Multiple system atrophy, parkinsonian type (MSA-p) is a form of multiple system atrophy (MSA; see this term) with predominant parkinsonian features (bradykinesia, rigidity, irregular jerky postural tremor, and postural instability).

Summary:
Epidemiology
MSA-p is observed predominantly in patients from the Western Hemisphere. 68% of MSA cases are MSA-p. Genders are equally distributed.
Clinical description
The mean age of disease onset is 55 to 60 years. MSA-p is characterized by parkinsonism (bradykinesia, rigidity, irregular jerky tremor and postural instability) and autonomic failure in the form of bladder dysfunction (including early urinary incontinence) and/or orthostatic hypotension. The presence of autonomic failure is mandatory for the diagnosis of MSA-p. Additional features include dysphonia, dysphagia and other autonomic features (respiratory disturbances such as sleep apnea, stridor and inspiratory sighs, as well as constipation and sexual dysfunction). In the course of the disease, all patients with MSA-p display at least some cerebellar signs (gait and limb ataxia, oculomotor dysfunction, dysarthria). Abnormal postures (camptocormia (see this term), Pisa syndrome and disproportionate antecollis) are frequently observed. Neuropsychiatric features and sleep disturbances may be observed and include: rapid eye movement (REM) sleep behavior disorder (RBD), periodic limb movements in sleep (PLMS), depression, apathy and anxiety. In some cases, pyramidal signs (generalized hyper-reflexia with a positive Babinski sign) may also be observed. Patients with MSA-p may develop early-onset levodopa-induced orofacial and craniocervical dystonia.
Etiology
The exact etiology of MSA-p is still unknown but the presence of cytoplasmic aggregates of α-synuclein, primarily in oligodendroglia, in combination with predominant neurodegeneration of the striatonigral pathway are the pathological hallmark features of MSA-p. Mutations in the COQ2 gene (4q21.23) (encoding an enzyme involved in the biosynthesis of coenzyme Q10) have been shown in multiplex families with MSA, while some variants were associated with an increased risk for sporadic MSA.
Genetic counseling
MSA-p occurs sporadically. However, some familial cases of MSA have been described.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Pr Wassilios MEISSNER


Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure (cardiovascular and/or urinary), parkinsonism, cerebellar impairment and corticospinal signs with a median survival of 6-9 years.

Summary:
Epidemiology
Prevalence ranges from 1/50,000-1/20,000. MSA-parkinsonian type (MSA-p) predominates in the Western Hemisphere and MSA-cerebellar type (MSA-c) predominates in the Eastern Hemisphere. Genders are equally distributed.
Clinical description
MSA is an adult-onset disorder (>30 years, mean age 55-60 years). Clinical manifestations include autonomic failure (orthostatic hypotension, syncope, respiratory disturbances (sleep apnea, stridor and inspiratory sighs), constipation, bladder dysfunction (early urinary incontinence), erectile dysfunction in males and Raynaud syndrome). In some cases, pyramidal signs (generalized hyperreflexia and positive Babinski sign) are observed. MSA-p, a form of MSA with predominant parkinsonian features, comprises bradykinesia, rigidity, irregular jerky postural tremor and abnormal postures (camptocormia, Pisa syndrome and disproportionate antecollis). Patients with MSA-p may develop levodopa-induced orofacial and craniocervical dystonia. Classic pill-rolling rest tremor is uncommon. MSA-c is a form of MSA with predominant cerebellar features such as gait and limb ataxia, oculomotor dysfunction and dysarthria. The predominant motor feature can change with time and patients with cerebellar ataxia can develop increasingly severe parkinsonian features which dominate the clinical presentation. Neuropsychiatric features, oculomotor dysfunction and sleep disturbances are also observed in MSA and include apathy, anxiety, depression, rapid eye movement sleep behavior disorder and periodic limb movements in sleep.
Etiology
Etiology of MSA is unknown but presence of cytoplasmic aggregates of α-synuclein, primarily in oligodendroglia, in combination with neurodegeneration in striatonigral and olivopontocerebellar structures are the pathological hallmark features. Mutations in COQ2 (4q21.23) (encoding an enzyme involved in biosynthesis of coenzyme Q10) have been shown in multiplex families with MSA, while some variants were associated with an increased risk for sporadic MSA.
Diagnostic methods
Diagnosis of ''probable'' MSA requires presence of parkinsonism with poor levodopa response or cerebellar signs together with severe autonomic failure (otherwise unexplained urinary incontinence or an orthostatic decrease of blood pressure within 3 min of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic). MRI findings include atrophy of putamen and middle cerebellar peduncles, as well as putaminal and cerebellar hypometabolism on [18F]-fluorodeoxyglucose positron emission tomography. ''Definite'' MSA requires post-mortem demonstration of α-synuclein positive glial cytoplasmic inclusions with neurodegeneration of striatonigral and olivopontocerebellar structures.
Differential diagnosis
Differential diagnosis of MSA-p includes Parkinson's disease and other atypical parkinsonian disorders (progressive supranuclear palsy, corticobasal syndrome). Differential diagnosis of MSA-c includes dominantly inherited spinocerebellar ataxias (SCAs 1, 2, 3, 6, and 7), fragile X-associated tremor/ataxia syndrome (FXTAS) and mitochondriopathies (POLG1 gene mutations).
Genetic counseling
MSA occurs sporadically. However, some familial cases have been described.
Management and treatment
Therapy mainly targets parkinsonism and autonomic failure. Levodopa may transiently improve parkinsonism (20-30% of patients). No effective neuroprotective therapy is available.
Prognosis
MSA is rapidly progressive and is associated with wheelchair dependence, unintelligible speech, intermittent urinary catheterization, disabling orthostatic hypotension, and cognitive impairment (executive dysfunction). Disease progression is assessed using the unified MSA rating scale (UMSARS), which rates activities of daily life, autonomic and motor impairment, as well as overall disability. Prognosis is poor with a median survival of 6-9 years.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Pr Wassilios MEISSNER


Multisystem inflammatory syndrome in children and adults

A rare systemic disease characterized by a life-threatening hyperinflammatory state several weeks after infection with SARS-CoV-2, predominantly occurring in children. The primary infection is typically mild or asymptomatic, and patients are generally previously healthy individuals. Typical presenting signs and symptoms are persistent fever, gastrointestinal symptoms, mucocutaneous inflammation, lymphopenia, and high levels of circulating inflammatory markers. Some patients develop severe disease with cardiac involvement, hypotension, and shock. Presentation is similar in adults, although the severity of cardiac dysfunction, incidence of thrombosis, and mortality may be higher.


Multisystemic smooth muscle dysfunction syndrome

A rare, genetic, vascular disease characterized by congenital dysfunction of smooth muscle throughout the body, manifesting with cerebrovascular disease, aortic anomalies, intestinal hypoperistalsis, hypotonic bladder, and pulmonary hypertension. Congenital mid-dilated pupils non-reactive to light associated with a large, persistent patent ductus arteriosus are characteristic hallmarks of the disease.


A Rickettsial disease characterized by headache, fever and macular or maculopapular rash, with only one-third of patients manifesting all three symptoms. Other common symptoms are chills, malaise, stomach pain, myalgia, loss of appetite, and in some cases confusion and altered level of consciousness. Classical laboratory abnormalities include elevated liver enzymes, lactate dehydrogenase, erythrocyte sedimentation rate and hypoalbuminemia. In children, typical symptoms occur in only half of patients, and abdominal pain, diarrhea, sore throat and anemia are more common.


Muscle filaminopathy is a rare myofibrillar myopathy characterized by slowly progressive, proximal skeletal muscle weakness, which is initially more prominent in lower extremities and involves upper extremities with disease progression. Patients present with difficulty climbing stairs, a waddling gait, marked winging of scapula, lower back pain, paresis of limb girdle musculature, hypo-/areflexia and/or mild facial muscle weakness in rare cases. Respiratory muscle weakness is common and cardiac anomalies (conduction blocks, tachycardia, diastolic dysfunction, left ventricular hypertrophy) have been reported in some cases.


Muscle-eye-brain disease with bilateral multicystic leucodystrophy

A rare congenital muscular alpha-dystroglycanopathy with brain and eye anomalies disease characterized by a severe muscle-eye-brain disease-like phenotype associated with intellectual disability, muscular dystrophy, macrocephaly and extended bilateral multicystic white matter disease.


A rare, congenital muscular dystrophy due to dystroglycanopathy characterized by early onset muscular dystrophy, severe muscular hypotonia, severe intellectual disability and typical brain and eye malformations including pachygyria, polymicrogyria, agyria, brainstem and cerebellar structural anomalies, severe myopia, glaucoma, optic nerve and retinal hypoplasia. A broad clinical spectrum is observed with variable involvement of each organ system.

Summary:
Epidemiology
Prevalence is unknown but it is very rare among other congenital muscular dystrophies. It is more frequently observed in Northern European countries (Scandinavian region) due to a founder mutation.
Clinical description
Patients carrying the Finish founder mutation present with marked hypotonia and global developmental delay from birth. They have generalized muscle weakness, including facial and neck muscles. Severe eye disease is often present and includes congenital myopia, pachygyria, polymicrogyria, agyria, cerebellar and brainstem hypoplasia, cerebellar cysts, congenital glaucoma, pallor of the optic discs, and /or retinal hypoplasia. Adults have severe intellectual and motor disability, extremely limited communication skills, visual impairment, epilepsy, and spine and joint deformities. Many patients have associated behavioral difficulties (bruxism, autism, temper tantrums, self-mutilation). Creatine kinase (CK) levels are increased, and the biopsy shows abnormal alpha-dystroglycan expression. Brain MRI may reveal cortical neuronal migration disorder, with type II lissencephaly in the most severe cases, white matter abnormalities, flat brainstem, cerebellar hypoplasia, and hydrocephalus. Electroencephalograms are abnormal and often show paroxysmal tracing. Patients with other mutations present with a broad clinical spectrum ranging from severe (prenatal death, and brain and posterior fossa malformations) to mild muscular dystrophies (with or without eye or brain structural abnormalities, constant speech and cognitive delay, but possible acquired walking). Almost all develop seizures, such as myoclonic jerks or refractory partial/generalized epilepsy.
Etiology
Muscle-eye-brain disease (MEB) is caused by mutations in the POMGnT1 gene (Chr 1p32-34), encoding protein O-linked mannose b1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). Other gene variants have been identified in a small number of patients.
Diagnostic methods
Diagnosis is suspected on clinical presentation, characteristic neuroimaging and electromyography findings, muscle biopsy results, and molecular genetic testing.
Differential diagnosis
Differential diagnosis includes other dystroglycanopathies and muscular dystrophies with brain and/or cognitive impairment. Patients presenting with MEB symptoms would be diagnosed with Fukuyama congenital muscular dystrophy (FCMD) in Japan. Therefore, there is an increasing tendency to use the global term MEB/FCMD syndrome. Other dystroglycanopathies include CMD due to FKRP, ISPD with brain involvement or cognitive delay, Walker-Warbourg Syndrome, laminin subunit alpha 2-related congenital muscular dystrophy, Duchenne muscular dystrophy with cognitive involvement, CDG-syndromes, and chromosomal disorders.
Antenatal diagnosis
Genetic prenatal 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 mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management includes physiotherapy, treatment of orthopedic, respiratory and cardiac complications, respiratory aid, and medical or surgical treatment for spinal or joint contractures, nutritional and gastrointestinal problems. Control of seizures requires antiepileptic drugs. Surveillance includes monitoring for respiratory and cardiac function. Severe intellectual disability and behavior disturbances may require specific care and management in specialized centers.
Prognosis
Prognosis depends mainly on the severity of neurologic, cardiac or respiratory complications. Patients may remain ambulant into adulthood.

