A rare, genetic, disease that manifests in childhood or early adolescence with a combination of chronic mucocutaneous candidiasis, hypoparathyroidism and autoimmune adrenal failure.

Summary:
Epidemiology
It is a rare disease that is more common in populations with higher rates of consanguineous marriage and, because of a founder effect, in Finland where the prevalence is estimated at 1/25,000. In the north-west of France the prevalence is estimated at 1/500,000.
Clinical description
The first manifestation of the disease (usually candidiasis) occurs in childhood with other manifestations appearing progressively. Candidiasis affects particularly the mucosa of the mouth, nails and, more rarely, the genitals, and rarely causes cutaneous effects. The most common autoimmune endocrine involvement is hypoparathyroidism (79-96% of cases). Adrenal failure most often manifests with concurrent mineralocorticoid and glucocorticoid deficiency (78% of cases). Ovarian failure is possible. Diabetes type 1, autoimmune thyroiditis, and lymphocytic hypophysitis are rarer. Other auto-immune manifestations are common: intestinal malabsorption, atrophic gastritis, autoimmune hepatitis, alopecia, vitiligo, hypoplasia of dental enamel, ungual dystrophy, keratoconjunctivitis, and rheumatologic, bony, muscular, renal, bronchiol and hematologic impairments. Splenic atrophy increases the likelihood for severe infections. There is high phenotypic variability, sometimes within the same family, and the number of manifestations is very variable, ranging from 1 to 10.
Etiology
The disease is caused by mutations of the AIRE gene (21q22.3) coding for the AIRE transcription factor, which is involved in immune tolerance mechanisms and contributes to the negative selection of autoreactive T lymphocytes in the thymus, lymph nodes and spleen.
Diagnostic methods
Diagnosis is based on the presence of at least two of the three following pathologies: mucocutaneous candidiasis, hypoparathyroidism and adrenal failure. In cases where one of the patient's siblings is affected, one of the three criteria is sufficient for initial diagnosis, which can then be confirmed by molecular analysis. The presence of a litany of antibodies, specifically organ antibodies (sometimes forewarning of a visceral attack) or more general antibodies (anti-interferon AC) can support the diagnosis.
Differential diagnosis
Differential diagnoses include IPEX syndrome and, principally, autoimmune polyendocrinopathy type 2 (see these terms).
Genetic counseling
Transmission is autosomal recessive. Although prenatal diagnosis is not recommended, genetic counseling should be offered.
Management and treatment
Management is essentially symptomatic. Hormone replacement is used to treat endocrine disorders. A long course of oral systemic antifungal treatment is effective to treat candidiasis, although some patients remain resistant. Immunosuppressive treatment is recommended for cases with autoimmune hepatitis or with severe malabsorption.
Prognosis
The prognosis is variable. The more early the manifestations appear, the more numerous the organs involved. The prognosis can be threatened by: oral or esophageal squamous cell carcinoma, sepsis, fulminant hepatitis, renal failure due to interstitial nephritis or bronchial involvement. On average patients live into their forties, but this varies considerably between patients depending on the severity of disorders.

                            Last update:
                            February 2009

                            - Expert reviewer(s):
                            Dr Emmanuelle PROUST-LEMOINE  - Pr Jean-Louis WEMEAU


A rare, endocrine disease characterized by autoimmune Addison disease associated with autoimmune thyroid disease or type I diabetes mellitus, or both, and without chronic candidiasis. Additional endocrine (hypogonadism, hypoparathyroidism) and non-endocrine diseases (vitiligo, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, and myasthenia gravies) may be present.


A rare, endocrine disease characterized by autoimmune thyroid disease associated with at least one other autoimmune disease, such as type I diabetes mellitus, chronic atrophic gastritis, pernicious anemia, vitiligo, alopecia, or myasthenia gravis, but excluding Addison disease.


A rare autoimmune polyendocrinopathy characterized by autoimmune activity against an endocrine organ in combination with at least one more endocrine or non-endocrine organ. Typical autoimmune diseases occurring in this type include insulin-requiring diabetes, pernicious anemia, alopecia, vitiligo, or myasthenia gravis, but not Addison disease, thyroid disease, or hypoparathyroidism.


A group of rare endocrine diseases characterized by autoimmune activity against more than one endocrine organ, with possible additional involvement of non-endocrine organs. Autoimmunity is typically directed against different target antigens in different tissues. The two more common autoimmune polyendocrine syndromes (APS), APS type 1 and type 2, have a strong genetic background and have Addison's disease as a major feature. The group furthermore includes APS type 3 and type 4.


Autoimmune pulmonary alveolar proteinosis

A rare primary interstitial lung disease characterized by the accumulation of lipids and proteins related to surfactant in the alveoli in association with the presence of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). The disease leads to a progressive impairment of gas exchange and respiratory insufficiency.

