periosteal cloaking. Laboratory analysis of lysosomal enzymes reveals normal activity. Histopathology shows numerous giant, multinucleated osteoclasts lining Howship lacunae, consistent with increased bone resorption. The condition manifests prenatally and is presumably lethal in the perinatal period.


Epiphysiolysis of the hip is a rare osteonecrosis disorder characterized by unilateral or bilateral disruption of the capital femoral physis with varying degrees of posterior epiphysis translation and simultaneous anterior metaphysis displacement. Patients typically present in pre-adolescence/adolescence with pain of variable intensity in varying locations (hip, groin, thigh, knee).


A frequent form of Hereditary episodic ataxia characterized by brief episodes of ataxia, neuromyotonia, and continuous interictal myokymia.


A rare form of Hereditary episodic ataxia characterized by vestibular ataxia, vertigo, tinnitus, and interictal myokymia.


A rare form of Hereditary episodic ataxia characterized by late-onset episodic ataxia, recurrent attacks of vertigo, and diplopia.


Episodic ataxia type 5 (EA5) is an extremely rare form of Hereditary episodic ataxia (see this term) characterized by recurrent episodes of vertigo and ataxia lasting several hours.


Episodic ataxia type 6 (EA6) is an exceedingly rare form of Hereditary episodic ataxia (see this term) with varying degrees of ataxia and associated findings including slurred speech, headache, confusion and hemiplegia.


Episodic ataxia type 7 (EA7) is an exceedingly rare form of Hereditary episodic ataxia (see this term) characterized by ataxia with weakness, vertigo, and dysarthria without interictal findings.


Episodic ataxia with slurred speech is a rare hereditary ataxia characterized by recurrent episodes of ataxia with variable frequency and duration, associated with slurred speech, generalized muscle weakness and balance disturbance. Other symptoms may occur between episodes, including intention tremor, gait ataxia, mild dysarthria, myokymia, migraine and nystagmus.


A rare corneal dystrophy characterized by thickened, redundant sheets of basement membrane extending into the corneal epithelium, as well as intraepithelial lacunae filled with cellular debris, together presenting as a pattern of ''maps'', ''dots'', and ''fingerprints'' on slit-lamp examination. Patients may be asymptomatic or present with recurrent episodes of painful corneal erosions with variable visual impairment, typically beginning after the age of thirty. The condition is bilateral and may be inherited in an autosomal dominant manner.


Epithelial recurrent erosion dystrophy (ERED) is a rare form of superficial corneal dystrophy (see this term) characterized by recurrent episodes of epithelial erosions from childhood in the absence of associated diseases, with occasional impairment of vision.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is unknown, but numerous cases have been reported to date.
Clinical description
The erosions begin spontaneously or are precipitated by minor trauma, dust or smoke. The condition may become apparent by 6 months of age, but as a rule it only starts at 4 to 6 years of age. Most patients have attacks of redness, photophobia, epiphora, and ocular pain. Some experience a burning sensation and report sensitive eyes for years. Exposure to sunlight or draught, dust and smoke and lack of sleep can precipitate attacks. The intensity and frequency of the recurrent epithelial erosions tend to diminish over time, and usually cease by the end of the fourth decade. Vision is sometimes impaired.
Etiology
The etiology has not been completely elucidated. The gene related to ERED remains to be mapped to a specific chromosomal locus.
Diagnostic methods
On slit-lamp examination, the erosions may be accompanied by a subepithelial haze or blebs, and subepithelial opacities, apparently due to fibrosis, or keloid-like nodules may develop. When present, subepithelial opacities continue to enlarge. Specific morphologic abnormalities have not been identified in ERED.
Differential diagnosis
Suspected cases of ERED should be differentiated from other conditions that are accompanied by recurrent epithelial erosions, particularly when erosions are the initial presenting manifestation, such as epithelial basement membrane dystrophy and other superficial or stromal corneal dystrophies (see these terms).
Genetic counseling
An autosomal dominant pattern of inheritance has been reported.
Management and treatment
ERED can be treated medically with the aim of healing the epithelial defect and protecting the loosely adherent epithelium. A topical antibiotic, cycloplegic and pressure patch are valuable. A lubricating ointment is useful at night. Hypertonic saline and bandage contact lens therapy may also be beneficial.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare vascular tumor characterized by a solitary lesion in the superficial or deep soft tissue of the extremities, most often originating from a small vein as a fusiform intravascular mass also infiltrating surrounding tissues. It is composed of epithelioid endothelial cells arranged in short cords and nests in a myxohyaline stroma. Patients present with an often painful nodule which may be associated with edema or thrombophlebitis. In classic epithelioid hemangioendothelioma lacking atypical histological features metastatic rate and mortality are low.


A rare, soft tissue tumor characterized by high incidence of local recurrence, regional lymph node involvement and distant metastases. It commonly affects the soft tissue under the skin of a finger, hand, forearm, lower leg or foot, less often other areas of the body.


A rare gestational trophoblastic neoplasmcharacterized histologically by invasion of the myometrium and/or cervix uteri by regular epithelioid cells of chorion laeve type intermediate trophoblasts which clusters in a hyaline stroma. The disease generally occurs several years after pregnancy and indicative signs are irregular metrorrhagia and moderate increases in chorionic gonadotropin levels.


Epstein-Barr virus-associated gastric carcinoma

A rare form of gastric carcinoma characterized by a latent EBV infection in gastric carcinoma cells, diffuse-type histology, a proximal location (in the body and cardia of the stomach) and a relatively favorable prognosis.


Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly is a rare form of diffuse large B-cell lymphoma occurring most commonly in patients over the age of 50 (usually between 70-75 years of age), without overt immunodeficiency, and presenting with nodal and extranodal involvement (in sites such as the stomach, lung, skin and pancreas) and B symptoms (fever, night sweats, weight loss). The tumor is characterized by an aggressive course and a short survival rate.


Erdheim-Chester disease (ECD), a non-Langerhans form of histiocytosis, is a multisystemic disease characterized by various manifestations such as skeletal involvement with bone pain, exophthalmos, diabetes insipidus, renal impairment and central nervous system (CNS) and/or cardiovascular involvement.

Summary:
Epidemiology
Prevalence is unknown. More than 500 cases (<15 pediatric) have been reported since 1930.
Clinical description
ECD usually presents in adults aged 40-60 with a 3:1 male to female ratio. Clinical course varies from asymptomatic to multisystemic, life-threatening forms. The pathognomonic feature of ECD is osteosclerosis of the long bones manifesting as bone pain, mainly affecting the distal lowerlimbs (50% of cases). Pituitary gland infiltration leads to diabetes insipidus and rarely hyperprolactinemia and gonadotropin insufficiency. Constitutional symptoms include fever, weakness and weight loss. Infiltrations in other organs can lead to intracranial hypertension, exophthalmos, papilledema, adrenal insufficiency, xanthelasmas and papulonodular skin lesions. CNS involvement can cause cerebellar and pyramidal syndromes, headaches, seizures, cognitive impairment, cranial nerve palsies and sensory disturbances. A frequent cardiovascular involvement is the ''coated aorta''. Renal arteries can also be involved, leading to reno-vascular hypertension. Pericardial involvement may be complicated by a tamponade. Pseudo-tumoral infiltration of the right atrium is also seen. Dyspnea, due to lung infiltration, has been reported. Pseudo retroperitoneal fibrosis is sometimes complicated by bilateral hydronephrosis.
Etiology
Etiology is unknown but it is thought to be either a reactive or neoplastic disorder. Elevated levels of interferon-alpha (IFN-alpha), interleukin (IL)-7, IL-12, monocyte chemoattractant protein-1 and decreased levels of IL-4 found in ECD patients support an associated systemic immune Th-1 oriented perturbation. Recent findings of mutations in the BRAF proto-oncogene in > 50% of ECD cases clearly add further complexity to the pathophysiology of ECD.
Diagnostic methods
The hallmark histological finding is the xanthogranulomatous or xanthomatous infiltration of tissues with spumous histiocytes. Immunohistochemical staining of a biopsy sample is CD68-positive and CD1a-negative. Bone x-rays usually display bilateral and symmetric cortical osteosclerosis of the long bones, while technetium 99m bone scintigraphy shows almost constantly evidence of symmetric and abnormally strong labeling of the distal ends of the long bones of the lower limbs (and sometimes the upper limbs). Abdominal CT scan may show a ''hairy kidney'' appearance (in 50%) which can be biopsied.
Differential diagnosis
Differential diagnosis includes Langerhans' cell histiocytosis, Rosai-Dorfman disease, Takayasu arteritis, Wegener's granulomatosis, primary hypophysitis, chronic recurrent multifocal osteomyelitis (see these terms), malignancies, neurosarcoidosis, mycobacterial infections and metabolic disorders.
Management and treatment
First line treatment is the administration of standard or pegylated IFN-alpha for all forms of ECD with higher doses (9 million units, 3 times per week) required on a long-term basis for those with CNS and cardiac localizations (if well tolerated). Bisphosphonates may be given to alleviate bone pain. Cladribine can be given to those with orbital involvement that have been resistant to other forms of treatment. Anakinra can improve symptoms of mild forms of ECD in patients where IFN-alpha was ineffective. Recently, infliximab and vemurafenib have been used with some success, this latter drug seeming very promising for patients with a BRAFV600 mutation. PET scans are recommended for the assessment of disease activity.
Prognosis
ECD has a variable prognosis but is overall poorer in those with CNS involvement. Before IFN-alpha, the mean survival after diagnosis was 19.2 months. Nowadays, with IFN-alpha treatments, the mortality rate is only 26%, and 5-year survival is 68%.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Pr Julien HAROCHE