                            Last update:
                            January 2023

                            - Expert reviewer(s):
                            Pr Enrico BERTINI | EURO-NMD* - Pr Susana QUIJANO-ROY | EURO-NMD*

                                * European Reference Network


Muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome

A rare hereditary ataxia characterized by neurogenic muscular atrophy associated with signs of cerebellar ataxia, hypesthesia, degeneration of the retina, and diabetes mellitus. Onset of the disease is in adolescence and the course is slowly progressive. There have been no further descriptions in the literature since 1983.


Selcen type muscular dystrophy is characterized by progressive limb and axial muscle weakness associated with cardiomyopathy and severe respiratory insufficiency during adolescence. The disease manifests during childhood and progresses rapidly.

Summary:
Epidemiology
To date, three cases have been described.
Clinical description
Two patients presented with a rigid spine and one a peripheral neuropathy. Disintegration of Z disks, extensive accumulation of granular debris and larger inclusions, and apoptosis of a small fraction of the nuclei characterize the disease.
Etiology
The disease is due to a mutation in the BAG3 gene, encoding a protein localized to the Z disk.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            October 2009


Muscular hypertrophy-hepatomegaly-polyhydramnios syndrome is a rare genetic disease characterized by symmetrical muscular hypertrophy, hepatomegaly, polyhydramnios, macrocephaly and mild delay in motor, speech and language development.


Muscular pseudohypertropy - hypothyroidism, also known as Kocher-Debre-Semelaigne syndrome is a rare disorder characterized by pseudohypertrophy of muscles due to longstanding hypothyroidism (see this term).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The syndrome usually presents between 18 months and 10 years but has been reported at earlier ages including during the neonatal period. Patients present with clinical features of hypothyroidism, including decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia, along with muscle pseudohypertrophy. Pseudohypertrophy involves the muscles of the extremities, limb girdle, trunk, hands and feet but is more prominent in the limbs, resulting in an athletic appearance.
Etiology
The etiology of the muscle pseudohypertrophy is not known but it is thought to be a result of long standing hypothyroidism. Hypothyroidism, or thyroid hormone deficiency, may be congenital and may be permanent or transient (see these terms).
Diagnostic methods
Diagnosis is based on the presence of clinical features and myopathic changes. In countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up thyroid-stimulating hormone (TSH) or primary TSH test), infants with congenital hypothyroidism are diagnosed after detection by screening tests.
Management and treatment
Treatment is based on thyroid supplements. With treatment, reversal of the pseudohypertrophy and clinical symptoms is possible.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


A rare systemic disease characterized by congenital multiple contractures, characteristic craniofacial features (like large fontanel, hypertelorism, downslanting palpebral fissures, blue sclerae, ear deformities, high palate) evident at birth or in early infancy, and characteristic cutaneous features like skin hyperextensibility, skin fragility with atrophic scars, easy bruising, and increased palmar wrinkling. Additional features include recurrent/chronic dislocations, chest and spinal deformities, peculiarly shaped fingers, colonic diverticula, pneumothorax, and urogenital and ophthalmological abnormalities, among others. Molecular testing is obligatory to confirm the diagnosis.


Mutilating hereditary sensory neuropathy with spastic paraplegia

A rare genetic neurological disorder characterized by infantile to childhood onset of progressive sensory neuropathy in association with spastic paraplegia and mutilating acropathy. Patients present lower limb spasticity and progressive severe sensory loss leading to chronic ulcerations in both upper and lower limbs. Electrophysiological studies are consistent with axonal sensory neuropathy, and nerve biopsy shows axonopathy with loss of myelinated nerve fibers of all diameters as well as of unmyelinated axons.


Mutilating palmoplantar keratoderma with periorificial keratotic plaques

A hereditary palmoplantar keratoderma characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma and periorificial keratotic plaques.


Myalgia-eosinophilia syndrome associated with tryptophan is a rare systemic disease characterized by severe myalgia and peripheral eosinophilia associated with tryptophan dietary supplementation. The symptoms do not subside after tryptophan discontinuation. Clinical presentation includes muscle tenderness and cramps, fatigue, weakness, paresthesia, peripheral edema, arthralgia, dyspnea, skin rash, dry mouth, and development of scleroderma-like skin abnormalities.


Myasthenia gravis (MG) is a rare, clinically heterogeneous, autoimmune disorder of the neuromuscular junction characterized by fatigable weakness of voluntary muscles.

Summary:
Epidemiology
The prevalence is estimated to be 1/5,000 and the incidence to be 1/250,000 to 1/33,000 in Europe. MG affects both males and females: mainly females before the age of 40 years and males and females equally after the age of 50 years.
Clinical description
Myasthenia gravis can develop at any age but there is a bimodal peak in the age of onset in the adult-onset form, with primarily female patients before 40 years of age, and primarily males after 50 years of age (adult-onset myasthenia gravis; see this term). Patients have fluctuating weakness, worsening with repetitive activities, heat and stress while improving with rest and with involvement of skeletal muscle groups of ocular, bulbar, extremities and neck. Ocular manifestations include fluctuating diplopia and ptosis. Bulbar involvement may manifest with fatigable chewing, dysphagia and dysarthria. Some patients develop generalized muscle weakness, which may become serious with respiratory muscle weakness. In the juvenile form, onset is before 18 years of age (juvenile myasthenia gravis; see this term) and patients also present with ocular and possibly generalized muscle weakness. A transient neonatal form causing hypotonia and feeding difficulties occurs in some newborns born to mothers with MG (transient neonatal myasthenia gravis; see this term). Congenital genetic forms of MG with a different pathogenesis also occur (congenital myasthenic syndrome, see this term).
Etiology
The exact pathogenesis is not known but MG is related to circulating antibodies to various muscle receptors, including acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK). Another target, the low density lipoprotein receptor-related protein 4 (LRP4), has been also described. The thymus is thought to trigger antibody production in the form with anti-AChR antibodies. These antibodies have been found to play a pathogenic role in all the forms of the disease. MG can also be drug induced (by D-penicillamine, interferon alpha, and bone marrow transplantation). An initial infection (EBV) may be responsible for some cases of MG. The role of infections has been strongly suggested by evidence of the involvement of interferon type I in the disease, but direct evidence is lacking.

                            Last update:
                            November 2014

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


MYBPC1-related autosomal recessive non-lethal arthrogryposis multiplex congenita syndrome

A rare arthrogryposis syndrome characterized by arthrogryposis multiplex congenita with contractures involving multiple joints of the upper and lower limbs, camptodactyly of fingers and toes, skeletal abnormalities such as scoliosis and pectus excavatum, as well as variable speech and motor delay and hypotonia. Facial dysmorphism includes long eyelashes, periorbital fullness, ptosis, epicanthal folds, high arched/cleft palate, and micrognathia.


Subcutaneous inflammatory pseudotumors containing fungal or actinomycetic (bacteria with branched filaments) granules or grains.

Summary:
Epidemiology
Annual incidence is unknown. The condition is endemic in the northern tropical zone and was first described by McGill in the area of Madura (hence the term 'Madura foot') during the last century.
Clinical description
The typical characteristic of fungal mycetomas is a painless tumefaction slowly forming on the foot with fistulae that release grains. Actinomycetic mycetomas are more frequent in Latin America and are more likely to cause inflammatory and painful tumefactions with many fistulae and grains. In both cases, the underlying bone is often affected.
Etiology
The agents causing mycetoma are very common saprophytes that are found in the soil and on thorny shrubs in semi-desert climates. Humans are infected as the result of localized skin trauma (implantation of a needle or wood splinter) or through a pre-existing wound.
Diagnostic methods
Diagnosis is made by microscopic examination of the grains and by analysis of cultures.
Differential diagnosis
Differential diagnoses include tumefactions of other origins.
Management and treatment
Medical treatment with sulfones can cure actinomycetic mycetomas, whereas surgery is the main treatment for fungal mycetomas. Prophylaxis consists of disinfecting wounds and wearing shoes.
Prognosis
The prognosis is poor for fungal mycetomas.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr Annick DATRY


Mycophenolate mofetil (MMF) embryopathy is a malformative syndrome due to the teratogenic effect of MMF, an effective immunosuppressive agent widely used for the prevention of organ rejection after organ transplantation.