Summary:
Epidemiology
The prevalence of autoimmune pulmonary alveolar proteinosis (aPAP) ranges from 1/38,000 in Japan to 1/150,000 in the United States, although the latter figure is likely an underestimate due to underdiagnosis.
Clinical description
Patients are usually 20 to 50 years of age at presentation (although earlier presentation is possible) and onset is mostly gradual. Some patients have very mild or even no clinical manifestations of the disease (one third of cases). The clinical course is variable with some patients spontaneously improving, others remaining stable and a subset progressing in severity. Symptoms may include fatigue, malaise, weight loss, progressive and exertional dyspnea, persistent cough (dry or productive), and chest discomfort. Pulmonary hypertension and hemoptysis are rarely reported. The lower and rear lung regions are most commonly affected. The main complication is chronic respiratory insufficiency with cor pulmonale, lung infections, and more rarely pulmonary fibrosis.
Etiology
GM-CSF is required to stimulate and maintain alveolar macrophage differentiation and function, particularly to catabolize and remove surfactant from the alveolar space. Dysfunction of GM-CSF signaling mediated by GM-CSF autoantibodies results in abnormal surfactant accumulation, leading to the clinical respiratory manifestations of the disease. Dust and fume inhalation also seem to be associated with the development of aPAP. A large proportion of patients have a history of smoking.
Diagnostic methods
The disease is generally suspected on the basis of the clinical signs and disease history. High resolution computed tomography with crazy-paving pattern is supportive. Bronchoalveolar lavage (BAL) is the primary diagnostic method on suspicion of the disorder. Positive periodic acid-Schiff (PAS) staining on BAL is required for diagnosis. In serum, elevated autoantibody concentrations against GM-CSF confirms diagnosis. Transbronchial lung biopsy shows alveoli filled with non-foamy surfactant. Surgical lung biopsy is rarely required to confirm diagnosis. Chest X-ray is useful as follow-up investigation.
Differential diagnosis
Differential diagnoses include alveolar filling syndromes, like diffuse alveolar hemorrhage and lung edema, as well as infectious diseases (pneumocystis jrovecii pneumonia) and lung cancer.
Management and treatment
Treatment depends on the severity of the clinical manifestations. Whole-lung lavage to remove lipoproteinaceous material from the lungs is the therapy of choice and generally has a good success rate. Inhaled and systemic GM-CSF has proven to be beneficial in up to two-thirds of patients. B-lymphocyte depletion through rituximab administration also seems to be a valid option for aPAP. In particular, the latter treatment is still experimental. Patients with a severe course and respiratory failure may be candidates for lung transplantation.
Prognosis
Prognosis has improved with introduction of whole lung lavage and is now considered excellent in most, but not all cases.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Pr Matthias GRIESE | ERN-LUNG*

                                * European Reference Network


Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

A rare, mixed autoinflammatory and autoimmune syndrome disorder characterized by recurrent neutrophilic blistering skin lesions, arthralgia, ocular inflammation, inflammatory bowel disease, absence of autoantibodies, and mild immunodeficiency manifested by recurrent sinopulmonary infections and deficiency of circulating antibodies. Inflammatory phenotype is not provoked by cold temperatures.


Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis

A rare, genetic, mixed autoinflammatory and autoimmune syndrome characterized by chronic systemic autoinflammation (presenting as recurrent fever in the neonatal or infantile period) and combined immunodeficiency (manifesting as recurrent viral and invasive bacterial infections). Muscular amylopectinosis may be subclinical or be complicated by myopathy/cardiomyopathy.


A rare form of agammaglobulinemia, a primary immunodeficiency disease, and is characterized by variable immune dysfunction with frequent and recurrent bacterial infections and/or chronic diarrhea.

Summary:
Epidemiology
Fewer than 100 cases of autosomal inherited agammaglobulinemia have been reported to date.
Clinical description
Patients with autosomal agammaglobulinemia are not able produce adequate amounts of immunoglobulins (Ig) and are therefore at increased risk of developing infections. They often come to medical attention with a dramatic infection at less than 2 years of age. Sepsis, meningitis, pneumonia with empyema, pyoderma (associated with neutropenia), severe diarrhea and enteroviral infection are common. They are generally healthy between episodes of infection. Age of onset is variable but infections generally develop from six months of age. Common clinical signs include upper respiratory tract infections with otitis and sinusitis, and lower respiratory tract infections with pneumonia and bronchiolitis, as well as gastrointestinal tract infections such as gastroenteritis. Less common manifestations include sepsis, meningitis, septic arthritis, osteomyelitis, and pyoderma. Severe bacterial infections with lung or CNS involvement may cause serious morbidity or be life-threatening. Associated autoimmune disorders and neurological complications are also found in some cases.
Etiology
The disorder is due to mutations in various genes involved in humoral immunity, including: IGHM (14q32.33), BLNK (10q23.2-q23.33), CD79A (19q13.2), CD79B (17q23), IGLL1 (22q11.23), PIK3R1 (5q13.1) and TCF3 (19p13.3) Common causative microorganisms include Streptococcus pneumonia, Haemophilus influenza, Staphylococcus aureus, Salmonella spp and Giardia spp and enterovirus.
Diagnostic methods
Diagnosis is suspected on the basis of early susceptibility to severe recurrent or persistent infections. particularly if the parents are consanguineous or belong to an isolated population. Abnormal laboratory parameters include low immunoglobulin levels and low or absent peripheral blood mature B lymphocyte counts. Molecular genetic testing should be performed to determine the genetic defect and to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include X-linked agammaglobulinemia in male patients, myelodysplasia or congenital infections.
Genetic counseling
In patients with this form of agammaglobulinemia, autosomal recessive transmission is more common than autosomal dominant transmission. Genetic counseling should be provided to affected families.
Management and treatment
There is no curative treatment but good disease control can be achieved through consistent gammaglobulin therapy. This can be given intravenously (400-600 mg/kg every 3 to 4 weeks) or subcutaneously (100 mg/kg every week). Therapy should be started as early as possible. Some immunologists advocate chronic prophylactic antibiotics and treatment of acute infections should be prolonged and at maximal doses of antibiotics.
Prognosis
The prognosis depends on the age at diagnosis, compliance with therapy and the development of complications. Most patients on treatment can lead a normal life.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                            Dr Marie Ellen CONLEY


Autosomal dominant adult-onset proximal spinal muscular atrophy

A rare, genetic, motor neuron disease characterized by adulthood-onset of slowly progressive, proximal muscular weakness with fasciculations, amyotrophy, cramps, and absent/hypoactive reflexes, without bulbar or pyramidal involvement.