A rare deafness characterized by the association of bilateral sensorineural hearing loss and white hair with scattered black tufts, as well as skin areas of hyper- and hypopigmentation. Additional reported features include global developmental delay and moderate intellectual disability, growth retardation, microcephaly, hypotonia, mild dysmorphic facial features (deeply set eyes, broad nasal bridge, slight bowing of the upper lip), retinal depigmentation, anomalies of the fingers and toes, and white matter abnormalities on brain imaging.


Erosive pustular dermatosis of the scalp is a rare chronic inflammation of the scalp usually occurring in elderly women (>70 years old) and characterized by the development of painful pustules, shallow erosions, and crusting on atrophic skin that eventually result in cicatricial alopecia.


Erythema elevatum diutinum (EED) is a distinctive form of chronic cutaneous vasculitis, belonging to the group of the neutrophilic dermatoses.

Summary:
Epidemiology
It is very rare, although the exact prevalence is unknown.
Clinical description
The disease manifests as chronic, red to purple papules, located mainly on the dorsal aspect of the main joints (knees, elbows, hands and feet). Acute lesions may appear bullous, necrotic or hemorrhagic. Older lesions are yellowish or brown.
Etiology
EED is not an inherited disease and the exact aetiology remains unknown. EED is a reactive process, which may occur in isolation or in the context of an inflammatory or systemic disease, or in association with blood abnormalities (gammopathies) or infections (including HIV infection).
Diagnostic methods
Diagnosis is made on the basis of the clinical presentation and after histological analysis of skin biopsies by a dermatopathologist.
Differential diagnosis
EED should be distinguished from other types of papular or nodular dermatoses, as well as fibrous tumors and xanthomas.
Management and treatment
Management includes a complete clinical examination by a dermatologist, together with screening for infections, digestive disorders, and gammopathies (serum electrophoresis). Dapsone is the first line of treatment for EED. Treatment must be monitored clinically and by blood examination. In cases were dapsone is inefficient or poorly tolerated, other drugs may provide an effective treatment.
Prognosis
Although EED is a chronic condition, it is usually sensitive to treatment and the prognosis is good.

                            Last update:
                            September 2007

                            - Expert reviewer(s):
                            Dr Daniel WALLACH


A rare skin disease characterized most typically by targetoid papules with 3-rings of concentric color variation (dark center, surrounded by lighter pink ring and an outer red ring) symmetrically distributed on the extensor surfaces of the extremities, or more diffuse, accompanied by 2 or more mucosal involvements (erosions of the oral, genital, anal mucosa, conjunctivitis, pseudomembranes). The condition is commonly proceeded by prodromal symptoms of malaise, fever, and myalgias, and is usually self-limiting, resolving within a few weeks; although, there is a risk of recurrence. The disease is mostly triggered by infectious agents (herpes virus, mycoplasma pneumoniae) but a subset of patients have auto-antibodies targeting plakins. Rare cases of severe mucosal sequelae have been described.


Erythema palmare hereditarium is a rare, benign, congenital genetic skin disorder characterized by permanent and asymptomatic erythema of the palmar and, less frequently, the solar surfaces. In most cases, it presents with sharply demarcated redness of the thenar and hypothenar eminences, as well as the palmar aspect of the phalanges, with scattered telangiectasia spots that do not cause any discomfort (pain, itching or burning) to the patient.


A rare immune deficiency with skin involvement characterized by early infantile onset of a clinical tetrad comprising generalized severe seborrheic-like erythroderma, recurrent secondary bacterial or fungal infections (most commonly Staphylococcus aureus, Candida, and gram-negative bacteria), persistent, profuse malabsorptive diarrhea, and failure to thrive or marked wasting. Associated systemic symptoms include fever, anemia, and weight loss. Further critical complications are impaired thermoregulation and severe fluid loss due to extensive exfoliation.


A rare, genetic, epidermal disorder characterized by intermittent (remitting and recurring), annular, polycyclic, target-like (or 'en cocardes') plaques with concentric rings of scaling erythema occurring on the extremities, flexural areas, and trunk. Concurrent erythrokeratoderma variabilis-like scaly plaques are commonly found in other parts of the body.


Erythrokeratoderma variabilis progressiva (EKVP) is a type of erythrokeratoderma characterized by the association of hyperkeratosis and erythema in persistent, although sometimes variable, circumscribed lesions. Progressive symmetric erythrokeratoderma (PSEK) and erythrokeratoderma variabilis (EKV) are probably no longer two distinctive diseases but rather the two clinical manifestations of a same disease, now known as EKVP.

Summary:
Epidemiology
Erythrokeratoderma is a rare skin disease whose prevalence has recently been estimated at around 1/ 2, 000,000 people. Both sexes are affected equally.
Clinical description
The disease usually starts in the early months of life or later in infancy. Erythema at birth has been described. Patients present with well-demarcated, erythematous patches and hyperkeratotic plaques that are arranged symmetrically. The lesions favor the extensor surface of the upper and lower extremities, buttocks and face. The plaques tend to progress during childhood, with lesions stabilizing thereafter. Considerable clinical overlap exists between PSEK and EKV, the main distinguishing feature being the presence of migratory erythema in patients with EKV. The migratory aspects of the lesions may also change over time, according to lifetime periods. The palms and soles are usually normal but some patients may have palmoplantar keratoderma. Minimal pruritus may be noted. Improvement has rarely been reported.
Etiology
EKVP is caused by mutations in the connexin genes GJB4 (1p35-p34), coding for connexin-30.3 or GJB3 (1p34), coding for connexin-31. Connexins are proteins that form gap junctions that allow the transport and signaling between neighboring cells in the epidermis. Since other unrelated multiethnic patients were negative for connexin genes, new causal genes are yet to be discovered. De novo mutations in GJA1 (6q22.31) were also reporting as causing EKVP.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical features. The histopathological features are non-specific. Light microscopy, in the case of EKV, reveals orthokeratotic basket-weave hyperkeratosis, moderate to severe acanthosis with prominent granular layer, and papillomatosis; and in the case of PSEK, there is acanthosis of the epidermis with basket-weave and often patchy parakeratotic hyperkeratosis. The granular layer is prominent and sometimes shows intracellular vacuolization. Follicular plugging is not uncommon. Electron microscopy reveals, in the case of EKV, a reduced number of keratinosomes within the stratum granulosum and sometimes clumped tonofilaments; and in the case of PSEK, perinuclear vacuolization and lipid-like vacuoles or laminated inclusions in the stratum corneum, but these features are not diagnostic.
Differential diagnosis
Differential diagnosis includes other diseases with erythematous and hyperkeratotic lesions such as KID syndrome, keratoderma hereditarium mutilans with ichthyosis, pityriasis rubra pilaris and psoriasis.
Genetic counseling
The majority of cases follow an autosomal dominant mode of inheritance but approximately 40% occur sporadically. Autosomal recessive inheritance has also been described and should be considered when providing genetic counseling, especially in consanguineous families.
Management and treatment
Treatment is symptomatic. Emollients are often used but their efficacy is limited. Topical keratolytics or oral acitretin can reduce the thickness of the lesions. Isotretinoin has been used instead of acitretin in some cases.
Prognosis
EKVP is not a life threatening disease, but it may have an impact on the patient's quality of life and cause social handicap due to the skin's appearance. General health is unaffected.