Summary:
Epidemiology
To date, 25 cases have been reported, the majority being offspring of women who received a solid organ transplant.
Clinical description
Newborns or fetuses generally show external ear anomalies ranging from hypoplastic auricle (microtia) to complete absence of external ear (anotia) almost always associated with hypoplasia or atresia of the auditory canal (aural atresia) which can ultimately lead to deafness. Cleft lip-palate (see this term) with micrognathia is frequently observed. Aberrant orofacial cleft has been observed in one case. Ocular anomalies, such as microphthalmia and iris or chorioretinal coloboma, (see this term) are also frequent and can induce visual defects including severe visual impairment. Distal limbs anomalies (hypoplastic toe nails) as well as congenital malformations of the heart, kidneys and/or central nervous system may also be observed. Esophageal atresia, congenital diaphragmatic hernia (see these terms) and vertebral anomalies have been described in some cases. Intellectual deficit is usually absent, or only mild.
Etiology
MMF embryopathy is due to exposure to MMF during the intrauterine developmental period. MMF is an immunosuppressive agent that has been increasingly used in recent years in the prevention of organ transplant rejection and treatment of many autoimmune diseases because of its high efficacy and good tolerability. No dose-related effect has been demonstrated; however, exposure to low doses of MMF seems potentially teratogenic.
Diagnostic methods
Diagnosis is based on clinical examination (presence of the characteristic features in the fetus/newborn) and on maternal history of exposure to MMF during pregnancy.
Differential diagnosis
The differential diagnosis includes 18q deletion (distal), CHARGE syndrome and isotretinoin embryopathy (see these terms). 18q deletion is excluded by cytogenetic studies, CHARGE syndrome by CHD7 gene mutation scanning, and isotretinoin embryopathy by maternal interview.
Antenatal diagnosis
When relevant malformations are present (oro-facial clefts, heart defects, central nervous system malformations, diaphragmatic hernia), prenatal diagnosis by fetal ultrasonography is possible before 18 week gestation.
Management and treatment
In more than 90% of cases, internal ear anomalies require hearing-aids, and speech therapy is recommended during childhood. Oro-facial clefts and heart defects are treated surgically. To prevent the disease, it is recommended for women on MMF planning a pregnancy to replace MMF by an alternative immunosuppressive agent at least 6 weeks before stopping contraception.
Prognosis
Cases with severe cardiac malformations and/or diaphragmatic hernia may have a poor prognosis with early neonatal death. If no life-threatening malformations are present, patients may have a normal life expectancy.

                            Last update:
                            September 2011

                            - Expert reviewer(s):
                            Dr Antonio PÉREZ AYTÉS


Mycoplasma encephalitis is a rare infectious encephalitis characterized by an acute onset of neurological signs and symptoms (e.g. altered consciousness, seizures, headaches, meningeal signs, behavioral changes) due to bacterial infection by Mycoplasma pneumoniae. Patients typically present unspecific signs and symptoms, such as fever, nausea, vomiting, fatigue, prior to onset of neurological manifestations and frequently have a history of a respiratory tract infection (e.g. pneumonia, bronchiolitis, pharyngitis).


A group of disorders including the most common forms of cutaneous T-cell lymphomas. The term Mycosis fungoides (MF) is restricted to the classical form characterized by the slow progression of patches, plaques and tumors, and to variants with a similar indolent course.

Summary:
Epidemiology
The annual incidence is estimated at between 1/350,000 and 1/110,000. The male to female ratio is 2:1. MF and its variants typically occur in adults and the elderly.
Clinical description
Besides "classical" MF (Alibert-Bazin type), three distinct variants have been considered as sufficiently distinct to be included in the WHO-EORTC (European organisation for research and treatment of cancer) classification of cutaneous lymphomas: follicular mycosis fungoides, characterized by pilotropic lesions with or without deposition of mucin within the hair follicles; pagetoid reticulosis, characterized by localized lesions with intraepidermal proliferation of neoplastic T-cells usually involving the extremities; and granulomatous slack skin, characterized by areas of pendulous lax skin predominantly in the major skin folds (see these terms). Patches are often hypo- or hyperpigmented in dark-skinned individuals. Pruritus may be present, particularly in cases of folliculotropic MF. Extracutaneous involvement may occur in classical MF.
Etiology
The etiology remains unknown.
Diagnostic methods
The diagnosis is based on clinical presentation and should be confirmed by a skin biopsy.
Differential diagnosis
Differential diagnoses include inflammatory dermatoses (i.e. atopic dermatitis) in the early stages of MF, and other large cell non-Hodgkin lymphomas (see this term) in later stages.
Management and treatment
Management in the early stages includes mainly PUVA (photochemotherapy), interferon alpha-2a, retinoids, topical chemotherapy, and topical steroids. Total body electron beam irradiation may be used in case of severe forms of the disease. A variety of more aggressive treatments have been used for advanced stages of MF.
Prognosis
MF and its variants are slowly progressive. The prognosis depends on the type of MF but is usually favorable.

                            Last update:
                            June 2009

                            - Expert reviewer(s):
                            Pr Lorenzo CERRONI


A rare closed neural tube defect characterized by cystic dilatation of the central canal of the spinal cord, herniating through a posterior vertebral arch defect (spina bifida) into an expanded cerebrospinal fluid (CSF) filled dural sac (meningocele). It can be located at the caudal part of the spinal cord (terminal myelocystocele) or above conus (non terminal myelocystocele).


Myelodysplastic neoplasm with increased blasts type 1

A severe type of RAEB characterized by cytopenias and the following hematological parameters: uni- or multilineage dysplasia, 5% to 9% blasts in bone marrow or 2% to 4% in peripheral blood, and no Auer rods (abnormal, needle-shaped or round inclusions in the cytoplasm of myeloblasts and promyelocytes). Median survival has been reported to be 18 months.


Myelodysplastic neoplasm with increased blasts type 2

A very severe type of RAEB characterized by cytopenias and the following hematological parameters: uni- or multilineage dysplasia, 10% to 19% blasts in bone marrow or 5% to 19% in peripheral blood, variable presence of Auer rods (abnormal, needle-shaped or round inclusions in the cytoplasm of myeloblasts and promyelocytes). Median survival has been reported to be 18 months.


Myelodysplastic neoplasm with increased blasts

Refractory anemia with excess blasts (RAEB) is a frequent severe subtype of myelodysplastic syndrome (MDS; see this term) characterized by cytopenias with unilineage or multilineage dysplasia and 5% to 19% blasts in bone marrow or blood.

Summary:
Epidemiology
Exact prevalence is unknown but RAEB accounts for about 40% of patients with MDS which has a prevalence estimated to be 1/25,000 to 1/33,000. The disease tends to occur in older adults with a male predominance.
Clinical description
Two types of RAEB are recognized: type 1 and type 2 (RAEB-1 and RAEB-2; see these terms) which are differentiated based on the percentage of blasts in bone marrow or blood. Patients usually present with symptoms related to one or more cytopenias. Survival is lower in patients with RAEB-2 and there is a higher rate of transformation into acute myeloid leukemia in these patients. Most RAEB patients die from neutropenia-, thrombocytopenia- and anemia-related complications.
Etiology
The etiology is not known but is thought to involve inherited susceptibility or hematopoietic stem cell damage.

                            Last update:
                            February 2015


Myelodysplastic neoplasm with low blasts

Refractory cytopenias with unilineage dysplasia (RCUD) is a frequent low-risk subtype of myelodysplastic syndrome (MDS; see this term) characterized by refractory cytopenias associated with dysplasia limited to one cell lineage.

Summary:
Epidemiology
Exact prevalence is unknown but RCUD accounts for about 10% to 20% of patients with MDS which has a prevalence estimated to be 1/25,000 to 1/33,000. The disease tends to occur in older adults with a male predominance.
Clinical description
Clinical features are often nonspecific and are related to the underlying cytopenia. Patients are often asymptomatic and cytopenia is detected on routine blood tests. RCUD often has a prolonged and sometimes indolent course. Most patients with RCUD have refractory anemia (unilineage erythroid dysplasia), and very rarely refractory neutropenia (unilineage granulocytic dysplasia) or thrombocytopenia (unilineage megakaryocytic dysplasia). Anemia may be normocytic/normochromic but is often macrocytic. Blasts are absent or account for less than 1% in peripheral blood or less than 5% in bone marrow, and no Auer rods are present.
Etiology
The etiology is not known but is thought to involve inherited susceptibility or hematopoietic stem cell damage.
Prognosis
Median survival is reported to be 6 to 7 years and 5% to 10% of patients progress to acute leukemia.

                            Last update:
                            February 2015


Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality

A rare myelodysplastic syndrome characterized by macrocytic anemia (with or without other cytopenias and/or thrombocytosis), and with del(5q) occurring either in isolation, or with one other cytogenetic abnormality, other than monosomy 7 or del(7q). The bone marrow is typically hypercellular with erythroid hypoplasia and increased numbers of megakaryocytes, which show non-lobated and hypolobated nuclei. Myeloblasts constitute less than 5% of the nucleated bone marrow cells and less than 1% of the peripheral blood leukocytes. Auer rods are absent. Ring sideroblasts may be observed. Patients present with anemia and often thrombocytosis, while thrombocytopenia or pancytopenia are uncommon. Transformation to acute myeloid leukemia may occur in a small number of patients.


A group of myeloid hemopathies characterized by blood cytopenias, marrow dysplasia and a high risk of progression to acute myeloid leukemia (AML).

Summary:
Epidemiology
The annual incidence is 1/17,000-25,000 people, with a median age at diagnosis of 70 years. Only 5-10% of patients are diagnosed below the age of 50.
Clinical description
Clinical symptoms are consequences of blood cytopenias, mainly anemia (e.g. fatigue, dyspnea, possible angina, etc.), and less often of thrombocytopenia (spontaneous bleeding) or neutropenia (bacterial or less often fungal infections).
Etiology
The etiology is unknown in 80% of the cases. In the remaining 20% it has either acquired causes (previous treatment with chemo or radiotherapy, occupational exposure to benzene derivatives or ionizing radiation) or inherited causes, such as inherited gene point mutations mainly in DDX41, GATA2, RUNX, and telomerase genes, or DNA instability (Fanconi anemia patients are prone to develop MDS).
Diagnostic methods
Blood count reveals aregenerative anemia, which is often macrocytic, with or without neutropenia and thrombocytopenia. Cytological/ Histological analysis of bone marrow aspirate or biopsy generally reveals hypercellularity, with dysplasia in one to three myeloid lineages, without (<5%) or with (5-20%) excess of blasts. Cytogenetics of bone marrow show acquired clonal abnormality in 50 % of the cases, especially chromosome loss (-7, del 5q, del 20q) or gain (+8). Marrow cell mutations analysis by NGS method reveals at least one acquired mutation in myeloid genes panel in 90% of the cases especially in spliceosome genes (SF3B1,SRSF2), epigenetic genes (TET2, DNMT3a, ASXL1), RUNX1, or TP53.
Differential diagnosis
The differential diagnosis includes other bone marrow failures such as aplastic anemia, AML, or peripheral and clonal hematopoiesis in the elderly.
Management and treatment
Management and treatment depends on the prognostic score of patients in the revised International Prognostic Scoring System for Myelodysplastic Syndromes (IPSS-R), recently improved by the addition of acquired mutations (IPSS-M). Higher risk MDS are treated with allogeneic bone marrow transplantation when possible, otherwise with hypomethylating agents (azacytidine, decitabine), and less often chemotherapy. Lower risk MDS patients receive treatment for anemia with erythropoietin or derivatives, or other drugs in specific cases (lenalidomide in case of 5q deletion; Luspatercept in MDS with ringed sideroblasts).
Prognosis
MDS may progress into AML in ~30% of patients. The prognosis differs depending on a set of criteria scored by the IPSS-R and IPSS-M, including the number and importance of cytopenias, marrow blast percentage, and marrow cytogenetic abnormalities. This score separates schematically patients into lower risk (mainly characterized by anemia and less often thrombocytopenia) and higher risk (with generally severe cytopenias, including also neutropenia) of progression to AML, into five (IPSS-R) or six (IPSS-M) categories going from very low risk (2.8% risk of transformation into AML by 4 years) to very high risk (42.8% risk of transformation into AML by 4 years).