Autosomal dominant aplasia and myelodysplasia

A rare, genetic, hematologic disorder characterized by bone marrow failure which manifests with aplastic anemia and/or myelodysplasia, associated with hearing/ear abnormalities (such as deafness, labyrinthitis), inherited in an autosomal dominant manner.


A relatively severe form of brachyolmia, a group of rare genetic skeletal disorders, characterized by short-trunked short stature, platyspondyly and kyphoscoliosis. Degenerative joint disease (osteoarthropathy) in the spine, large joints and interphalangeal joints becomes manifest in adulthood.

Summary:
Epidemiology
The precise prevalence of this form of brachyolmia is not known. About 30 cases have been reported.
Clinical description
Patients with Brachyolmia type 3 generally have a normal birth weight and length. Affected individuals present with moderately short trunk/short stature and mildly short limbs in childhood. Kyphoscoliosis is common and sometimes severe. Adult patients develop degenerative joint disease in the spine, large joints and small joints of the hands and feet, which may cause significant musculoskeletal morbidity, such as chronic pain in the extremities and spine, and paresthesia. Final adult height is reported to be 155-168 cm (males) and 136-150 cm (females). The radiographic features include severe platyspondyly particularly in the cervical spine, elongated vertebral bodies (overfaced pedicles), broad ilia, and mild metaphyseal irregularity in the proximal femora. Carpal ossification may be mildly delayed, and mild brachydactyly may exist.
Etiology
Heterozygous mutations in the TRPV4 gene (12q24.11) are responsible for autosomal dominant brachyolmia. TRPV4 mutations are associated with other skeletal dysplasias, including lethal and nonlethal metatropic dysplasia, spondyloepiphyseal dysplasia Maroteaux type, and spondylometaphyseal dysplasia Kozlowski type (see these terms). Autosomal dominant brachyolmia falls into the mildest end of the TRPV4-associated skeletal dysplasia group. TRPV4 encodes a Ca-permeable, non-selective cation channel that participates in the regulation of osmotic sensitivity and mechanosensitivity. It remains to be explained how dysregulation of the cation channel causes the skeletal abnormalities.
Genetic counseling
Genetic counseling should be provided to affected families, in consideration of the autosomal dominant mode of inheritance.

                            Last update:
                            March 2015

                            - Expert reviewer(s):
                            Dr Gen NISHIMURA


Autosomal dominant centronuclear myopathy

A rare, autosomal dominant congenital myopathy characterized by numerous centrally placed nuclei on muscle biopsy and clinical features of a congenital myopathy (hypotonia, distal/proximal muscle weakness, rib cage deformities (sometimes associated with respiratory insufficiency), ptosis, ophthalmoparesis and weakness of the muscles of facial expression with dysmorphic facial features.

Summary:
Epidemiology
The exact prevalence remains unknown.
Clinical description
The age of onset is typically in adolescence, although earlier (neonatal to childhood) and later presentations have been reported. Muscle weakness of variable severity is the major clinical manifestation. Distal muscle involvement, particularly in the lower limb, may precede more proximal weakness; the latter finding corresponds to a sequential pattern of involvement on muscle magnetic resonance imaging (MRI) with early involvement of the ankle plantarflexors, namely the medial gastrocnemius, followed by signal changes in the posterior and, eventually, anterior compartment of the thighs. Marked ocular involvement including ptosis and ophthalmoparesis are common, whilst contractures other than those affecting the Achilles tendon and/or long finger flexors are rare. Cardiorespiratory function has been reported as normal in most cases. Patients with early onset may improve in terms of muscle strength but may develop restrictive respiratory impairment over time. Neuropathic signs (absence of tendon reflexes on neurological examination and fibrillations or reduction of the compound muscle action potential on electrophysiological examination) may be present.
Etiology
The disorder is most commonly caused by mutations in the DNM2 (19p13.2). A geno-phenotype has been reported with mutations in the PH domain associated with disease onset in infancy and early childhood, and mutations in the middle-domain associated with presentation in late childhood or early adulthood. DNM2 mutations also cause Charcot-Marie-Tooth (CMT) disease Type B and CMT2M. Other rare causative genes identified include BIN1 (2q14.3) and CCDC78 (16p13.3), which causes a centronuclear myopathy-like phenotype.
Diagnostic methods
Diagnosis is based on typical histopathological findings in combination with suggestive clinical features, and is confirmed by genetic testing. Histological findings include centrally placed nuclei and type 1 predominance; in addition, hypotrophy oxidative stains may reveal radial distribution of sarcoplasmic strands in fibers with central nuclei. Muscle MRI may aid the diagnosis.
Differential diagnosis
The main differential diagnoses include other congenital myopathies with predominant distal involvement, myotonic dystrophy and, if facial involvement is prominent, fascio-scapulo-humeral dystrophy.
Antenatal diagnosis
Prenatal diagnosis is possible where the mutation has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal dominant. The risk to siblings or offspring of an affected individual inheriting the disease is 50%. Genetic counseling should be offered to all patients and families.
Management and treatment
There is no curative treatment currently available. Management is supportive and based on a multidisciplinary approach.
Prognosis
The disease has usually a slowly progressive course with potential loss of independent ambulation after the sixth decade.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Enrico BERTINI  - Dr Adele D'AMICO  - Pr Fabiana FATTORI


Autosomal dominant cerebellar ataxia type I

A group of spinocerebellar ataxias (SCAs) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement.