                            Last update:
                            October 2015

                            - Expert reviewer(s):
                            Pr Juliette MAZEREEUW-HAUTIER  - Dr Emilie TOURNIER


Erythrokeratodermia-cardiomyopathy syndrome is a rare, genetic erythrokeratoderma disorder characterized by generalized cutaneous erythema with fine white scales and pruritus refractory to treatment, progressive dilated cardiomyopathy, palmoplantar keratoderma, sparse or absent eyebrows and eyelashes, sparse scalp hair, nail dystrophy, and dental enamel anomalies. Variable features include failure to thrive, developmental delay, and development of corneal opacities. Histology shows psoriasiform acanthosis, hypogranulosis, and compact orthohyperkeratosis.


Erythropoietic uroporphyria associated with myeloid malignancy

A rare porphyria characterized by a pre-existing myeloid disorder, skin fragility and blistering on the exposed areas, and hemorrhagic bullae typically on the back of the hands. Urine, plasma and fecal porphyrins are increased.


A rare congenital malformation characterized by an interruption in the continuity of the esophagus, with or without persistent communication with the trachea. The clinical presentation varies according to the anatomy, and can lead to the inability to swallow or, in the most severe cases, respiratory distress.

Summary:
Epidemiology
Esophageal atresia (EA) occurs in approximately 1/5000 live births worldwide. The birth prevalence in Europe is slightly higher at 1/4,000.
Clinical description
The Gross classification describes five different types. Type A (1%) without fistula, type B (2%) with a fistula to upper esophageal pouch, type C (86%) with a fistula to distal esophageal pouch, type D (1%) with fistula to upper and distal esophageal pouch, and type E (4%) with an isolated fistula without interruption in the esophageal continuity. A distance between the two pouches corresponding to the height of three vertebra or more is classified as long-gap esophageal atresia. The newborn infants with EA are unable to swallow saliva and are noted to have excessive salivation requiring repeated suctioning in children with Gross type A, B and C. In Gross type D the respiratory distress and coughing will be the prevailing symptom. In the Gross type E (isolated fistula without esophageal interruption) episodes of choking and cyanosis on feeding to subtle symptoms of wheezing and recurrent respiratory infections in neonatal or childhood may be seen.
Etiology
The etiology is largely unknown and is likely to be multifactorial. Genomic analysis have identified de novo variants in protein-coding regions in different gene loci.
Diagnostic methods
The likelihood of an atresia is increased by the presence of polyhydramnios. Inserting a nasogastric tube at birth allows the diagnosis to be confirmed or excluded and should be performed in all infants born to a mother with polyhydramnios, as well as in infants who produce excessive mucus soon after delivery. In EA, the tube will not progress beyond 10 cm from the mouth. Further confirmation is obtained by plain X-ray of the chest and abdomen. In patients with Gross type E the diagnosis may be confirmed by bronchoscopy or esophageal contrast studies.
Differential diagnosis
In 50% of cases, EA is associated with other anomalies, the majority involving one or more of the VACTERL association anomalies (vertebral, anorectal, cardiac, tracheoesophageal, renal and limb defects).
Antenatal diagnosis
The diagnosis may be suspected prenatally by a small or absent stomach bubble on ultrasound scan at around 18 weeks of gestation. The likelihood of an atresia is increased by the presence of polyhydramnios. Magnetic resonance imaging (MRI) has the highest diagnostic sensitivity and specificity.
Genetic counseling
The vast majority of cases are sporadic and the recurrence risk for siblings is 1%.
Management and treatment
Definitive management involves disconnection of the tracheooesophageal fistula, closure of the tracheal defect and primary anastomosis of the esophagus during the neonatal period. Delayed primary repair should be attempted when there is a 'long gap' between the ends of the esophagus. Various traction methods have been developed to increase the length of the pouches to facilitate a primary anastomosis. If it fails, organ replacement (stomach, jejunum or colon) may be necessary. In Gross type E, the fistula must be transected and closed. Open surgical or endoscopic (thoracoscopic) procedures may be used. Anastomotic stenosis and leakage are the most common postoperative complications and are usually handled endoscopically.
Prognosis
Survival is directly related to birth weight and to the presence of a major cardiac defect. Infants weighing over 1500 g and having no major cardiac problems have a near 100% survival rate, but the survival rate decreases in the presence of additional risk factors. Dysphagia and gastroesophageal reflux disease are common long-term sequelae.

                            Last update:
                            May 2022

                            - Expert reviewer(s):
                            Pr Niels QVIST | ERNICA*

                                * European Reference Network


A rare, congenital, non-syndromic esophageal malformation characterized by tubular or spherical cystic masses that have a double layer of surrounding smooth muscle lined with squamous or enteric epithelium, and are continuous or contiguous to the esophagus. The cyst is typically distally located and may or may not communicate with the esophageal lumen. Most become symptomatic presenting with a wide range of symptoms including dysphagia, non-productive cough, chest pain or failure to thrive. Others like palpitations due cardiac arrhythmia, thoracic back pain, and fever due to mediastinitis, have also been reported.


Essential fructosuria is a rare autosomal recessive disorder of fructose metabolism (see this term) caused by a deficiency of fructokinaseenzyme activity. It is characterized by elevated fructosemia and presence of fructosuria following ingestion of fructose and related sugars (sucrose, sorbitol). Essential fructosuria is clinically asymptomatic and harmless. Dietary restriction is not indicated.


A clinical variant of iridocorneal endothelial (ICE) syndrome, characterized by progressive iris atrophy and holes present on the surface of the iris, corneal edema, corectopia, uveal ectropion and anterior synechiae. Secondary glaucoma is also a common complication of the disease.


Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN, see this term) characterized by a sustained elevation of platelet number (> 450 x 109/L) with a tendency for thrombosis and hemorrhage.

Summary:
Epidemiology
Prevalence is estimated at 1/4,200 in the US and is reported at 1/3,333 in Sweden. Median age at diagnosis is 60-65 years, but the disease may occur at any age, with another peak in incidence in younger women. The female to male ratio is about 2:1.
Clinical description
The clinical picture is dominated by a predisposition to vascular occlusive events and hemorrhages. Some patients with ET are asymptomatic, while others may experience microcirculatory disturbances or vasomotor events: headaches, visual disturbances, lightheadedness, atypical chest pain, distal paresthesias, erythromelalgia, and other symptoms of transient neurological ischemia. Less frequently ET is associated with an increased risk of hemorrhage. Main risks for patients include thromboses (arterial and venous), which can induce severe neurological, cardiac or peripheral artery manifestations. Transformation to myelofibrosis (see this term) or acute leukemia is possible in a small proportion of patients on the long term.
Etiology
Somatic mutations in the JAK2 gene are the most common genetic alterations found in ET. Mutations in  LNK  gene down regulate JAK2 pathway and can be causative. Mutations in MPL gene has also been found in cases of ET with myeloproliferation. Recently mutations in  CALR  have been identified in many patients who were negative for JAK2  and  MPL. The detailed pathogenic mechanism is unknown. Although ET is usually an acquired (non hereditary) disease, a familial form, primary familial thrombocytosis (see this term) has also been observed.
Diagnostic methods
Diagnosis is based on a sustained high level of platelets (over 450x109/L) in the absence of reactive causes (like iron deficiency or inflammation, see below), evidence of a clonal marker (somatic mutation in JAK2, CALR , MPL  or other genes involved in MPN pathogenesis), bone marrow showing increased megakaryocytes with large and mature morphology with no increase in reticulin and an absence of MPN among relatives to rule out primary familial polycythemia (see this term).
Differential diagnosis
Differential diagnoses include the other myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis, chronic myeloid leukemia; see these terms), myeloid malignancies (myelodysplastic syndrome), causes of secondary thrombocytosis (inflammation, cancer, iron deficiency, asplenia) and primary familial thrombocytosis (see this term).
Management and treatment
Management is currently based on the risk of thrombosis, and may involve anti-aggregation therapy and/or platelet cytoreduction. Hydroxycarbamide and aspirin are effective in high risk patients. Anagrelide is approved in European Union as platelet lowering agent in patients resistant or intolerant to hydroxycarbamide. Conventional and pegylated recombinant interferon alpha (IFN) are effective in controlling platelet counts, although there is no evidence of efficacy in preventing thrombosis and could be preferred to conventional cytoreductive therapies in younger patients. Risk factors associated with arteriosclerotic disease (hypertension, diabetes, smoking etc) must be actively managed. Conventional cytoreductive therapies are contra-indicated in pregnancy.
Prognosis
Overall survival is similar to that of a healthy population matched by age and sex during the first decade after diagnosis and may differ thereafter (due to disease complications such as thrombosis, transformation to myelofibrosis, acute leukemia or myelodysplasia). When properly managed and carefully followed, life expectancy of ET patients can be similar to that of general population.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Jean-Jacques KILADJIAN