                            Last update:
                            July 2023

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

                                * European Reference Network


Myeloid sarcoma is a rare solid tumor of the myelogenous cells occurring in an extramedullary site.

Summary:
Epidemiology
The exact prevalence is unknown.
Clinical description
The clinical presentation depends on the site of involvement. Commonly involved sites of occurrence include the subperiosteal bone structures of the skull, paranasal sinuses, sternum, ribs, vertebrae, pelvis, as well as the lymph nodes and skin. Rare sites include the pancreas, heart, brain, mouth, breast, gastrointestinal and biliary tract, prostate, urinary bladder and gynecologic tract.

                            Last update:
                            January 2007


Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement

A rare, malignant, neoplastic disease characterized by clonal proliferation of myeloid and/or lymphoid precursors harboring translocations or insertions involving the chromosome band 8p11 and the FGFR1 gene, in the blood, bone marrow and often other tissues as well (spleen, liver, lymph nodes, breast, etc.). It usually presents as myeloproliferative neoplasm with eosinophilia, T lymphoblastic lymphoma with eosinophilia or, less frequently, acute myeloid leukemia. The presenting signs and symptoms include eosinophilia, leukocytosis with leukemoid reaction, monocytosis, fatigue, sweating, weight loss, lymphadenopathy, splenomegaly and/or hepatomegaly. Extranodal involvement may include the tonsils, lungs and breasts.


Myeloid/lymphoid neoplasm associated with PDGFRA rearrangement

A rare, malignant, neoplastic disease characterized by clonal proliferation of myeloid and/or lymphoid precursors harboring rearrangements in the PDGFRA gene, in the blood, bone marrow and often other tissues as well (spleen, lymph nodes, skin, etc.). It usually presents as chronic eosinophilic leukemia or, less commonly, as acute myeloid leukemia or T-lymphoblastic leukemia with eosinophilia. Patients usually present with eosinophilia, anemia, thrombocytopenia, neutrophilia, splenomegaly, lymphadenopathy, fever, sweating and/or weight loss. Tissue infiltration by eosinophils can manifest with skin rash, erythema, cough, neurological alterations, gastrointestinal symptoms or, rarely, endomyocardial fibrosis and restrictive cardiomyopathy.


Myeloid/lymphoid neoplasm associated with PDGFRB rearrangement

A rare, malignant, neoplastic disease characterized by clonal proliferation of myeloid and/or lymphoid precursors harboring rearrangements in the PDGFRB gene, in the blood, bone marrow and often other tissues as well (spleen, lymph nodes, skin, etc.). It usually presents as chronic myelomonocytic leukemia with eosinophilia, chronic eosinophilic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, acute myeloid leukemia or acute lymphoblastic leukemia. Patients usually present with anemia, leukocytosis, monocytosis, eosinophilia and/or splenomegaly, or systemic symptoms, such as fever, sweating and/or weight loss.


A rare primary immunodeficiency due to a defect in innate immunity characterized by a marked decrease or absence of myeloperoxidase activity in neutrophils and monocytes. Clinically, most patients are asymptomatic. Occasionally, severe infectious complications may occur, particularly recurrent candida infections, being especially severe in the setting of comorbid diabetes mellitus.


MYH9-related disease (MYH9-RD) is an inherited giant platelet disorder with a complex phenotype characterized by congenital thrombocytopenia and possible subsequent manifestations of sensorineural hearing loss, presenile cataracts, elevation of liver enzymes, and/or progressive nephropathy often leading to end-stage renal disease (ESRD). Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly and Sebastian syndrome, previously described as distinct disorders, represent some of the different clinical presentations of MYH9-RD.

Summary:
Epidemiology
Prevalence in Italy is estimated at 1/400,000-1/300,000. More than 300 MYH9-RD pedigrees have been reported worldwide.
Clinical description
Thrombocytopenia is present at birth and can be associated with spontaneous bleeding (usually mild or moderate). Bleeding symptoms include easy bruising, epistaxis, gum bleeding, and/or menorrhagia. Life-threatening hemorrhage is rare. Patients have an increased risk of hemorrhages after surgery, biopsy, or deliveries. Hearing loss is seen in almost all cases with the age of onset ranging from the 1st to 6th decade and the severity of hearing loss varying greatly (from mild defects to profound deafness). Proteinuric nephropathy occurs in about 30% of patients and in 75% is diagnosed before the age of 35. The majority of patients with kidney damage progress to ESRD within a few years. Patients that develop kidney involvement later in life often have a slower progression towards ESRD. Cataracts occur in about 20% of patients, are often bilateral and usually appear in early adulthood, but congenital cases have been reported.
Etiology
MYH9-RD is due to mutations in the MYH9 gene (22q13.1), encoding the heavy chain of the isoform A of the non-muscle myosin of class II (myosin-9). Myosin-9 is expressed in most cell types and tissues, including blood cells, cochlea, kidney, and hepatocytes. Neutrophil inclusions originate from co-precipitation of mutant myosin-9 with wild-type proteins within the cytoplasm.
Diagnostic methods
Diagnosis is suspected on hematological findings and possible association with extra-hematological manifestations. Diagnosis is confirmed by immunofluorescence assay on peripheral blood slides revealing typical myosin-9 neutrophil inclusions. Kidney damage is revealed by proteinuria with or without renal failure. Audiometric and ophthalmologic examinations identify a hearing defect and/or cataract, respectively. About 50% of patients have chronic or intermittent elevation of liver enzymes. Molecular genetic testing can identify the causative MYH9 mutation, which can predict the clinical evolution.
Differential diagnosis
Differential diagnoses include Bernard-Soulier syndrome, Alport syndrome and immune thrombocytopenia purpura (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible in families where a disease causing mutation has been identified.
Genetic counseling
MYH9-RD is inherited in an autosomal dominant manner with sporadic de novo mutations also being observed. Genetic counseling is possible.
Management and treatment
In cases of severe hemorrhages or before major hemostatic stresses (pregnancy, surgery), platelet transfusions (when possible from HLA-matched donors) are recommended. Eltrombopag has been successful in increasing platelet counts and abolishing the tendency to bleed. Desmopressin can shorten bleeding time in some patients; a test dose should be given to observe responsiveness. Surgery treats cataracts. A cochlear implant was beneficial in one patient with severe deafness. Angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors may reduce proteinuria in those with renal involvement. ESRD requires treatment with dialysis or kidney transplantation. Regular blood counts, annual urine analysis as well as audiometric and ophthalmologic evaluations are recommended. Medications that interfere with platelet function should be avoided.
Prognosis
Overall life-expectancy is not affected. Quality of life can be seriously affected in patients who develop kidney involvement and deafness, as well as in rare cases with severe spontaneous bleeding.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Alessandro PECCI


A rare multiple congenital anomalies syndrome characterized by short stature, distinctive facial dysmorphism, brachydactyly, stiff and thick skin, muscular pseudohypertrophy, restricted joint mobility, hearing loss, and variable intellectual disability. Cardiovascular and respiratory involvement are common.

Summary:
Epidemiology
To date, less than 100 cases have been reported, with no apparent ethnic or sex predilection.
Clinical description
The first manifestation is typically intrauterine growth retardation; however, diagnosis is typically later in childhood due to the absence of cardiac features early on. During the first years of life the main features are short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails. The more common clinical features become recognizable in late childhood and include the distinctive facial features (short palpebral fissures, mid-face hypoplasia, short philtrum, prognathism, narrow mouth, small ears), short stature, limited joint mobility (with particular difficulty in fist-clenching and in arm-raising), thickened skin, and muscular pseudohypertrophy. Mild-to-moderate intellectual disability and developmental delay are common, but not constant. Autistic-like behavior has been reported. Morphological cardiovascular anomalies affect about 70% of patients (septal defects, patent ductus arteriosus, obstructive defects of the left heart, aortic coarctation and arterial obstructions), and pericarditis, restrictive cardiomyopathy and systemic and pulmonary hypertension are frequently observed. Respiratory involvement consists of choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease (increasing with age). Gastrointestinal (GI) involvement includes pyloric stenosis, duodenal atresia and severe constipation. Proliferative fibrosis/scarring (on the serosal surfaces of heart, airway, lungs, GI tract, skin) may occur spontaneously or following trauma, endotracheal intubation or surgery. Ocular anomalies may include refractive errors and strabismus. Recurrent infections (particularly otitis media and pneumonia) are frequently reported. Hearing loss is observed in most (83%) individuals. Additional anomalies include cleft lip and/or palate, velopharyngeal insufficiency, and facial nerve weakness/paralysis (rare).
Etiology
Myhre Syndrome is due to heterozygous pathogenic variant in the SMAD4 gene (18q21.2).
Diagnostic methods
The diagnosis may be challenging and relies on the characteristic clinical features and the radiological findings (thickened skull, brachydactyly, broad ribs, vertebral fusions, large vertebral pedicles and hypoplastic iliac wings) and is confirmed by genetic analysis.
Differential diagnosis
Differential diagnosis include other genetic syndromes characterized by short stature, brachydactyly, stiff and thick skin, restricted joint mobility and cardiovascular involvement.
Antenatal diagnosis
Prenatal genetic testing is possible for at-risk pregnancies, where a pathogenic variant has previously been identified in an affected family member.
Genetic counseling
The inheritance pattern is autosomal dominant, but most cases occur de novo. Penetrance seems to be complete, but data about familial cases are limited.
Management and treatment
Treatment is mainly symptomatic, requiring a multidisciplinary medical team. Annual ophthalmologic, audiology, respiratory, cardiovascular, physical skill development and joint mobility evaluations are recommended. Hearing aids may be necessary for hearing loss. Oxygen supplementation may be necessary, as well as long-term tracheostomy. Limiting tissue trauma is important due to the increased risk of scarring/stenosis and proliferative fibrosis after surgical procedures and endotracheal intubation; alternative non-invasive approaches should be considered where possible. Restrictive lung disease, systemic/pulmonary hypertension and heart failure should be managed accordingly. Treatment may be necessary for constipation. Physical therapy may be helpful for joint mobility, as well as supportive management of intellectual disability and developmental delay.
Prognosis
Myhre syndrome is a progressive disorder with life-threatening complications. Restrictive and obstructive respiratory disease, pericarditis and laryngotracheal involvement are major causes of morbidity.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Dr Livia GARAVELLI | ITHACA* - Dr Simonetta ROSATO

                                * European Reference Network


Myoclonic epilepsy in non-progressive encephalopathies

A rare epilepsy syndrome characterized by recurrent, long-lasting myoclonic status in infants and young children with a non-progressive encephalopathy, associated with transient and recurring motor, cognitive and/or behavioral disturbances.