Summary:
Epidemiology
The overall prevalence of SCAs is 1/33,000-1/50,000. The prevalence of ADCA (all types) is estimated at 1/37,000 worldwide. The most common ADCA type I is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations.
Clinical description
Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations that include spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric disorders, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated.
Etiology
To date, 27 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12- SCA14, SCA15/SCA16, SCA17- SCA23, SCA25, SCA27, SCA28, SCA32, SCA34- SCA37, autosomal dominant cerebellar ataxia, deafness and narcolepsy, and dentatorubral pallidoluysian atrophy (DRPLA) (see these terms). ADCA type I can be further divided based on the proposed pathogenetic mechanism into 3 subclasses. Subclass 1 includes ADCA type I caused by CAG repeat expansions such as in SCA1-SCA3, SCA17 and DRPLA. Subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12, as well as hexanucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA36. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/SCA16, SCA27- SCA28 and SCA35.
Diagnostic methods
Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases.
Differential diagnosis
Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation.
Genetic counseling
Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics.
Management and treatment
There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential.
Prognosis
Prognosis is variable depending on the type of SCA and even among kindreds.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Zbigniew WSZOLEK


Autosomal dominant cerebellar ataxia type III

A group of neurodegenerative disorders characterized by mostly pure cerebellar syndromes with occasional non-cerebellar signs (e.g. pyramidal signs, peripheral neuropathy, writer's cramp) and includes spinocerebellar ataxia (SCA) type 5 (SCA5), SCA6, SCA11, SCA26, SCA30, and SCA31.

Summary:
Epidemiology
The prevalence is unknown but varies within populations and between geographical locations. SCA6 is the most common form of this group with an estimated prevalence of less than 1/100,000. SCA31 is the second most common form and is found mainly in Japan while the other forms of ACDA type III are rarer.
Clinical description
Age of onset for these disorders is variable but is usually in adulthood. This group of disorders is characterized by mainly pure cerebellar signs such as dysarthria and gait and limb ataxia (starting with difficulty walking and loss of balance/coordination and progressing to loss of mobility and dysphagia). A spectrum of oculomotor dysfunction is also present in most patients and can include nystagmus as well as impaired vestibulo-ocular reflex and smooth pursuit. Non-cerebellar signs are less common but can include pyramidal signs (SCA11), peripheral neuropathy (SCA6), and writer's cramp (SCA5). The vast majority of these diseases have a slowly progressive course.
Etiology
Causal mutations of ACDA type III have been reported in several genes: CACNA1A (19p13) in SCA6, SPTBN2 (11q13.2) in SCA5, TTBK2 (15q15.2) in SCA11, EEF2 (19p13.3) in SCA26 and BEAN1 (16q21) in SCA31. The causal gene of SCA30 has not yet been discovered.
Diagnostic methods
Diagnosis is based on characteristic clinical findings, molecular genetic testing and magnetic resonance imaging (MRI) findings. Cerebellar atrophy with Purkinje cell degeneration is the common finding seen in all types of ACDA type III.
Differential diagnosis
Differential diagnosis includes other forms of rare hereditary ataxias, in particular other types of autosomal dominant cerebellar ataxia (see this term).
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation.
Genetic counseling
This group of diseases is inherited in an autosomal dominant manner and genetic counseling is possible.
Management and treatment
There is no cure for ADCA type III and treatment is supportive. Physical and occupational therapy is essential for maintaining activity along with the use of walking aids, canes and wheelchairs when necessary. Computer devices can help patients with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. In those with vertigo, vestibular suppressants may be beneficial. Consultation with an ophthalmologist is recommended and prism glasses can help with nystagmus. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
The majority of patients with ACDA type III eventually become disabled and cannot walk unassisted. Life-expectancy is slightly reduced (average age of death being 65 years or older).

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Zbigniew WSZOLEK


A rare polymorphic disorder, subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1), characterized by ataxia, sensorineural deafness and narcolepsy with cataplexy and dementia.

Summary:
Epidemiology
Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome (ADCA-DN) has been reported in more than 80 patients to date from Sweden, the United States, Italy, Brazil, Belgium, China, New Zealand, UK, Taiwan, Germany, and Canada.
Clinical description
Disease onset usually occurs in adulthood (from the ages of 30-40). Cases have been reported in adolescents. The clinical features include cerebellar ataxia, narcolepsy with cataplexy, sensorineural deafness and dementia including executive dysfunction and global cognitive impairement. Optic atrophy, cataracts, psychosis, depression, sensory neuropathy, pseudobulbar signs, incontinence and limb lymphedema have also been reported but present later in the disease course. Mild brain atrophy with cerebellum involvement is visible with magnetic resonance imaging (MRI).
Etiology
ADCA-DN is caused by a mutation in the DNA methyltransferase (DNMT1) gene located on chromosome 19p13.2. It encodes an enzyme essential for the repression of transcriptional activity in numerous postmitotic cells.
Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing, the finding of a mutation in the DNMT1 gene.
Differential diagnosis
Differential diagnosis includes other types of autosomal dominant cerebellar ataxia (ADCA), and hereditary.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known mutation.
Genetic counseling
ADCA-DN is inherited autosomal dominantly and genetic counseling is possible. Sporadic cases have also been reported. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for ADCA-DN and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity as well as to avoid falls. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.
Prognosis
Disease duration from disease onset to death is estimated to be between 10 to 30 years. Almost all affected individuals survive at least until late 40's.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