Esthesioneuroblastoma (ENB) is a rare malignant neoplasm of the sinonasal cavity, arising from the basal layers of olfactory neuroepithelial cells in the superior nasal vault, which usually occurs in the 5th to 6th decades of life and is characterized clinically by non-specific symptoms such as progressive ipsilateral nasal block, sinusitis, facial pain, intermittent headaches, hyposmia/dysosmia, rhinorrhea and epistaxis as well as proptosis, diplopia and excessive lacrimation due to orbital extension. With early treatment and in the absence of distant metastases, ENB appears to have a good prognosis (compared to other superior nasal malignancies), despite a high rate of cervical metastases.


Estrogen resistance syndrome is a rare, genetic endocrine disease characterized by estrogen-receptor insensitivity to estrogens and the presence of elevated estrogen and gonadotropin serum levels. Clinical manifestations include absent breast development and primary amenorrhea in association with multicystic ovaries and/or hypoplastic uterus in female patients, normal or abnormal gonadal development in male patients and markedly delayed bone maturation, persistence of open epiphyses, reduced bone mineral density, and variable tall stature in both sexes. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present.


A rare poisoning resulting in elevated anion gap metabolic acidosis, due to the production of glycolic acid, glyoxylic acid, and oxalic acid by alcohol dehydrogenase (ADH) in the liver when ethylene glycol is metabolized, characterized initially by euphoria, slurred speech, encephalopathy, coma and seizures, and followed by late manifestations such as tachycardia, arrhythmias, myocardial depression, hemodynamic imbalance and, finally, acute renal failure.


A rare, early-onset, progressive neurologic disease characterized by elevated excretion of ethylmalonic acid (EMA) with recurrent petechiae, orthostatic acrocyanosis and chronic diarrhea associated with neurodevelopmental delay, psychomotor regression and hypotonia with brain magnetic resonance imaging (MRI) abnormalities.

Summary:
Epidemiology
More than 70 cases have been described in the literature so far.
Clinical description
The disease manifests at birth or in the first few months of life with neurological, intestinal and vascular manifestations. Neurological symptoms include progressive encephalopathy, developmental delay, hypotonia, seizures and movement disorders. MRI abnormalities include symmetric patchy T2-weighted signals in the basal ganglia, periventricular white matter and dentate nuclei, brain stem, and cerebellar white matter. In some instances, cortical atrophy and diffuse leukoencephalopathy are present. Common gastrointestinal signs are chronic hemorrhagic diarrhea and failure to thrive. Vascular lesions include petechial purpura and orthostatic acrocyanosis. Spastic tetraplegia may be present. In addition to increased excretion of EMA, methylsuccinic acid, thiosulphate and C4-C6-acylglycines (isobutyryl-, isovaleryl-, 2-methylbutyryl-, hexanoylglycine) may also be found in small, but elevated, amounts in the urine. Blood levels of lactic acid and C4-C5-acylcarnitines may be elevated.
Etiology
EE is inherited in an autosomal recessive manner and is caused by variants of the ETHE1 gene (chromosome 19q13), encoding a mitochondrial sulfur dioxygenase (SDO) involved in the catabolic oxidation of hydrogen sulfide (H2S) to sulfate.
Diagnostic methods
Diagnosis is based on clinical examination, urinalysis, blood test, brain MRI and genetic analysis. As a large number of different disease-causing variants have been identified, DNA sequencing of all seven exons of the ETHE1 gene is necessary for the molecular diagnosis. The diagnosis of EE due to ETHE1 variants is clear if homozygosity (which should be confirmed by genotyping of the parents) or compound heterozygosity are present in the patient.
Differential diagnosis
In some cases, the urine and blood patterns identified in EE patients may resemble those seen in multiple acyl-CoA dehydrogenase deficiency (MADD or glutaric aciduria type 2) but in others they resemble those seen in short chain acyl-CoA dehydrogenase deficiency (SCADD), where the only abnormalities seen may be elevated EMA in urine with or without blood elevation of butyryl-carnitine. It seems, at least in severe cases, that the clinical picture of recurrent petechiae, orthostatic acrocyanosis and chronic diarrhea is specific for EE. However, more cases need to be identified before it can be determined whether milder cases of EE exist with clinical features like MADD or SCADD. In the absence of any detectable ETHE1 gene variant, molecular analysis should include sequencing of the SCAD gene (for variants which lead to SCADD) and, eventually, of the two-electron transfer flavoprotein (ETFA and ETFB) genes and the ETFDH gene (one of which may carry variants in patients with MADD).
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
At the moment, no treatment approved by the FDA or EMA exists. Treatment is primarily supportive including antispastic medications, muscle relaxants, and anti-seizure medication. L-carnitine, riboflavin and/or Q10 supplements, as well as other vitamin therapies, may improve energy metabolism and alleviate oxidative stress. N-acetylcysteine (NAC) in combination with metronidazole are the only drugs known to slow disease progression and improve the metabolic abnormalities of EE. NAC, a cell-permeable precursor of glutathione, is the physiologic acceptors of the sulfur atom of hydrogen sulfide (H2S), which has deficient clearance in persons with EE. Metronidazole is an anaerobic bactericide, which can reduce the sulfide-producing bacterial load in the large intestine. Liver transplantation has been proposed and used in few cases with the aim to restore the liver ability to scavenge the most of the circulating H2S from intestinal blood.
Prognosis
The prognosis is generally poor: although milder chronic cases are known, most patients die before the age of 10 years.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Dr Ivano DI MEO  - Dr Valeria TIRANTI | EURO-NMD*

                                * European Reference Network


Euryblepharon is a rare congenital eyelid anomaly of unknown etiology characterized by the bilateral horizontal enlargement of the palpebral fissure with vertically shortened eyelids, lateral canthus malpositioning and lateral ectropion. It may be isolated or associated with other ocular anomalies (e.g. strabismus or telecanthus; see this term) or systemic anomalies (e.g. blepharo-cheilo-odontic syndrome, see this term). In severe cases, it may result in lagophthalmos and exposure keratopathy, requiring surgical treatment.


A rare genetic endocrine disease characterized by increased affinity of a mutated transthyretin for T4. Total and free T4 may be normal or elevated, but affected individuals are clinically euthyroid.


A rare ophthalmic disorder characterized by clinical signs of Graves orbitopathy (i. e. unilateral or bilateral lid retraction, exophthalmos, soft tissue involvement, restrictive myopathy, and/or optic neuropathy) with normal thyroid function and without any signs of hyperthyroidism. Laboratory examination typically reveals low serum levels of thyroid-stimulating hormone receptor autoantibodies.


A rare chronic hematologic disorder characterized by the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA; a disorder in which auto-antibodies are directed against red blood cells causing anemia of varying degrees of severity) with immune thrombocytopenic purpura (ITP; a coagulation disorder in which auto-antibodies are directed against platelets causing hemorrhagic episodes) and occasionally autoimmune neutropenia, in the absence of a known underlying etiology.