A rare infantile epilepsy syndrome characterized by infancy-onset of myoclonic seizures in otherwise neurologically and developmentally normal patients. Jerks may vary in severity, can be singular or occur in a series, and occur spontaneously or (less commonly) after sensory stimuli. Seizures are self-limiting and remit within several months to years from onset, although generalized tonic-clonic seizures or other forms of epilepsy may be seen later in life. Developmental delay and cognitive and behavioral difficulties have been reported in a considerable percentage of patients.


A rare, childhood onset epilepsy syndrome characterized by multiple seizure types including myoclonic-atonic (MA) seizures that occur usually in previously healthy children.

Summary:
Epidemiology
The prevalence is estimated at 1-2% of all childhood epilepsies with a sex ratio of 2.7-3.1:1 males to females.
Clinical description
Onset is between 2-5 years (peak 3-4 years), occurring typically in normally developing children. In 20 % of patients, simple febrile seizures have occurred before onset. Generalized tonic-clonic seizure (GTCS) is usually the first seizure type. After days to months, additional myoclonic, atonic and/or myoclonic-atonic seizures and atypical absences occur with increasing frequency until a ''stormy phase''. MA seizure consists of proximal muscle myoclonic jerks followed by an atonic phase. Brief tonic seizures may be seen in some patients. Children often display a non-convulsive status epilepticus (NCSE) with episodes of drowsiness, gait impairment and erratic myoclonus, which may last hours to days.
Etiology
Etiology is unknown in the majority of cases and a polygenic inheritance is suspected. The most common monogenic causes include SLC6A1 (3p25.3), CHD2 (15q26.1), AP2M1 (10q23.2). Other causal variants reported include SLC2A1 (1p34.2), SCN1A (2q24.3), SYNGAP1 (6p21.32), KCNA2, and NEXMIF (Xq13.3).
Diagnostic methods
Diagnosis is based on history, seizure semiology, neurologic examination and electroencephalogram (EEG) findings. EEG may be normal at onset or display a slowing of the background activity and generalized 2-3 Hz spike-wave discharges. Myoclonic, atonic and MA seizures can cause drops, and video-EEG with electromyogram (EMG) of deltoids and neck is essential to differentiate them from other seizures types (tonic, epileptic spasms). Neuroimaging is normal. Genetic and metabolic testing should be performed if differential diagnosis is suspected, and when clinical features are suspicious for a specific genetic mutation. Intermittent photic stimulation at low frequencies should be systematically performed during EEG to exclude neuronal ceroid lipofuscinosis type 2 (CLN2 disease).
Differential diagnosis
Dravet disease differs by earlier onset and prolonged febrile seizures. Myoclonic epilepsy of infancy also occurs earlier and displays brief myoclonic seizures as the single seizure type; Lennox-Gastaut syndrome is frequently associated with structural/metabolic etiology and tonic seizures in sleep and atypical absences as the main seizure types. CLN2 disease, with onset in the same age range, is the other important differential diagnosis.
Genetic counseling
Patients with an identified de novo variant and families with a known genetic mutation can benefit from genetic counseling.
Management and treatment
Even in children with a favorable clinical course, seizures can be initially resistant to anti-seizure medicines (ASMs). Broad spectrum ASMs are recommended, often a bi or tri-therapy is needed: sodium valproate, combination of sodium valproate with lamotrigine (synergistic effect), levetiracetam, ethosuximide (especially if myoclonic seizures are prominent). Other alternatives are zonisamide, topiramate, clobazam or clonazepam. Ketogenic diet is the most effective therapy in myoclonic-astastic epilepsy (> 50% seizure reduction in 50-90% of cases) and is recommended as soon as the first line ASMs fail. Vigabatrin and sodium channel blockers like carbamazepine or phenytoin are contraindicated as they worsen seizures. Benzodiazepines or steroids are suggested for treating NCSE. Few cases have undergone epilepsy surgery (corpus callosotomy, vagal nerve stimulator).
Prognosis
Outcome is variable. 60% of patients evolve with normal cognition or a mild cognitive delay. Cognition and behavior are impaired in unfavorable cases where seizures persist after 3 years of evolution. NCSE, tonic seizures, atypical absence seizures and epileptic encephalopathy are risk factors of unfavorable outcome.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Nicolas JANNONE-PEDRO | EpiCARE* - Dr Anna KAMINSKA | EpiCARE* - Dr Vicente VILLANUEVA | EpiCARE*

                                * European Reference Network


This syndrome is characterised by the association of myoclonus, cerebellar ataxia and sensorineural hearing loss.

Summary:
Epidemiology
So far, less than 10 cases have been reported in the literature.
Clinical description
The hearing loss was generally diagnosed during childhood or early adulthood and the myoclonic jerks began during adolescence.
Genetic counseling
Transmission appears to be autosomal dominant.

                            Last update:
                            July 2008


Myoclonus-dystonia syndrome (MDS) is a rare movement disorder characterized by mild to moderate dystonia along with 'lightning-like' myoclonic jerks.

Summary:
Epidemiology
The estimated prevalence of MDS in Europe is 1/500,000.
Clinical description
Disease onset usually occurs in the first or second decade of life. Myoclonus is usually the presenting manifestation and is described as swift ''lightning-like'' jerks that can rarely appear at rest but that are usually triggered by complex motor tasks such as drawing and writing. These movements mainly affect the neck, arms and trunk but can also rarely be seen in the legs or the larynx. In two thirds of cases, dystonia is also experienced in the form of focal or cervical dystonia (see these terms), which may be only mild and does not exacerbate with time. Postural and other forms of tremor have sometimes been reported. MDS is often associated with depression, anxiety, panic attacks, obsessive-compulsive behavior and personality disorders and alcohol abuse. Isolated torticollis is seen in extremely rare cases.
Etiology
The only known causative gene of MDS is the epsilon-sarcoglycan (SGCE) gene (7q21.3), encoding a transmembrane protein that is part of the dystrophin-associated glycoprotein complex found in skeletal and cardiac muscle. The epsilon-sarcoglycan protein is also abundant in monoaminergic neurons, cerebellar Purkinje cells, the cortex and the hippocampus of the brain. In one family with MDS, linkage to chromosome 18p has been reported (named DYT15), but the gene has not yet been identified.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical symptoms. Neuroimaging studies are normal. Genetic molecular testing of SGCE can confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes cervical dystonia, Dopa-responsive dystonia, Tourette syndrome, familial cortical myoclonus, Wilson disease, spinocerebellar ataxia type 3 (SCA3) and type 14 (SCA14), ataxia with vitamin E deficiency, genetic disorders with myoclonus as a major component (e.g. Unverricht-Lundborg disease, Lafora disease) (see these terms) and other secondary forms of dystonia.
Antenatal diagnosis
Prenatal testing is possible in families where a disease-causing mutation is identified.
Genetic counseling
MDS is inherited in an autosomal dominant manner. However, the SGCE gene is maternally imprinted, therefore in most cases (95%) a patient who inherits the mutation from their mother will remain healthy and only those that inherit the mutation from their father will develop MDS. De novo mutations also occur. Genetic counseling is recommended in those with a known mutation.
Management and treatment
Treatment plans are individualized to a patient's presenting symptoms. Benzodiazepines (clonazepam) and antiepileptic drugs (valproate, levetiracetam) are effective in relieving myoclonus and tremor, but patients should be carefully monitored. Similarly, alcohol frequently improves symptoms temporarily, but its long term use is not recommended. Injections of botulinum toxin can relieve focal and cervical dystonia. If these treatments fail or are insufficient, bilateral deep brain stimulation (DBS) of the internal globus pallidum (Gpi) and the central intermediate nucleus (VIM) of the thalamus have shown positive results in providing lasting relief from both myoclonus and dystonia. Gpi stimulation is often sufficient in treating MDS, and may be favored over VIM stimulation, which generally has very little effect on dystonia. In a staged surgical procedure, quadruple stimulation (VIM and Gpi) may also be considered in selected cases.
Prognosis
Patients with MDS have normal life-expectancy, but quality of life can be severely affected.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


Myofibrillar myopathy (MFM) describes a group of skeletal and cardiac muscle disorders, defined by the disintegration of myofibrils and aggregation of degradation products into intracellular inclusions, and is typically clinically characterized by slowly-progressive muscle weakness, which initially involves the distal muscles, but is highly variable and that can affect the proximal muscles as well as the cardiac and respiratory muscles in some patients.


A rare systemic disease characterized by congenital muscle hypotonia and/or muscle atrophy that improves with age, proximal joint contractures (knee, hip, elbow), and hypermobility of distal joints. Additional features include soft, doughy skin, atrophic scarring, delayed motor development, and myopathic findings in muscle biopsy. Abnormal craniofacial features have been reported in some patients. Molecular testing is obligatory to confirm the diagnosis.


A rare, genetic, mitochondrial DNA-related mitochondrial myopathy disorder characterized by slowly progressive muscular weakness (proximal greater than distal), predominantly involving the facial muscles and scapular girdle, associated with insulin-dependent diabetes mellitus. Neurological involvement and congenital myopathy may be variably observed.