A clinically and genetically heterogeneous group of neurodegenerative diseases characterized by a slowly progressive ataxia of gait, stance and limbs, dysarthria and/or oculomotor disorder, due to cerebellar degeneration in the absence of coexisting diseases. The degenerative process can be limited to the cerebellum (ADCA type 3) or may additionally involve the retina (ADCA type 2), optic nerve, ponto-medullary systems, basal ganglia, cerebral cortex, spinal tracts or peripheral nerves (ADCA type 1). In ACDA type 4, a cerebellar syndrome is associated with epilepsy.


Autosomal dominant Charcot-Marie-Tooth disease type 2 due to DGAT2 mutation

A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by childhood onset of slowly progressive distal muscle weakness and atrophy primarily affecting the lower limbs, associated with sensory impairment and ataxia presenting with an unsteady, broad-based gait and frequent falls. Additional signs include decreased deep tendon reflexes and hand tremor.


Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation

A rare form of axonal peripheral sensorimotor neuropathy characterized by classical CMT2 signs and symptoms (progressive weakness and atrophy of distal limb muscles, mild sensory deficits of position, vibration and pain/temperature, pes cavus, and symmetrically absent or reduced muscle and sensory action potentials with relatively preserved nerve conduction velocities in neurophysiological studies) as well as pyramidal tract involvement (spasticity, hyperreflexia). Spasticity and pain may be the presenting symptoms.


Autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation

A rare, axonal hereditary motor and sensory neuropathy characterized by adult onset of slowly progressive distal muscle weakness and atrophy, decreased deep tendon reflexes of lower limbs, and mild distal sensory loss leading to gait difficulties in most patients.


Autosomal dominant Charcot-Marie-Tooth disease type 2 with giant axons

A rare subtype of axonal hereditary motor and sensory neuropathy characterized by distal muscle weakness and atrophy (principally of peroneal muscles) associated with distal sensory loss (tactile, vibration), pes cavus present since infancy or childhood, and axonal swelling with neurofilament accumulation on nerve biopsy. Other features may include hand muscle involvement, hypo/arreflexia, gait disturbances, muscle cramps, toe abnormalities and mild cardiomyopathy.


Autosomal dominant Charcot-Marie-Tooth disease type 2A1

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, presenting with a more prominent muscle weakness in lower than upper limbs and frequent postural tremor.


Autosomal dominant Charcot-Marie-Tooth disease type 2A2

A subtype of Autosomal dominant Charcot-Marie-Tooth disease type 2 characterized by the childhood onset of distal weakness and areflexia (with earlier and more severe involvement of the lower extremities), reduced sensory modalities (primarily pain and temperature sensation), foot deformities, postural tremor, scoliosis and contractures. Optic atrophy, vocal cord palsy with dysphonia, sensorineural hearing loss, spinal cord abnormalities and hydrocephalus have also been reported.


Autosomal dominant Charcot-Marie-Tooth disease type 2B

A severe form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, with onset in the 2nd or 3rd decade, characterized by ulcerations and infections of feet. Symmetric and distal weakness develops mostly in the legs together with a severe symmetric distal sensory loss, tendon reflexes are only reduced at ankles and foot deformities, including pes cavus or planus and hammer toes, appear in childhood.


Autosomal dominant Charcot-Marie-Tooth disease type 2C

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by the association of vocal cord anomalies, impairment of respiratory muscles and sensorineural hearing loss with the distal hands and feet weakness. Onset is between infancy and the 6th decade.


Autosomal dominant Charcot-Marie-Tooth disease type 2D

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by distal weakness primarily and predominantly occurring in the upper limbs and tendon reflexes absent or reduced in the arms and decreased in the legs. Progression is slow.


Autosomal dominant Charcot-Marie-Tooth disease type 2DD

A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by predominantly distal weakness and muscle atrophy, decreased or absent tendon reflexes, and reduced vibratory sensation in the lower and upper extremities. Pes cavus develops in many patients. Additional symptoms like ataxia, tremor, or swallowing difficulties have been reported. Patients usually remain ambulatory even late in the disease. Age of onset ranges from childhood to adulthood, with earlier onset tending to be associated with a more severe disease phenotype.


Autosomal dominant Charcot-Marie-Tooth disease type 2E

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, with onset in the first to 6th decade with a gait anomaly and a leg weakness that reaches the arms secondarily. Tendon reflexes are reduced or absent and, after years, all patients have a pes cavus. Other signs may be present, including hearing loss and postural tremor.


Autosomal dominant Charcot-Marie-Tooth disease type 2F

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by symmetric weakness primarily occurring in the lower limbs (distal muscles in a majority of cases) and reaching the arms only after 5 to 10 years, occasional and predominantly distal sensory loss and reduced tendon reflexes. It presents with gait anomaly between the 1st and 6th decade and early onset is generally associated to a more severe phenotype which may include foot drop.