Summary:
Epidemiology
The prevalence in Europe is estimated at 1/1,000,000 but there are no robust epidemiological data available.
Clinical description
The syndrome can manifest both in childhood or adulthood. Episodes of thrombocytopenia may precede, occur concurrently with (50% of cases), or follow episodes of AIHA. The severity of symptoms and the delay between episodes of AIHA and/or ITP is variable. In non simultaneous cases in adults, the delay between the episodes is on average of 4 years. ITP is often revealed by mucocutaneous hemorrhage with epistaxis, petechiae, purpura, and ecchymoses. In case of severe thrombocytopenia, hematuria, gastrointestinal and/or cerebromeningeal hemorrhage may be observed in rare cases. AIHA manifests as an unusual weakness, pallor, fatigue with tachycardia and exertional dyspnea, and also in some cases jaundice, dark urine and/or splenomegaly.
Etiology
Evans syndrome is an autoimmune disorder in which non-cross-reacting autoantibodies are targeted towards different antigenic determinants on red cells, platelets, sometimes neutrophils; however, the exact pathophysiologic mechanism is unknown. Because of the observation of a decrease in T-helper and an increase in T-suppressor lymphocyte population, it is suggested that the cytopenia may be related to T-cell abnormalities. Evans syndrome is frequently associated with other diseases, such as systemic lupus erythematosus, antiphospholipid syndrome, autoimmune lymphoproliferative syndrome, and common variable immunodeficiency (see these terms), which could point to a common cellular and humoral abnormality.
Diagnostic methods
Diagnosis is based on a complete blood count showing anemia (hemoglobin level <12g/dL) and thrombocytopenia (platelet count <100,000/microL), associated or not with neutropenia (neutrophil count <1500/microL). A raised lactate dehydrogenase (LDH) and/or direct bilirubin level, and a decreased haptoglobin level indicate hemolysis. A positive direct antiglobulin test (Coombs test) confirms the presence of antibodies targeting red blood cells (RBCs) antigens. The presence of autoantibodies targeting both platelets and neutrophils cans also be observed.
Differential diagnosis
Differential diagnosis mainly includes microangiopathies such as thrombotic thrombocytopenic purpura, and typical or atypical hemolytic uremic syndrome (see these terms).
Genetic counseling
Most of the cases are sporadic. Familial cases have exceptionally been observed, mainly in the setting of an underlying primary immunodeficiency.
Management and treatment
Immunosuppressive therapy combined or not with intravenous immunoglobulin for ITP constitutes the first-line treatment. Administration of corticosteroids (prednisone) is the mainstay of treatment but other drugs can be prescribed for refractory cases such as rituximab, cyclosporine, azathioprine, cyclophosphamide, and danazol. Splenectomy is performed as a third-line treatment; however long-term remission is less frequent and patients show a high risk of sepsis. In severe cases, hematopoietic stem cell transplantation may be required.
Prognosis
Evans syndrome is a chronic disease with alternating periods of remission and relapse of AIHA and/or ITP despite treatment, which can be associated with significant morbidity and mortality due to severe hemorrhage and infections in case of severe thrombocytopenia and neutropenia.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Pr Marc MICHEL


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by epiphyseal and vertebral dysplasia and abnormalities of the external ears (severe microtia or anotia) and the nose (hypoplastic nose with bifid tip, triangular nares, or anteverted nares). Additional variable findings include short stature, localized aplasia cutis, hypodontia, synophrys, agenesis of the corpus callosum, and cardiac, gastrointestinal, and/or urogenital malformations, among others. Psychomotor development may be delayed.


A rare form of congenital diazoxide-sensitive diffuse hyperinsulinism characterized by episodes of hypoglycemia induced by exercise due to an inappropriate lactate and pyruvate sensitivity in pancreatic beta-cells. Presentation is of recurring episodes of hypoglycemia associated with elevated insulin levels, within 30 minutes of a short period of anaerobic exercise. The degree of hypoglycemia associated with exercise is variable and is only partially responsive to diazoxide.


A rare disease with malignant hyperthermia characterized by exercise-induced life-threatening hyperthermia with a body temperature over 40°C and signs of encephalopathy ranging from confusion to convulsions or coma. Incidence increases with rising ambient temperature and relative humidity. Manifestations may include rhabdomyolysis (presenting with myalgia, muscle weakness, and myoglobinuria), tachycardia, and in severe cases multiorgan failure.


Exfoliative ichthyosis is an inherited, non-syndromic, congenital ichthyosis disorder characterized by the infancy-onset of palmoplantar peeling of the skin (aggravated by exposure to water and by occlusion) associated with dry, scaly skin over most of the body. Pruritus and hypohidrosis may also be associated. Well-demarcated areas of denuded skin appear in moist and traumatized regions and skin biopsies reveal reduced cell-cell adhesion in the basal and suprabasal layers, prominent intercellular edema, numerous aggregates of keratin filaments in basal keratinocytes, attenuated cornified cell envelopes, and epidermal barrier impairment.


Exostoses-anetodermia-brachydactyly type E syndrome

An association reported in a single kindred characterized by the variable presence of the following features: anetodermia (macular atrophy of the skin), multiple exostoses, and brachydactyly type E. There have been no further descriptions in the literature since 1985.


Exstrophy-Epispadias Complex (EEC) represents a spectrum of genitourinary malformations ranging in severity from epispadias (E) and classical bladder exstrophy (CEB) to exstrophy of the cloaca (EC) as the most severe form (see these terms). Depending on severity, the EEC may involve the urinary system, the musculoskeletal system, the pelvis, the pelvic floor, the abdominal wall, the genitalia and sometimes the spine and the anus.

Summary:
Epidemiology
The prevalence at birth for the whole spectrum is reported at 1/10,000, ranging from 1/30,000 for CEB to 1/200,000 for EC, with an overall greater proportion of affected males.
Clinical description
EEC is characterized by a visible defect of the lower abdominal wall, either with an evaginated bladder plate (CEB), or with an open urethral plate in males or a cleft in females (E). Urine drips from the ureteric orifices, visible on the bladder surface or per urethram. In the rare cases of CE, two exstrophied hemibladders, as well as omphalocele, an imperforate anus and spinal defects, can be seen after birth. Atypical forms of the EEC (duplicated exstrophy, covered exstrophy and pseudo-exstrophy) have also been described. EEC results from mechanical disruption or enlargement of the cloacal membrane, which prevents the invasion of mesodermal cells along the infraumbilical midline and thereby results in exstrophy. The timing of the rupture determines the severity of the malformation.
Etiology
The underlying cause remains unknown: rare cases of familial occurrence have been reported and both genetic and environmental factors are likely to play a role in the etiology of EEC.
Diagnostic methods
Diagnosis at birth is made on the basis of the clinical presentation but EEC may be detected prenatally during careful ultrasound examinations with the index finding of repeated non-visualization of a normally filled fetal bladder.
Genetic counseling
Extensive counseling should be provided to parents but due to a generally favorable outcome with appropriate surgical management, termination of the pregnancy should no longer be systematically recommended.
Management and treatment
Management is primarily surgical, with the main aims of obtaining secure abdominal wall closure, achieving urinary continence with preservation of renal function, and, finally, adequate cosmetic and functional genital reconstruction. Currently, several methods for bladder reconstruction with creation of an outlet resistance (either as a staged or a one-stage approach) during the newborn period are favored worldwide. Removal of the bladder template with complete urinary diversion to a rectal reservoir can be an alternative. After reconstructive surgery of the bladder, continence rates of about 80% are expected during childhood. Though spontaneous voiding is the main issue, additional surgery might be needed to optimize bladder storage and emptying function. In cases of definite reconstruction failure, urinary diversion should be undertaken. In puberty, genital and reproductive functions constitute increasingly important issues for both sexes. Psychosocial and psychosexual outcome reflect the importance of long-term care (from birth into adulthood) from a multidisciplinary team of experts for parents and children with EEC to facilitate an adequate quality of life.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Pr Anne-Karoline EBERT  - Dr Michaël LUDWIG  - Pr Heiko REUTTER  - Pr Wolfgang RÖSCH


Extensive peripapillary myelinated nerve fibers

A rare ophthalmic disorder characterized by visual abnormalities (such as myopia, strabismus, or amblyopia) due to the presence of myelinated retinal nerve fibers, which appear as whitish patches with feathery edges at the level of the retinal nerve fiber layer and may be continuous or discontinuous with the optic nerve head. The defect can be unilateral or bilateral.


Extensor tendons of finger anomalies is a rare, genetic, congenital limb malformation characterized by bilateral anomalous attachment of the extensor tendons of the four ulnar fingers. Attachment occurrs to the medial and lateral aspects of the middle phalanges leading to constant flexion in the midphalangeal joints and inability to extend the fingers. There have been no further descriptions in the literature since 1980.