Myopathy with hexagonally cross-linked tubular arrays is a rare, congenital, non-dystrophic, mild, slowly progressive, proximal myopathy characterized by exercise intolerance and post-exercise myalgia without rhabdomyolysis, associated with highly organized hexagonally cross-linked tubular arrays in skeletal muscle biopsy. Additional features may include muscle atrophy (or diffuse hypotrophy), myalgia with or without musclar weakness, paresis of truncal and limb-girdle musculature, minimal ptosis, lumbar hyperlordosis, decreased deep tendon reflexes, contractures and pes equinovarus.


A rare soft tissue tumor characterized by a benign subcutaneous lesion composed of oval-to-spindle shaped myoid appearing cells with a tendency for concentric perivascular growth. The tumor usually presents as a painless, slowly growing nodule, which may be solitary or appear as multiple lesions, which then arise metachronously and usually involve a particular anatomic region. Recurrence after surgical excision may occur in poorly circumscribed tumors. Malignancy is very rare.


Myosclerosis is a rare, genetic, non-dystrophic myopathy characterized by early, diffuse, progressive muscle and joint contractures that result in severe limitation of movement of axial, proximal, and distal joints, walking difficulties in early childhood and toe walking. Patients typically present thin, sclerotic muscles with a woody consistency, mild girdle and proximal limb weakness with moderate distal weakness and scoliosis. Muscle biopsy shows partial collagen VI deficiency at the myofiber basement membrane and absent collagen VI around most endomysial/perimysial capillaries.


A rare congenital myopathy characterized by generalized proximal and distal muscle weakness and/or atrophy with slow progression. A subset of patients present with scapuloperoneal weakness and scapular winging. Disease onset usually occurs during infancy/childhood, but adult-onset cases have also been reported. Patients may have respiratory problems and/or cardiomyopathy. Muscle biopsies show hyaline body inclusions in type I fibers.


A rare maxillo-facial surgical disease characterized by an inflammatory, granulomatous lesion, most commonly of iatrogenic origin due to interaction of extravasated erythrocytes with exogenous lipids, in particular petrolatum-based antibiotic ointment used after surgical procedures. Most frequent locations are the paranasal sinuses and jaws, although the lesion can occur in any part of the body. It is typically found incidentally as an asymptomatic soft tissue swelling.


A form of potassium-aggravated myotonia (PAM) which is cold insensitive, dramatically fluctuating and profoundly worsened by potassium ingestion.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Fluctuating myotonia develops during childhood or adolescence and involves the extraocular, bulbar and limb muscles. Eyelid myotonia is often the first sign of the disease. Episodes of stiffness vary in severity and frequency and may be separated by prolonged periods of normality. Myotonia is aggravated by potassium ingestion and appears with a delayed onset (10-30 min) after exercise (exercise-induced delayed-onset myotonia). Cold has no effect on myotonia. Paralysis is never observed. Episodic weakness is rare.
Etiology
Myotonia fluctuans is a sodium muscle channelopathy due to missense mutations of the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            October 2010

                            - Expert reviewer(s):
                            Dr Savine VICART


A very rare, persistent and more severe form of potassium-aggravated myotonia (PAM).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Continuous and severe myotonia begins during childhood (usually before 10 years of age) and involves mainly the face, neck, limbs, and thoracic muscles. It can be aggravated by exercise or potassium ingestion and less often by cold. Occasionally, patients have muscle hypertrophy, especially of the neck and shoulders. Paralysis is never observed. Severe stiffness of the pharyngeal and respiratory muscles may provoke episodes of hypoxia and acidosis that can compromise the respiratory function. Close monitoring is necessary during surgery as rigidity and rhabdomyolysis may occur. Depolarizing agents can cause severe ventilation problems due to a paradoxical increase of stiffness in respiratory muscles and must be avoided.
Etiology
Myotonia permanens is a muscle sodium channelopathy due to missense mutations of the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            October 2010

                            - Expert reviewer(s):
                            Dr Savine VICART


A rare soft tissue sarcoma characterized by a malignant, fibroblastic lesion with variably myxoid stroma, pleomorphism, and a distinctively curvilinear vascular pattern. The majority of tumors arise in the limbs including the limb girdles, more often in dermal/subcutaneous tissues than in the underlying fascia and skeletal muscle, and usually present as a slowly growing, painless mass. Depth of the lesion and tumor grade do not influence the high rate of local recurrence, while the percentage of metastasis and tumor-associated mortality are much higher in deep-seated and high-grade neoplasms.


Myxoid/round cell liposarcoma (MRCLS) is a type of liposarcoma (LS; see this term) mostly located in the limbs, with a variable behavior depending on the histological subtype. Both myxoid and round cell are distinct histological subtypes of LS.

Summary:
Epidemiology
The incidence is approximately 1/769, 000 per year and it accounts for 30% or less of all LS cases.
Clinical description
MRCLS presents at a younger age than other LS subtypes with typical age of diagnosis ranging from 35-55 years. It predominantly occurs in the limbs (most frequently in the thighs) and rarely arises in the retroperitoneum or subcutaneous tissue. One third of MRCLS cases will become metastatic with tumors spreading to unusual bone and soft tissue locations with multifocal synchronous or metachronous spread to fat pad areas in the retroperitoneum, trunk, pericardium and axilla.
Etiology
Ninety percent of MRCLS lesions have a characteristic chromosomal translocation leading to the fusion of the DDIT3 and FUS genes on chromosome regions 12q13 and 16p11. The consequence is the creation of a FUS-DDIT3 hybrid protein that promotes malignant transformation by dysregulating RNA transcription and thereby dysregulating adipocyte differentiation and cell-cycle control.
Diagnostic methods
When a mass is detected, computed tomography (CT) or magnetic resonance imaging (MRI) is performed. Chest and abdominal lesions do not require pretreatment biopsy unless resection is likely to be incomplete or highly morbid. Extremity lesions are generally sampled by multiple core biopsies to identify the histological subtype (myxoid versus round cell component) and to stage the disease. MRCLS tumors are composed of uniform, round to oval, primitive nonlipogenic mesenchymal cells and small signet-ring lipoblasts in a prominent myxoid stroma with plexiform vasculature. The diagnosis can be confirmed by evidence of the DDIT3-FUS translocation from fluorescence in situ hybridization (FISH) or RT-PCR. High levels of the round cell component predict a poorer outcome, so it must be determined whether the tumor is more myxoid (<5% round cell component) or round cell (>5% round cell component).
Differential diagnosis
MRCLS can be mistaken for Ewing sarcoma, lymphoma and pleomorphic undifferentiated sarcomas (see these terms). Other myxoid neoplasms must also be excluded.
Management and treatment
Treatment involves the surgical excision of the tumor and surrounding tissue for low grade myxoid liposarcoma. In rare cases amputation of the limb is necessary. High grade round cell LS that is large (>5 cm), or marginally resectable tumors, may be treated with pre-operative chemotherapy and/or pre-operative or post-operative radiotherapy. MRCLS, compared to other subtypes, responds well to radiotherapy and chemotherapy. Chemotherapeutic agents doxorubicin and ifosfamide are usually first line treatment options whereas ecteinascidin is used as a second line treatment. Lifelong follow-up is recommended in order to monitor for recurrence at the initial site as well as distant metastasis.
Prognosis
The prognosis of MRCLS is good for patients with low grade myxoid liposarcoma (defined as pure myxoid or less than a 5% round cell component), the 5-year survival rate is 92%. A significant (5% or greater) round cell component is associated with a much poorer prognosis, with a 5-year survival rate of 74%.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Dr Samuel SINGER


Myxopapillary ependymoma (MEPN) describes a slow growing ependymoma located almost exclusively in the conus medullaris-cauda equina-filum terminale region of the spinal cord, presenting in all age groups, and manifesting with variable symptoms such as neck pain, vomiting and unsteady gait and metastasis. It has a more aggressive disease course and is seen in the pediatric population.


Ménétrier disease (MD) is a rare premalignant hyperproliferative gastropathy characterized by massive overgrowth of foveolar cells in the gastric lining, resulting in large gastric folds, and manifesting with epigastric pain, nausea, vomiting, peripheral edema and, less commonly, anorexia and weight loss.

Summary:
Epidemiology
Exact prevalence and incidence data are not available. MD appears to affect males slightly more than females.
Clinical description
The usual age of onset is between 30 and 60 years (average 55 years), although cases in childhood have been reported. The childhood variant often involves sudden onset and spontaneous regression. In adults, onset is often insidious with a wide spectrum of clinical manifestations. Affected patients typically present with abdominal pain, vomiting and nausea. Edema of peripheral tissues is often found. Other symptoms include asthenia, anorexia, and weight loss. Some individuals with MD are only mildly affected or are asymptomatic. Loss of protein from the gastrointestinal tract leads to hypoalbuminemia and peripheral edema. Mucosal ulceration is also described and can result in gastrointestinal bleeding. Disease course tends to be progressive, leading to gastric adenocarcinoma in 2-15% of cases. Complications include severe or recurrent infections and vascular thromboembolism.
Etiology
The etiology is currently unknown but is thought to be acquired and to involve enhanced epidermal growth factor receptor (EGFR) signaling in the gastric mucosa with local overproduction of transforming growth factor-alpha (TGF-alpha). In children, some MD cases have been linked to cytomegalovirus (CMV) and in adults some have been linked to Helicobacter pylori; however, the possible role of these infections remains to be elucidated. Rare familial cases point to a possible genetic component. The mechanism(s) underlying carcinogenesis in MD remain unknown.
Diagnostic methods
MD is suspected on the basis of the constellation of clinical signs and symptoms but there are no formal diagnostic criteria. Diagnosis requires gastroscopic examination (showing enlarged gastric folds primarily involving the gastric corpus) with biopsy, preferably of full thickness gastric mucosa, which reveals characteristic histological features (extensive foveolar hyperplasia with corkscrew morphology in the absence of distortion of overall linear architecture, decreased or absent parietal cells, variable amounts of chronic inflammation with scattered clusters of eosinophils, and scattered strands of smooth muscle between mucous glands). Gastric acid secretion is generally markedly decreased or absent, while gastric mucous secretion is elevated. Serum gastrin levels remain relatively normal.
Differential diagnosis
Differential diagnoses include Zollinger-Ellison syndrome (see this term), hypertrophic hypersecretory gastropathy, hypertrophic lymphocytic gastritis, infiltrating neoplasm, polyps, and polyposis syndromes (e.g. juvenile polyposis syndrome, Peutz-Jeghers syndrome, and gastric adenocarcinoma and proximal polyposis of the stomach; see these terms).
Genetic counseling
MD is an acquired gastropathy but a genetic predisposition with autosomal dominant inheritance has been suggested in a few families.
Management and treatment
There is no recommended standard treatment. In some patients, treatment may be limited to supportive care with a high-protein diet. Inconsistent results have been achieved with anticholinergic drugs, acid suppression therapy, treatment against CMV infection in children, and H. pylori eradication in adults. Treatment with cetuximab, an EGFR neutralizing monoclonal antibody, has been successfully carried out. If there is concern about malignant transformation or in severe cases, partial or total gastrectomy may be required. Although there is no official recommendation, endoscopic surveillance may be offered every 1-3 years.
Prognosis
MD tends to be a progressive disorder. Most of the patients ultimately require gastrectomy, either due to worsening symptoms or the risk of developing gastric cancer. The risk of malignant transformation is not well characterized.