Autosomal dominant Charcot-Marie-Tooth disease type 2G

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy with onset associated to development of foot deformity and walking difficulties between the 1st and the 8th decades, with a median range in the 2nd one. Weakness and sensory loss involve primarily the legs and ankles tendon reflexes are reduced. This disorder has a slowly progressive course.


Autosomal dominant Charcot-Marie-Tooth disease type 2I

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by a late onset with severe sensory loss (paresthesia and hypoesthesia) associated with distal weakness, mainly of the legs, and absent or reduced deep tendon reflexes.


Autosomal dominant Charcot-Marie-Tooth disease type 2J

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by a relatively late onset, pupillary abnormalities and deafness, in most patients, associated with distal weakness and muscle atrophy.


Autosomal dominant Charcot-Marie-Tooth disease type 2K

An axonal Charcot-Marie-Tooth (CMT) peripheral sensorimotor polyneuropathy.

Summary:
Epidemiology
CMT2K is a rare form of CMT with only three families reported in the literature so far.
Clinical description
It is characterized by a mild phenotype with onset during the second decade of life and very slow progression. Walking ability is retained (one of the reported patients was still able to walk at 70 years of age).
Etiology
CMT2K is caused by mutations in the GDAP1 gene (8q13.3), encoding a protein required for mitochondrial fission. Mutations in the same gene are associated with severe early-onset forms of CMT: CMT4A (an autosomal recessive demyelinating form of CMT4) and CMT4C4 (another autosomal recessive form of CMT4 with an axonal phenotype and an association with vocal cord paralysis; see this term).

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Carmen ESPINÓS  - Pr Francesc PALAU


Autosomal dominant Charcot-Marie-Tooth disease type 2L

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy. In the single family reported to date, CMT2L onset is between 15 and 33 years. Patients present with a symmetric distal weakness of legs and occasionally of the hands, absent or reduced tendon reflexes, distal legs sensory loss and frequently a pes cavus. Progression is slow.


Autosomal dominant Charcot-Marie-Tooth disease type 2M

A form of axonal Charcot-Marie-Tooth disease, a peripheral motor and sensory neuropathy, characterized by congenital pstosis and early cataract associated to a mildly progressive peripheral neuropathy of variable onset from birth to the 6th decade, pes cavus, reduced to absent ankles tendon reflexes and sometimes neutropenia.


Autosomal dominant Charcot-Marie-Tooth disease type 2N

A mild form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by distal legs sensory loss and weakness that can be asymmetric. Tendon reflexes are reduced in the knees and absent in ankles. Progression is slow.


Autosomal dominant Charcot-Marie-Tooth disease type 2O

A rare, genetic, subtype of autosomal dominant Charcot-Marie-Tooth disease type 2 characterized by early childhood-onset of slowly progressive, predominantly distal, lower limb muscle weakness and atrophy, delayed motor development, variable sensory loss, and pes cavus in the presence of normal or near-normal nerve conduction velocities. Additional variable features may include proximal muscle weakness, abnormal gait, arthrogryposis, scoliosis, cognitive impairment, and spasticity.


Autosomal dominant Charcot-Marie-Tooth disease type 2Q

A rare subtype of autosomal dominant Charcot-Marie-Tooth disease type 2, characterized by adolescent to adulthood-onset of symmetrical, slowly progressive distal muscle weakness and atrophy (with a predominant weakness of the distal lower limbs) associated with reduced or absent deep tendon reflexes, pes cavus and mild to moderated deep sensory impairment.


Autosomal dominant Charcot-Marie-Tooth disease type 2U

A subtype of autosomal dominant Charcot-Marie-Tooth disease type 2, characterized by late adult-onset (50-60 years of age) of slowly progressive, axonal, peripheral sensorimotor neuropathy resulting in distal upper limb and proximal and distal lower limb muscle weakness and atrophy, in conjunction with distal, panmodal sensory impairment in upper and lower limbs. Tendon reflexes are reduced and nerve conduction velocities range from reduced to absent. Neuropathic pain has also been associated.


Autosomal dominant Charcot-Marie-Tooth disease type 2V

A rare, axonal hereditary motor and sensory neuropathy characterized by adult onset of recurrent pain in legs with or without cramps, progressive loss of deep tendon reflexes and vibration sense, paresthesias in the feet and later in the hands. Patients often experience sleep disturbances and mild sensory ataxia.


Autosomal dominant Charcot-Marie-Tooth disease type 2W

A rare predominantly axonal hereditary motor and sensory neuropathy characterized by a broad phenotypic spectrum of slowly progressive signs and symptoms mainly affecting the lower limbs. Most patients present with gait difficulties and distal sensory impairment, while some may lack sensory symptoms altogether. Pes cavus is frequently reported. Age of onset is also highly variable, ranging from childhood to late adulthood.


Autosomal dominant Charcot-Marie-Tooth disease type 2Y

A rare, axonal hereditary motor and sensory neuropathy characterized by progressive distal muscle weakness and atrophy of variable onset and severity. Patients present with postural instability, gait and running difficulties, decreased deep tendon reflexes, foot deformities, fine motor impairment, and distal sensory impairment. Dysarthria, dysphagia, and mild cognitive and behavioral abnormalities have also been reported.


Autosomal dominant Charcot-Marie-Tooth disease type 2Z

A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by early onset of generalized hypotonia and weakness, or later onset of distal lower limb muscle weakness and atrophy, cramps, and sensory impairment. Weakness and atrophy progress in an asymmetric fashion to involve also the proximal and upper limbs in the course of the disease. Additional features are pyramidal signs like increased muscle tone and extensor plantar reflexes, as well as learning difficulties.