External auditory canal aplasia/hypoplasia

A rare, otorhinolaryngological malformation characterized by failure in development of the external ear canal resulting in variable degree of malformations ranging from complete absence to mild stenosis and malformation of the middle ear. It is typically unilateral, it manifests with hearing loss on the affected side, and might be associated with microtia or hypoplastic pinna, an aberrant facial nerve course, and cholesteatoma.


External auditory canal atresia-vertical talus-hypertelorism syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the triad: congenital, bilateral, symmetrical, subtotal, external auditory canal atresia, bilateral vertical talus and increased interocular distance.


A rare vascular anomaly characterized by dilation of the internal or the common carotid artery greater than 150% of the diameter of the normal, healthy vessel. Lesions of the carotid bifurcation are typically fusiform, degenerative in nature, and may occur bilaterally, while saccular aneurysms are usually unilateral and mostly located in the middle segment of the internal carotid artery. Symptomatic patients may present with a palpable pulsating mass, local pain, cerebral ischemia, peripheral nerve dysfunction, stridor, or voice changes due to local compression.


A rare neoplastic disease characterized by a localized, unifocal, low-grade tumor composed of mature mast cells, without evidence of systemic mastocytosis or skin lesions. The tumor most commonly arises in the lung and shows a non-destructive growth pattern.


A rare, malignant germ cell tumor that occur in the midline of the body as a result of abnormal germ cell migration during embryogenesis. Clinical manifestations are variable and depend on the location and size of the tumor. Central nervous system tumor might present with headache, visual disturbances, endocrine abnormalities, and signs of increased intracranial pressure. A mediastinal tumor commonly presents with chest pain, dyspnea, cough and fever. Abdominal mass with or without pain, backache and weight loss are common clinical presentations in retroperitoneal tumor.


Extragonadal teratoma is an extremely rare, benign or malignant germ cell tumor characterized, clinically, by a teratoma presenting in an extragonadal location (e.g. retroperitoneum, mediastinum, craniofacial or sacrococcygeal region, intraosseous, solid organs) and, histologically, by displaying well-differentiated structures, as well as immature elements. Presenting symptoms are variable depending on size and location of tumor.


A rare skin tumor characterized by predominantly intraepithelial growth of an adenocarcinoma which may either arise primarily in the skin (primary extramammary Paget disease) or result from intraepithelial spread of a visceral carcinoma (secondary extramammary Paget disease). The lesion is typically located in the anogenital region, presenting as a scaly, oozing, pruritic or painful erythematous plaque often resembling eczema. It may exhibit an invasive component with a significant risk of lymph node metastasis.


Extraneural perineurioma is a rare tumor of cranial and spinal nerves arising from peripheral nerve sheet and composed exclusively or predominantly of cells showing perineurial differentiation. It presents as a well-circumscribed, rarely encapsulated mass, not associated with a recognizable nerve, most commonly arising in the dermis and subcutis of the extremities or trunk, or, rarely, in deep soft tissue or skin (e.g., in the stomach, kidney, pancreas, maxillary sinus, mandible, bronchial tree and the face). The clinical presentation depends on the localization.


Extranodal nasal NK/T cell lymphoma (NKTCL) is a rare, malignant neoplasm mainly affecting men in the fifth decade of life, that usually arises in the nose, paranasal sinuses, orbits or upper airway, and that can present with a nasal mass, nasal bleeding, nasal obstruction, palate perforation (i.e. midline perforation of the hard palate), and mid-facial and/or upper airway destructive lesions. In advanced disease stages, which are associated with a poor prognosis, NKTCL may disseminate to other organs. A few cases of NKTCL presenting primarily in the lymph nodes have also been described.


A rare, non-malformative gynecologic disease characterized by the presence of functional endometrial glands and stroma in extrapelvic locations, such as lungs, pleura, kidneys, bladder, abdominal wall, umbilicus, and cesarean section scar among others. Clinical manifestations are menstrually-related and depend on the location of the ectopic tissue, but in general include pain, mass/nodule, swelling and/or bleeding in the involved area.


Extraskeletal Ewing sarcoma is a rare, poorly differentiated, highly malignant, soft tissue tumor, derived from neuroectoderm, that is morphologically indistinguishable from skeletal Ewing sarcoma but is located in extraosseous locations, with the most common being: chest wall, paravertebral region, abdominopelvic area (with predilection for the retroperitoneal space), gluteal region and lower extremities. Clinical presentation is highly variable and depends on tumor localization. Local recurrence is common and metastatic disease most frequently involves the bones and lungs.


A rare soft tissue sarcoma characterized by a lesion in the deep soft tissues of the proximal extremities and limb girdles, composed of malignant chondroblast-like cells arranged in cords, clusters, or networks, and an abundant myxoid matrix. The tumor is typically encased by a pseudocapsule and divided into multiple nodules by fibrous septa. Patients present with a soft tissue mass which can be painful and may ulcerate the skin or restrict range of motion if located next to joints. Despite prolonged survival, local recurrence and metastasis are frequent.


Extrasystoles-short stature-hyperpigmentation-microcephaly syndrome is a rare, genetic, malformation syndrome with short stature characterized by microcephaly, borderline intellectual disability, hyperpigmentation of the skin, short stature, and ventricular extrasystoles. Cardiac syncope may also be associated. There have been no further descriptions in the literature since 1975.


Extraventricular neurocytoma (EVN), a variant of central neurocytoma (see this term), is a rare neuronal neoplasm, composed of round cells with neuronal differentiation, which is located outside of the ventricular system, usually within the spinal cord or cerebral hemispheres and that manifests with headache, nausea, vomiting, complex partial seizures or focal neurological deficits. In some cases it may exhibit atypical features consistent with aggressive clinical behavior.


Eyebrow duplication-syndactyly syndrome is characterised by partial duplication of the eyebrows and syndactyly of the fingers and toes. It has been described in three patients (a brother and sister and an isolated case). Skin hyperelasticity, hypertrichosis and long eyelashes, and abnormal periorbital wrinkling were also reported in some of the patients. Transmission is autosomal recessive.


F12-related hereditary angioedema with normal C1Inh

A rare hereditary angioedema characterized by normal serum levels and function of C1 inhibitor, normal C1 activity, and, clinically, recurrent subcutaneous edema, abdominal pain attacks, and episodes of potentially life-threatening upper airway obstruction. The disorder occurs almost exclusively in women, and episodes are often precipitated or worsened by high estrogen levels (such as during pregnancy or treatment with oral contraceptives).


A rare genetic, multisystemic lysosomal disease characterized by specific cutaneous (angiokeratoma), neurological (pain), renal (proteinuria, chronic kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular manifestations (transient ischemic attacks, strokes). The phenotypic expression depends on age of onset and, in females, the level of X-inactivation.

Summary:
Epidemiology
Worldwide, the average prevalence at birth is approximately 1/15,000, but Fabry disease is an underdiagnosed condition and the frequency may be higher.
Clinical description
The clinical picture covers a wide spectrum ranging from mild cases in some heterozygous females, to severe cases in classically affected hemizygous males with no residual alpha-galactosidase A activity. The classical form typically has onset in childhood and may have all the characteristic neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and cerebrovascular signs of the disease. Female patients may have very mild to severe symptoms. Pain is a common early symptom (chronic pain characterized by burning and tingling paresthesia and occasional episodic crises) but may wane in adulthood. Anhidrosis or hypohidrosis may occur causing heat and exercise intolerance. Other signs include angiokeratoma, corneal deposits, tinnitus, hearing loss, fatigue, cardiac and cerebrovascular abnormalities (left ventricular hypertrophy, arrhythmia), dyspnea, and chronic kidney disease. The later-onset form starts in adulthood and in such cases cardiac involvement is the prevailing feature.
Etiology
Fabry disease is a disorder of glycosphingolipid metabolism caused by the functional deficiency of the lysosomal alpha-galactosidase due to pathogenic variants in the GLA gene (Xq21.3-q22). Deficient activity results in accumulation of globotriaosylceramide (Gb3) and its deacylated form, lyso-Gb3, within lysosomes which is then believed to trigger a cascade of cellular events.
Diagnostic methods
The definitive laboratory diagnosis involves demonstration of marked enzyme deficiency in hemizygous males and identification of a pathogenic variant in GLA. Enzyme analysis may occasionally help to detect heterozygotes but is often inconclusive due to X-chromosomal inactivation, making molecular testing (GLA genotyping) of females mandatory.
Differential diagnosis
In childhood, other possible causes of pain such as rheumatoid arthritis and "growing pains" must be ruled out. In adulthood, multiple sclerosis and irritable bowel syndrome (IBS) are occasionally considered.
Antenatal diagnosis
Prenatal diagnosis, available by determination of DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses (after non-invasive prenatal testing for fetal sex determination). Pre-implantation genetic diagnosis is possible.
Genetic counseling
The pattern of inheritance is X-linked. The existence of atypical, later-onset, variants and the availability of specific therapies for Fabry disease should be considered when delivering genetic counseling.
Management and treatment
A disease-specific therapeutic option (enzyme replacement therapy using in vitro engineered alpha-galactosidase A) has been available since 2001 and meta-analyses of its long-term efficacy suggest promising outcomes. Enzyme enhancement with a pharmacological chaperone is approved in patients with amenable GLA variants following recent clinical trials. Plant-derived enzyme replacement therapy, substrate reduction therapy (SRT) and gene therapy using adeno-associated viral vectors are currently under investigation in clinical trials. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors or angiotensin receptors blockers), antiarrhythmic agents, pace-maker or implantable cardioverter defibrillator, dialysis, and kidney transplant.
Prognosis
With age, progressive damage to tissues develops, leading to organ failure. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit the life-expectancy of untreated males and females versus the general population.