                            Last update:
                            October 2016

                            - Expert reviewer(s):
                            Dr Won Jae HUH  - Pr ROBERT J. COFFEY


A rare syndrome with 46,XX difference of sex development characterized by Müllerian duct hypoplasia or agenesis associated with clinical and biological evidence of hyperandrogenism in 46,XX females. Patients present with hypoplastic or absent uterus, variable abnormalities of other reproductive organs, primary amenorrhea, acne, hirsutism, and sometimes renal anomalies. External genitalia and secondary sexual characteristics are normal. Hormonal analysis shows variably elevated serum levels of androstenedione, dehydroepiandrosterone, and/or total and free testosterone.


A rare genetic disease characterized by the presence of Müllerian duct derivatives (rudimentary uterus, fallopian tubes, and atretic vagina) and other genital anomalies (cryptorchidism, micropenis) in male newborns, intestinal and pulmonary lymphangiectasia, protein-losing enteropathy, hepatomegaly, and renal anomalies. Postaxial polydactyly, facial dysmorphism (including broad nasal bridge, bulbous nasal tip, long and prominent upper lip with smooth philtrum, hypertrophic alveolar ridges, and mild retrognathia, among other features), and short limbs have also been described. The syndrome is fatal in infancy.


Müllerian duct anomalies-limb anomalies syndrome

A rare disorder characterized by the association of mullerian duct and distal limb anomalies. Females present with anomalies ranging from a vaginal septum to complete duplication of uterus and vagina, and males present with micropenis. The limb anomalies varied from postaxial polydactyly to severe upper limb hypoplasia with split hand.


A rare, fatal multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphism (incl. dolichocephaly/scaphocephaly, high frontal hairline, laterally overlapping upper eyelids, hypertelorism, prominent eyelashes, deep-set eyes, macrocornea, nystagmus, dysplastic ears, abnormal auricles, prominent nasal bridge, dental dysplasia), visual impairment, deafness, seizures, generalized skeletal dysplasia, high fingerprint ridge count, cryptorchidism, hypospadias, spasticity and severe intellectual disability. An increased chromosome breakage and a fatal lymphoid malignancy have been reported. There has been no further description in the literature since 1974.


A rare neurometabolic disease characterized by infantile onset of repeated episodes of developmental regression and neurodegeneration, often triggered by febrile illnesses. Patients present with lethargy, hypotonia, irritability, gait ataxia, loss of speech, movement disorder, seizures, ophthalmoplegia, and hearing loss. Brain imaging shows generalized cerebral atrophy and bilateral basal ganglia abnormalities. Extensive skin lesions, cardiomyopathy, and pancytopenia have been reported in association. The condition is fatal in the first years of life.


A rare neurometabolic disease characterized by infantile onset of rapidly progressive neurological deterioration, typically precipitated by a febrile illness. Patients present with hypotonia, loss of previously acquired motor milestones and cognitive skills, ataxia, nystagmus, tremor, seizures, tetraparesis, and respiratory failure, eventually resulting in a vegetative state. Imaging of the brain and spinal cord may show white matter abnormalities, cerebral atrophy, cerebellar edema, and spinal myelopathy. Subacute development of extensive bullous skin lesions within weeks of onset of neurological symptoms has also been reported.


A rare ectodermal dysplasia that affects the skin, sweat glands, nails, and teeth.

Summary:
Epidemiology
Several families with multiple affected members (males and females) from several generations have been reported so far. Prevalence is estimated at 1 in 3 million.
Clinical description
The cardinal features are absence of dermatoglyphics (fingerprints), reticular cutaneous hyperpigmentation (starting at about the age of 2 years without a preceding inflammatory stage), hypohidrosis with diminished sweat gland function and discomfort provoked by heat, nail dystrophy, tooth enamel defects, and moderate hyperkeratosis of the palms and soles. Diffuse palmoplantar keratoderma may coexist with punctate keratoses that are sometimes accentuated in the creases or exhibit a linear pattern. Congenital misalignment of the great toenails was reported in some patients.
Etiology
NFJ is inherited as an autosomal dominant condition and is caused by mutations in the KRT14 gene (17q11.2-17q21) encoding keratin 14. The disease is allelic to dermatopathia pigmentosa reticularis (see this term).
Diagnostic methods
Diagnosis is based on the typical clinical features and can be confirmed by molecular analysis.
Differential diagnosis
Differential diagnoses include incontinentia pigmenti, dermatopathia pigmentosa reticularis, dyskeratosis congenita, pachyonychia congenita and Dowling-Degos disease (see these terms).
Antenatal diagnosis
Prenatal diagnosis has not been reported so far.
Management and treatment
Treatment is symptomatic. The dry skin has to be moisturized with emollients, and hyperthermia should be prevented by use of appropriate clothing and physical cooling with wet dressings or cool water during warm periods. Dental care is imperative to prevent caries and tooth loss.
Prognosis
The reticulate pigmentation fades after puberty and sometimes disappears completely in old age. Hypohidrosis, the most problematic symptom for patients, remains constant. Teeth are always severely affected, leading to early total loss.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Pr Peter ITIN


A congenital malformation syndrome characterized by mandibulofacial dystosis (malar hypoplasia, micrognathia, external ear malformations) and variable preaxial limb defects.

Summary:
Epidemiology
The prevalence is unknown; more than 100 cases of NAFD have been published.
Clinical description
NAFD is characterized by mandibulofacial anomalies that include downward slant of palpebral fissures, ptosis of upper lids, coloboma of lower lids, deficiency of eyelashes of the medial one-third to two-thirds of the lower eyelids, hypoplasia of the malar eminences, hypoplasia of the maxilla, cleft palate, absence or hypopoplasia of the palatal velum, choanal atresia, extension of a ''tongue'' of temporal hair down the sides of the cheeks. Cleft lip is rare. Limb defects are predominantly preaxial with hypoplasia or absence of thumbs being the most characteristic feature, frequently associated with radio-ulnar synostosis and/or aplasia/hypoplasia of the radius. Triphalangeal thumbs and other abnormalities of the digits have also been reported and a small percentage of patients also have lower limb malformations. Otologic and oral anomalies frequently lead to bilateral conductive hearing loss, speech difficulties and upper respiratory airways obstruction. Most Nager syndrome individuals have normal vision and intelligence.
Etiology
In approximately 50% of patients, NAFD has been associated with heterozygous mutations in the SF3B4 gene (1q21.2), coding for a component of the splicing machinery.
Diagnostic methods
Diagnosis is based on physical and radiological examination or the identification of a mutation in SF3B4.
Differential diagnosis
Differential diagnosis may include mandibulofacial dysostosis syndromes such as Treacher-Collins syndrome, and other acrofacial dysostoses (AFD) such as the AFD Catania type, the AFD Palagonia type, the AFD Genee-Wiedemann type, the AFD Rodriquez type as well as mandibulofacial dysostosis with microcephaly (see these terms). Patients with the oculoauriculovertebral (OAV) spectrum (see this term) may also have overlapping features.
Antenatal diagnosis
Antenatal diagnosis can be performed by ultrasonography or molecular testing of SF3B4.
Genetic counseling
Nager syndrome is likely genetically heterogenous with confirmed autosomal dominant inheritance, but autosomal recessive inheritance is suspected based on sibling recurrence in consanguineous families. Genetic counseling requires careful evaluation of parents and sibs of an affected child, in order to determine if the disease has a familial origin or if it occurred sporadically. If one parent is mildly affected, recurrence risk is 50% and a 25% risk cannot be excluded when parents are apparently normal.
Management and treatment
Management must focus on neonatal respiratory distress (tracheostomy) and feeding difficulties (gastrostomy). Surgery can be considered for repair of clefts, management of severe micrognathia as well as temporomandibular joint dysfunction. Hearing aids can be proposed. Language and phonological impairment must be managed by a specific speech therapy.
Prognosis
After infancy, most patients are healthy and are presumed to have a normal lifespan. Ongoing medical issues are usually only related to airway obstruction or temporomandibular joint dysfunction in patients with more severe manbibular malformations.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr François BERNIER


Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome is a rare genetic ectodermal dysplasia syndrome characterized by short stature, nail dystrophy and/or nail loss, oral mucosa and/or tongue hyperpigmentation, dentition abnormalities (delayed teeth eruption, hypodontia, enamel hypoplasia), keratoderma on the margins of the palms and soles and focal hyperkeratosis on the dorsum of the hands and feet. Additionally, dysphagia with esophageal strictures, sensorineural deafness, bronchial asthma and severe iron-deficiency anemia have been observed.


A rare hereditary patellar dysostosis characterized by nail hypoplasia or aplasia, aplastic or hypoplastic patellae, elbow dysplasia, and the presence of iliac horns as well as renal and ocular anomalies.