Autosomal dominant childhood-onset proximal spinal muscular atrophy

A rare genetic neuromuscular disease characterized by early onset muscular weakness with predominant proximal lower limb involvement. The disorder is static or only mildly progressive. The severity of manifestations ranges from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features.


Autosomal dominant congenital benign spinal muscular atrophy

A rare distal hereditary motor neuropathy, with a variable clinical phenotype, typically characterized by congenital, non-progressive, predominantly distal, lower limb muscle weakness and atrophy and congenital (or early-onset) flexion contractures of the hip, knee and ankle joints. Reduced or absent lower limb deep tendon reflexes, skeletal anomalies (bilateral talipes equinovarus, scoliosis, kyphoscoliosis, lumbar hyperlordisis), late ambulation, waddling gait, joint hyperlaxity and/or bladder and bowel dysfuntion are usually also associated.


A rare connective tissue disorder characterized by wrinkled, redundant and sagging inelastic skin associated in some cases with internal organ involvement.

Summary:
Epidemiology
The prevalence of ADCL is unknown but less than 50 cases have been reported in the literature so far.
Clinical description
Patients are usually diagnosed at birth or in early childhood due to the presence of excessive skin folds and loose, redundant skin. ADCL is considered to be a mild form of cutis laxa with limited systemic involvement although associated features may include hernias, cardiac valve anomalies (redundant mitral and tricuspid valves), cardiovascular manifestations (pulmonary stenosis and aortic and arterial dilatation and tortuosity), gastrointestinal diverticuli and emphysema.
Etiology
ADCL is genetically heterogeneous: mutations in the elastin gene (ELN; 7q11.1-q21.1) have been reported in some cases, whereas mutations in the gene encoding fibulin-5 (FBLN5; 14q31) have been identified in others. Homozygous mutations in the FBLN5 are associated with the more severe form of CL with extensive systemic involvement, autosomal recessive CL type 1 (ARCL1; see this term).
Diagnostic methods
Diagnosis is based on clinical examination, family history and pathognomonic histological findings (sparse, fragmented elastic fibers) on skin biopsies. Molecular testing may allow confirmation of the diagnosis.
Differential diagnosis
The differential diagnosis may include other forms of CL (ARC1 and ARCL2, and X-linked CL) and related syndromes (gerodermia osteodysplastica, wrinkly skin syndrome and De Barsy syndrome), together with the Ehlers-Danlos syndromes, Cantu syndrome and Costello syndrome (see these terms).
Genetic counseling
Genetic counseling should be provided to affected families and prenatal diagnosis may be feasible for families in which the disease-causing mutation has been identified.
Management and treatment
There is no specific treatment for cutis laxa. Management should include symptomatic treatment of any associated manifestations. ADCL is generally a mild cutaneous disease and internal organ involvement is rare.
Prognosis
Most patients have a good prognosis and life expectancy is usually normal.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS


Autosomal dominant deafness-onychodystrophy syndrome

A rare multiple congenital anomalies syndrome characterized by congenital hearing impairment, small or absent nails on the hands and feet, and small or absent terminal phalanges.

Summary:
Epidemiology
The prevalence is unknown but it has been reported in 22 individuals from ten families to date.
Clinical description
The main clinical characteristics of dominant deafness-onychodystrophy (DDOD) syndrome are severe sensorineural hearing loss or deafness and onychodystrophy (small or absent fingernails and toenails, sometimes limited to the nails of the first and fifth digits). Brachydactyly, long, finger-like or tri-phalangeal thumbs as well as conical, hypoplastic teeth or oligodontia have also been reported in several patients. Syndactyly, minor facial dysmorphism (mild hypotelorism, deep set eyes and midface hypoplasia), and epilepsy have been seen in individual cases. Unlike DOORS syndrome, most patients with DDOD follow a normal development and have normal intelligence.
Etiology
DDOD syndrome is caused, in some cases, by heterozygous mutations in the ATP6V1B2 gene (8p21.3) encoding a vacuolar ATPase (V-ATPase) involved in protein translocation. It is at present unknown whether there can be genetic heterogeneity or not, as not all known families have been tested.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical findings. X-rays of the hands and feet and a brain stem auditory evoked response (BAER) test for hearing loss should be performed. Molecular genetic testing identifying a ATP6V1B2 mutation may confirm the diagnosis but as it is at present uncertain whether DDOD syndrome is genetically heterogeneous, the absence of a mutation will not mean that a diagnosis of DDOD syndrome is incorrect.
Differential diagnosis
The main differential diagnosis is DOORS syndrome and Coffin-Siris syndrome. The limb anomalies seen in DDOD syndrome can also be found in several other entities including Zimmermann-Laband syndrome, Adams-Oliver syndrome, Temple-Baraitser syndrome and Fontaine Progeroid Syndrome.
Antenatal diagnosis
Prenatal diagnosis of DDOD syndrome has not been performed to date.
Genetic counseling
DDOD syndrome is inherited autosomal dominantly so if the clinical diagnosis has been established reliably, genetic counseling is possible. In this case, affected families should be informed that risk of transmission from an affected parent to offspring is 50%.
Management and treatment
Treatment is supportive and involves special education for the hearing impaired as well as regular follow-up. Corrective surgery is in principle possible for those with syndactyly, although generally not necessary.
Prognosis
The disease is not life threatening. The main influence on quality of life is hearing loss.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Philippe CAMPEAU


Autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome

A rare genetic neuromuscular disease characterized by length-dependent axonal motor neuropathy predominantly affecting the lower limbs, in combination with a myopathy with morphological features of myofibrillar myopathy with aggregates and rimmed vacuoles. Age of onset is typically in the second to third decade of life. Patients present with slowly progressive muscle weakness and atrophy initially affecting the distal lower limbs and later progressing to involve proximal limbs and also truncal muscles. There is no involvement of respiratory and cardiac muscles.