                            Last update:
                            March 2022

                            - Expert reviewer(s):
                            Pr Dominique GERMAIN


Facial arteriovenous malformation is a rare vascular anomaly characterized by abnormal communication between arteries and veins, bypassing the capillary bed, located in the facial area. Lesions may be asymptomatic or may manifest with pain, ulceration, pulsation, tinnitus, minor bleeding or potentially life-threatening hemorrhage, blurred vision, impaired hearing, headache, paresthesia, enlargement of facial bones with intraosseous lesions, intraosseous hemangiomas, and speech, breathing and swallowing difficulties, as well as neuropathy.


Facial dermoid cyst is a rare, benign cutaneous neoplasm containing keratinized epithelium and dermal derivatives, such as hair follicles, sweat and sebaceous glands, smooth muscle or fibroadipose tissue, which usually manifests as a firm, nonpulsatile mass, often with a sinus opening or a hair-bearing punctum, most commonly located in the periorbital and nasal area.


A rare localized variant of Guillain-Barré syndrome characterized by rapidly progressive bilateral facial nerve palsy, distal paresthesias, and minimal or no motor weakness. Deep tendon reflexes are usually diminished or absent but can be present or even exaggerated in rare cases. CSF analysis may reveal albuminocytologic dissociation. Nerve conduction velocity studies often show demyelinating type of neuropathy, although axonal polyneuropathy has been also described.


Facial dysmorphism-anorexia-cachexia-eye and skin anomalies syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphism (mild eyelid ptosis, xanthelasma, anterverted nostrils, bifid nasal tip, short palate), severe muscle wasting and cachexia, retinitis pigmentosa, numerous lentigines and café-au-lait spots, as well as mild, soft tissue syndactyly. Additional features include nasal speech, chest asymmetry, pectus excavatum, genu varum, pes planus, and thyroid papillary carcinoma and diffuse enlargement. There have been no further description in the literature since 1984.


Facial dysmorphism-developmental delay-behavioral abnormalities syndrome due to 10p11.21p12.31 microdeletion

A rare, genetic syndromic intellectual disability characterized by developmental delay, hypotonia, speech delay, mild to moderate intellectual disability, abnormal behavior (autistic, aggressive, hyperactive) and dysmorphic facial features, including synophrys or thick eyebrows, deep set eyes, bulbous nasal tip and full cheeks. Congenital heart and brain anomalies, visual and hearing impairment are also common.


Facial dysmorphism-hypertrichosis-epilepsy-intellectual disability/developmental delay-gingival overgrowth syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by variable intellectual disability and/or developmental delay, epilepsy, generalized hypertrichosis, severe gingival overgrowth and visual impairment in some patients. Common craniofacial features include bitemporal narrowing, bushy and straight eyebrows, long eyelashes, low-set ears, deep/short philtrum, everted upper lip, prominent upper and lower vermilion, wide mouth, micrognathia, and retrognathia.


Facial dysmorphism-immunodeficiency-livedo-short stature syndrome is a rare genetic disease characterized by facial dysmorphism with malar hypoplasia and high forehead, immunodeficiency resulting in recurrent infections, impaired growth (with normal growth hormone production and response) resulting in short stature, and livedo affecting face and extremities. Immunological analyses show low memory B-cell and naïve T cell counts, decreased T cell proliferation, and reduced IgM, IgG2 and IgG4 titers. Patients do not exhibit increased susceptibility to cancer.


Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome is a syndromic developmental defect of the eye characterized by dislocated or subluxated crystalline lenses, anterior segment abnormalities, and distinctive facial features such as flat cheeks and a prominent, beaked nose. Affected individuals may develop nontraumatic conjunctival cysts, also referred to as filtering blebs.


Facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by severe intellectual deficit, Dandy-Walker malformation, macrocephaly, severe myopia, brachytelephalangy with short and broad fingernails, and dysmorphic facial features (such as thick eyebrows, synophrys, epicanthal folds, low-set ears, short philtrum, and high-arched palate). Additional reported manifestations include seizures and skeletal and genital anomalies, among others. There have been no further descriptions in the literature since 1989.


Facial dysmorphism-ocular anomalies-osteopenia-intellectual disability-dental anomalies syndrome

A rare, genetic developmental defect during embryogenesis disorder characterized by craniofacial dysmorphism (incl. brachycephaly, prominent forehead, sparse lateral eyebrows, severe hypertelorism, upslanting palpebral fissures, epicanthal folds, protruding ears, broad nasal bridge, pointed nasal tip, flat philtrum, anteverted nostrils, large mouth, thin upper vermilion border, highly arched palate and mild micrognathia) associated with osteopenia leading to repeated long bone fractures, severe myopia, mild to moderate sensorineural or mixed hearing loss, enamel hypoplasia, sloping shoulders and mild intellectual disability.


Facial dysmorphism-shawl scrotum-joint laxity syndrome is characterised by facial dysmorphism (hypertelorism, telecanthus, downslanting palpebral fissures, ptosis, malar hypoplasia, broad nasal bridge, thin upper lip, smooth philtrum, and low-set prominent ears) and associated with joint anomalies (genu valgum or cubitus valgus, hyper-extensible joints, etc.). It has been described in two patients (a mother and her son). The boy also had hypoplastic shawl scrotum and cryptorchidism, and the mother had mild intellectual deficit.


Facial onset sensory and motor neuronopathy is characterised initially by paraesthesia and numbness in the region of the trigeminal nerve distribution, which later progresses to involve the scalp, neck, upper trunk and upper limbs. Onset of motor manifestations occurs later with cramps, fasciculations, dysphagia, dysarthria, muscle weakness and atrophy. This syndrome has been described in four males and appears to be a slowly progressive neurodegenerative disease.


A very rare syndrome characterized by intellectual deficit, horseshoe kidney, and congenital heart defects.

Summary:
Epidemiology
Four cases have been reported in the literature in two unrelated families.
Clinical description
Dysmorphic features include plagiocephaly, malar hypoplasia, broad nasal bridge, poorly developed philtrum and nasal alae, cleft palate and hypodontia. Congenital heart defects were endocardial fibroelastosis in one family and prolapse of the tricuspid valve in the other.
Genetic counseling
The condition is probably hereditary, and transmitted as an autosomal recessive trait.

                            Last update:
                            February 2010


A rare neuromuscular disease characterized by progressive muscle weakness with focal involvement of the facial, shoulder and limb muscles.