Summary:
Epidemiology
The reported prevalence is 1/50,000; however, epidemiological studies are lacking.
Clinical description
Nail-patella syndrome (NPS) is a multisystemic disorder characterized by significant inter- and intrafamilial variability in clinical manifestations and severity of the disease. Cases can range from mild with no functional impact to severe leading to disability. The classical tetrad involves nails dysplasia, absent or hypoplastic patellae, presence of iliac horns, and elbow deformities. Adults can have a slight lower bone mineral density of the hip and spine (8 -20%) leading to a higher risk of fractures and scoliosis. Glaucoma and ocular hypertension have been described in NPS patients and may require early ophthalmological screening. Renal complications are reported in 30-60% of the cases. Other extraskeletal abnormalities described are loss of the normal skin creases over the distal interphalangeal joints and, neurological symptoms such as numbness, tingling and neuropathic pain.
Etiology
NPS is an autosomal-dominant disorder and the majority of the cases are caused by LMX1B mutations (9q33.3) leading to loss of function of the LMX1B protein. About 10% are caused by a de novo pathogenic variant.
Diagnostic methods
The diagnosis is based on clinical findings. Molecular test can identified the LMX1B gene mutations in around 95% of the cases, thus helping to confirm the clinical diagnosis or cases where clinical signs and symptoms are not clear.
Differential diagnosis
As patients with NPS may present a broad phenotypic spectrum, differential diagnosis may be necessary, as the association of systemic and musculoskeletal findings may also occur in other genetic syndromes including Coffin-Siris, Meier-Gorlin, Genitopatellar, RAPADILINO, DOORS, and coxopodopatellar syndrome.
Antenatal diagnosis
Prenatal diagnosis is possibile when there is a positive familiar history for the disorder. Some skeletal signs (ie, talipes equinovarus or large iliac horns) may be identified on fetal ultrasound examination in the third trimester of pregnancy. When the disease-causative variant is found in the affected individual of the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Genetic counseling
NPS is inherited in an autosomal dominant manner. Each child of an NPS affected individual has a 50% chance of inheriting the LMX1B pathogenic variant of the disease. The penetrance of the disease is complete, but the clinical expression is variable even in individuals of the same family. About 90% of NPS patients have an affected parent. In NPS, somatic and germline mosaicism has been reported in unaffected parents.
Management and treatment
The management and treatment is focused on the clinical manifestations, which may require a multidisciplinary team. Joint limitations or anatomical abnormalities may need surgical treatment. Early ocular and renal screening may be helpful and a medical follow up can be required if any alteration is identified. Pain management is important and physical and pharmacological options are available.
Prognosis
Patients with NPS live a normal lifespan. The renal pathology is a major determinant of the prognosis, as proteinuria, hypertension, and hematuria occur in 30 - 60% of the patients; 5 % progress to chronic renal failure.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Luca SANGIORGI | ERN BOND*

                                * European Reference Network


A rare genetic glomerular disease characterized by variably severe nephropathy with microscopic hematuria and proteinuria, in the absence of nail and bone abnormalities. Characteristic ultrastructural findings are irregular thickening and moth-eaten appearance of the glomerular basement membrane with focal deposition of type III collagen fibrils.


Nance-Horan syndrome (NHS) is characterized by the association in male patients of congenital cataracts with microcornea, dental anomalies and facial dysmorphism.

Summary:
Epidemiology
Prevalence is unknown. NHS is a rare but probably underdiagnosed disorder; 36 families have been reported in the literature.
Clinical description
The ocular problem consists of congenital cataract (100% of cases), bilateral, usually severe, dense and most often total, associated with microcornea (96%), or even microphthalmia. In 93% of the cases, it is responsible for severe visual impairment evidenced by nystagmus (93%), sometimes associated with strabismus (43%). Dental abnormalities, although easily overlooked, are nearly constant, involve permanent and deciduous teeth and are of high diagnostic value. The most frequent are diastema, supernumerary incisors or posterior teeth, which are often impacted, and shape abnormalities (the most typical being screwdriver-shaped teeth). Facial dysmorphism is frequent and characterized by a long face, prognathism, a large nose, with a high nasal bridge, and large often protruding ears. Intellectual impairment is observed in about 30% of cases with inter- and intrafamilial variability. It is usually mild or moderate (80%), without motor delay, but in 20% of cases it is severe/profound and associated with autistic features. In heterozygote females, clinical manifestations are identical to those of affected males but they are attenuated and often limited to infraclinical findings.
Etiology
Causative mutations have been identified in the NHS gene (localized to Xp22.2) and typically result in a truncated protein. The differential expression of two NHS isoforms, NHS-A and NHS-1A, and differences in the subcellular localization of these isoforms may partly explain the various clinical manifestations.
Diagnostic methods
Diagnosis is based on clinical findings as there is no biological marker. The recognition of dental abnormalities requires careful physical and radiological dental examination.
Differential diagnosis
Differential diagnosis includes: X-linked microphthalmia, Lenz syndrome, Oculo-facio-cardio-dental (OFCD) syndrome, and Oculo-cerebro-renal (Lowe) syndrome (see these terms).
Antenatal diagnosis
Molecular study may be performed for the purpose of genetic counseling and antenatal diagnosis.
Genetic counseling
NHS is a genetic condition with X-linked semi-dominant transmission and high penetrance in heterozygote females.
Management and treatment
Ocular abnormalities usually require surgery for cataract extraction although the results are poor. Complications (glaucoma, retinal detachment, etc) are treated medically or surgically depending on the type and severity. The ocular problem requires education appropriate for the degree of visual handicap and often necessitates education in a special school for the visually impaired. Dental anomalies may require orthodontic treatment. Intellectual impairment requires special education.

                            Last update:
                            September 2007

                            - Expert reviewer(s):
                            Pr Annick TOUTAIN


A rare ophthalmic disease and a severe form of microphthalmia (small eye phenotype) characterized by a small eye with a short axial length, severe hyperopia, an elevated lens/eye ratio, and a high incidence of angle-closure glaucoma.

Summary:
Epidemiology
The exact prevalence of nanophthalmos is unknown but is likely to be below 1/2,000. However, the prevalence is higher among consanguineous populations.
Clinical description
The disease occurs neonatally or during infancy. Typical clinical signs include an axial length inferior to 20 mm, a lens/eye ratio 4 to 8 times greater than normal, thickened and abnormally dense sclera, a thickened lens and choroids, and severe hyperopia (+7.00 D to +13.00 D). Despite its small size, the functionality and organization of the eye are preserved. Nanophthalmos is generally bilateral. Strabismus is present in most patients. The association of nanophthalmos and pigmentary retinopathy or Best disease has been reported. The condition can be simple (occurring in isolation), complex (associated with other malformations such as colobomas, anterior segment dysgenesis, and lens and posterior segment abnormalities) or syndromic (as part of a rare syndrome).
Etiology
To date, five genes have been associated with the disease : MFRP (11q23.3, coding for a frizzled protein playing a role in the regulation of cell growth, differentiation and polarity during development), TMEM98 (17q11.2, coding for an ubiquitous protein which could be involved in the scleral pathologic thickening and secondary glaucoma development in the disease), PRSS56 (2q37.1, the exact physiopathological mechanism is unknown), BEST1 (11q12.3, involved for example in the development of angle-closure glaucoma) and CRB1 (1q31.3, coding for a protein essential for the neuronal development of the retina). Other loci are also associated with nanophthalmos.
Diagnostic methods
Diagnosis is based on clinical findings and ophthalmologic examinations involving ocular biometry, ultrasonography, as well as corneal diameter and intraocular pressure measurements.
Differential diagnosis
Nanophthalmos should be differentiated from posterior microphthalmos.
Genetic counseling
The disease may be inherited as an autosomal dominant or recessive trait. It can also occur sporadically.
Management and treatment
Treatment may include surgery (iridotomy, iridoplasty, glaucoma filtering surgery, and lens extraction), but side effects (malignant glaucoma, uveal effusion, nonrhegmatogenous retinal detachment and expulsive hemorrhage) may occur. Complications can be prevented by performing a sclerectomy before any intraocular intervention.
Prognosis
Angle-closure glaucoma is a constant finding in patients with nanophthalmia but the prognosis is favorable if this manifestation is correctly managed.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Alain BRON  - Pr Paul FOSTER


A rare neurologic disease characterized by excessive daytime sleepiness associated with uncontrollable sleep urges and cataplexy (sudden loss of muscle tone while awake, often triggered by pleasant emotions).

Summary:
Epidemiology
Narcolepsy type 1 prevalence is estimated between 1/2,000 and 1/5,000.
Clinical description
The age of onset varies between 10 and 30 years old and symptoms are lifelong. The average time between the age of appearance of the symptoms and the diagnosis is still very long, 10 years. Other, non specific, clinical signs include hypnagogic hallucinations, sleep paralysis, disturbed nocturnal sleep, and weight gain, especially in children.
Etiology
The disease is due to loss or impairment of the orexin/hypocretin neurons of the lateral hypothalamus that results in decreased hypocretin-1 levels in the cerebrospinal fluid. An autoimmune origin for the disease is highly suspected, particularly environmental factors interacting with susceptibility genes (more than 98% of the patients carry the HLA-DQB1*0602 allele); however, this is unproven.
Diagnostic methods
Definitive diagnosis requires the presence of clinical symptoms, characteristic polysomnography findings and/or low hypocretin-1 levels in cerebral spinal fluid. Nocturnal and daytime polysomnography demonstrate an average sleep latency of under eight minutes with at least two sleep onset rapid eye movement periods (SOREMP) on multiple sleep latency tests. The presence of low hypocretin-1 levels (<110 pg/ml) in the cerebrospinal fluid can confirm the diagnosis with an excellent sensibility and specificity.
Differential diagnosis
Cataplexy must be typical to be confident with the diagnosis. In absence of typical cataplexy, other causes of sleepiness must be considered, such as chronic insufficient sleep, idiopathic hypersomnia or narcolepsy without cataplexy, now called narcolepsy type 2.
Genetic counseling
Rare familial cases have been reported (<2%); however the mode of inheritance is unclear.
Management and treatment
Treatment is nowadays only symptomatic, as the loss of orexin neurons is irreversible. It comprises stimulants (modafinil, methylphenidate, amphetamine, pitolisant, solriamfetol), anticataplectic drugs (antidepressants) or sodium oxybate. First-line treatment of diurnal sleepiness is often with modafinil but it can be also with pitolisant or sodium oxybate. Second-line treatments are methylphenidate, solriamfetol or amphetamines. Sodium oxybate is efficient for sleepiness, cataplexy and disturbed nocturnal sleep. A good sleep hygiene is always recommended, with scheduled short naps, and regular sleep habits.
Prognosis
Narcolepsy can severely disable scholarly and professional performances. The evolution of the disease is often stable with a frequent improvement of sleepiness and cataplexy, but with age there is an aggravation of the poor quality of night sleep.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Lucie BARATEAU  - Pr Yves DAUVILLIERS