Summary:
Epidemiology
Facioscapulohumeral muscular dystrophy (FSHD) is a rare familial disease with an estimated prevalence from 1/8,000 to 1/20,000. It is the third most common form of hereditary myopathy.
Clinical description
Onset occurs at any age. Disease progression is usually slow but some patients display periods of stability followed by periods of rapid deterioration. Early onset of FSHD is associated with more widespread muscle weakness. The initial manifestation is frequently facial weakness (difficulties whistling, smiling and closing the eyes) but the main complaint could be shoulder involvement (difficulties rising the arms, scapular winging and sloping shoulders). The disease progresses to include forearm weakness and wrist extension weakness. Abdominal and distal lower limb muscle, principally tibialis anterior, may also be affected early in the disease, while proximal lower leg muscles are affected later. Asymmetry of muscle involvement is frequently described. Significant clinical variability exists and atypical presentations have been reported. Sensory, cardiac and neurological signs may be present in rare cases.
Etiology
Two genetic subtypes of FSHD have been identified: the classical form (FSHD1) which is associated with a pathogenic contraction of the D4Z4 repeat on a 4qA chromosome 4 and FSHD2 which is associated with mutations in SMCHD1 (18p11.32). In FSHD1, repeat contractions are associated with local hypomethylation and change in chromatin relaxation on chromosome 4 that increases the likelihood of toxic DUX4 (4q35.2) gene expression in skeletal muscle. In FSHD2, patients harboring mutation in SMCHD1 have a profound hypomethylation of chromosomes 4 and 10, allowing chromosome 4 to express the toxic DUX4 transcript.
Diagnostic methods
Diagnosis of FSHD1 is achieved by identification of a D4Z4 pathogenic contraction (D4Z4 repeat number less than 10) on the permissive 4qA allele of chromosome 4. In this situation, the residual number of D4Z4 units inversely correlates with severity. SMCHD1 mutations should be screened when FSHD phenotype is not associated with the D4Z4 pathogenic contraction and in FSHD1 families diagnosed with between 7 to 10 D4Z4 repeats and a severe phenotype.
Differential diagnosis
Atypical cases should be accurately studied to exclude a concomitant pathology. Differential diagnosis mainly includes limb-girdle muscular dystrophy but also neuromuscular diseases presenting with scapular winging such as glycogen storage disease due to acid maltase deficiency, late-onset endocrine myopathy, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, proximal neuropathies or neuronopathies.
Genetic counseling
Transmission is autosomal dominant in both FSHD1 and FSHD2. Penetrance in FSHD1 is incomplete and around 30% of carriers do not manifest the disease. Mosaicism may explain the occurrence of severe forms in children born to parents showing no signs of the disease. In some families, digenic inheritance of both FSHD1 and FSHD2 genetic conditions can modify the severity. Genetic counseling and prenatal diagnosis are therefore challenging.
Management and treatment
Treatment is symptomatic, aiming towards prevention of joint stiffness and pain by passive mobilization and administration of antalgics. In severe cases, ventilator support may be required. Surgical treatment involves fixation of the scapula and may lead to an improvement in the range of motion of the arms.
Prognosis
Prognosis depends upon the extent of functional capacity loss. Life expectancy is not reduced unless respiratory functions are affected; however, this is a rare occurrence.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Sabrina SACCONI | EURO-NMD*

                                * European Reference Network


FADD-related immunodeficiency is a rare genetic immunological disease reported in a single consanguineous Pakistani family with several affected members presenting with severe bacterial and viral infections, recurrent hepatopathy (portal inflammation, fibrosis), and recurrent, stereotypical febrile episodes, sometimes lasting several days, with encephalopathy and difficult-to-control seizures. Variable cardiac malformations were also reported. Although there were autoimmune lymphoproliferative syndrome (ALPS)-like biological features, clinical ALPS was not present. A homozygous missense mutation in the FADD gene (11q13.3) was found in the family and the disease is thought to follow an autosomal recessive pattern of inheritance.


Fallot complex-intellectual disability-growth delay syndrome

Fallot complex - intellectual deficit - growth delay is a rare disorder characterized by tetralogy of Fallot, minor facial anomalies, and severe intellectual deficiency and growth delay.

Summary:
Epidemiology
To date, five patients have been reported in two families.
Clinical description
Dysmorphic features include large, protruding, abnormally modeled ears and broad nasal root. Microcephaly and syndactyly of 2nd and 3rd toes have also been recorded. All five patients have severe intellectual deficiency.
Genetic counseling
The condition is probably hereditary, and is transmitted as an autosomal recessive trait.

                            Last update:
                            April 2010


Familial acute necrotizing encephalopathy or ADANE is a potentially fatal neurological disease characterised by neuropathological lesions principally involving the brainstem, thalamus and putamen.

Summary:
Epidemiology
It has been described in 11 members of one family.
Clinical description
Onset occurs during early childhood, typically a few days after a febrile illness. Manifestations include vomiting, seizures, spasticity, language regression, rigidity and abnormal posturing of the head. Residual neurologic impairment (muscle weakness, speech disturbance, intellectual deficit and mood disorders) persists in some patients. The disease is chronic in one out of two cases.
Genetic counseling
The mode of transmission appears to be autosomal dominant with incomplete penetrance.

                            Last update:
                            September 2007


Familial adenomatous polyposis (FAP) is characterized by the development of hundreds to thousands of adenomas in the rectum and colon during the second decade of life.

Summary:
Epidemiology
FAP has a birth incidence of about 1/8,300, manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the EU, prevalence is estimated at 1/11,300-1/37,600.
Clinical description
Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present some extraintestinal manifestations such as osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP; see this term), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner syndrome, whereas the association of FAP and medulloblastoma is referred to as the Turcot syndrome (see these terms).
Etiology
Classic FAP results from a germline mutation in the APC gene (5q21-q22). Most patients (about 70%) have a family history of colorectal polyps and cancer. In one patient subset, a MUTYH mutation (1p34.1) causes a recessively inherited polyposis condition, MUTYH-related familial adenomatous polyposis (see this term), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract.
Diagnostic methods
Diagnosis is based on family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing.
Differential diagnosis
Differential diagnoses include other disorders causing multiple polyps (Peutz-Jeghers syndrome, familial juvenile polyposis or hyperplastic polyposis, hereditary mixed polyposis syndrome, and Lynch syndrome; see these terms).
Antenatal diagnosis
Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing, is possible. Referral to a geneticist or genetic counselor is mandatory.
Genetic counseling
Classic FAP is inherited in an autosomal dominant manner. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed.
Management and treatment
Cancer prevention and maintaining a good quality of life are the main goals of management, and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy, and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy. They need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery. Celecoxib has received marketing authorization by the US Food and Drug Administration (FDA) and the European Medicines Agency to be used as an adjunctive therapy in patients with FAP.
Prognosis
Patients with FAP carry a 100% risk of CRC. However, this risk is reduced significantly when patients enter a screening-treatment program.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Dr Dani BERCOVICH  - Dr Elizabeth HALF  - Pr Paul ROZEN


Familial adrenal hypoplasia with absent pituitary luteinizing hormone

A rare endocrine disease characterized by a miniature adult type of congenital adrenal hypoplasia (residual adrenal cortex is composed of a small amount of permanent adult cortex with normal structural organization), selective absence of pituitary luteinizing hormone in otherwise normal brain, and neonatal demise. Patients present with hypogonadotropic hypogonadism, hypoglycemia, seizures, encephalopathy and diabetes insipidus. There have been no further descriptions in the literature since 1988.


A rare genetic neurological disorder characterized by very early sleep onset and offset. Plasma melatonin levels and body core temperature rhythms are also phase-advanced. The sleep-wake cycle is generally shortened. Additional reported features include migraine with or without aura and seasonal affective disorder.


Familial afibrinogenemia is a coagulation disorder characterized by bleeding symptoms due to a complete absence of circulating fibrinogen.

Summary:
Epidemiology
Prevalence of afibrinogenemia is estimated at 1/1,000,000.
Clinical description
Common manifestations of afibrinogenemia include umbilical cord bleeding, epistaxis, hemarthrosis, gastrointestinal bleeding, menorrhagia, traumatic and surgical bleeding and, rarely, intracranial hemorrhage. Recurrent spontaneous abortions may occur.
Etiology
The deficiency is due to various mutations in the FGA, FGB, or FGG genes.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            October 2009


Familial Alzheimer-like prion disease is an exceedingly rare form of prion disease (see this term) characterized by the neuropathological features of Alzheimer disease including memory impairment and depression, related to abnormal prion protein (PrP) caused by a gene mutation in PRNP. Patients present with a prolonged, atypical course (absence of myoclonus or ataxia) unlike other forms of prion disease with severe neurofibrillary tangle pathology and high levels of cerebral amyloidosis.