Autosomal dominant distal renal tubular acidosis

A rare autosomal dominant form of distal renal tubular acidosis characterized by hyperchloremic metabolic acidosis often but not always associated with hypokalemia. Disease onset is in adolescence or adulthood and initial manifestations can include polyuria, polydipsia, muscle weakness and fatigue. Osteomalacia or osteopenia, hypercalciuria, nephrolithiasis and nephrocalcinosis may also develop. Renal failure has not been described.


Autosomal dominant dopa-responsive dystonia

A rare neurometabolic disorder characterized by childhood-onset dystonia that shows a dramatic and sustained response to low doses of levodopa (L-dopa) and that may be associated with parkinsonism at an older age.

Summary:
Epidemiology
The estimated European prevalence of dopa-responsive dystonia (DRD) ranges from 1/1,000,000-1/200,000. DYT5a occurs more frequently than autosomal recessive DRD (DYT5b).
Clinical description
Onset usually occurs in childhood (average age 6 years), and females are 2-4 times more likely to suffer from this disease than males. At onset, DYT5a is typically characterized by lower limb dystonia, most commonly with flexion-inversion of the foot (equinovarus posture) resulting in gait disturbances (that can result in stumbling and falling) with diurnal fluctuations, with symptoms worsening in the evening and improving after sleep. Physical exercise may also aggravate the symptoms. Rarely, arm dystonia, postural tremor of the hands, slowness of movements (bradykinesia) or cervical dystonia are presenting symptoms. In many patients, brisk deep-tendon reflexes and/or dystonic extension of the big toe (striatal toe) are obvious at examination. The disease usually progresses to generalized dystonia, and some patients, especially those with onset in adolescence or adulthood, also develop parkinsonism (manifesting with bradykinesia, rigidity and mainly postural tremor). There is no effect on cognitive or intellectual functioning. Patients with a later disease onset have a milder phenotype. In rare cases depression, anxiety, sleep disturbances and obsessive-compulsive disorder have been reported. Without treatment, adults may suffer from limb contractures.
Etiology
DYT5a is caused by mutations in the GCH1 gene (14q22.1-q22.2), encoding the enzyme GTP cyclohydrolase 1 (GTPCH1). This enzyme is essential in the biosyntheisis of tetrahydrobiopterin (the essential co-factor for tyrosine hydroxylase), which is the rate-limiting enzyme in the biosynthesis of dopamine.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical symptoms and the dramatic and sustained improvement of symptoms with the administration of low doses of oral L-dopa. Reduced levels of both total biopterin and neopterin in cerebrospinal fluid (CSF) are typically found in DYT5a patients. Reduced GTPCH1 activity in blood cells is also noted. Molecular genetic testing can identify a mutation in the GCH1 gene.
Differential diagnosis
Differential diagnoses include other forms of DRD (e.g. autosomal recessive DRD), early onset torsion dystonia, myoclonic dystonia, hyperphenylalaninemia, hereditary spastic paraplegia, young adult-onset parkinsonism or cerebral palsy.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known GCH1 mutation.
Genetic counseling
DYT5a is inherited in an autosomal dominant manner, but due to gender-based incomplete penetrance, not everyone with a mutation will display the disease phenotype. Approximately 30-50% of patients with DRD do not report a family history of dystonia. De novo mutations are also possible.
Management and treatment
This form of dystonia shows a dramatic and sustained response to L-dopa therapy. The current suggested initial dosage of L-dopa/decarboxylase inhibitor for children is 25 mg or less, once a day, and in adults 50 mg once or twice a day. These dosages can be increased in small increments if needed, with typical optimal or maximum doses of approximately 10-20 mg/kg/day. If dyskinesia appears after administration of L-dopa, dosage should be decreased. Treatment is life-long, and alleviation of symptoms can usually be noted after a few weeks to a few months.
Prognosis
There is no decrease in life expectancy, and typically there is a complete or almost complete resolution of symptoms with the administration of L-dopa.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


Autosomal dominant epidermolytic ichthyosis

A rare keratinopathic ichthyosis (KPI) characterized by a blistering phenotype at birth which progressively becomes hyperkeratotic.

Summary:
Epidemiology
The prevalence range of all types of KPI is estimated at 1/909,000 in France. The exact worldwide prevalence of epidermolytic ichthyosis (EI) is unknown but is in the 1/2,300,000-4,350,000 range in Japanese and Danish population studies.
Clinical description
Infants present at birth, or shortly after, with erythroderma, mild scaling, severe blistering, and superficial erosions at sites of trauma and flexural areas. Yellow-brown hyperkeratotic plaques, often with mild background erythroderma, develop in the first months of life. The skin has a characteristic dirty looking appearance. Hyperkeratosis has a ridged appearance along skin lines and a cobblestone pattern in the extensor surfaces of joints. It is most often generalized but may be limited to joint flexures, anterior neck, abdominal wall, and infragluteal folds, with relative sparing of the face. Over time, hyperkeratosis worsens and blister formation decreases but may still occur (following skin trauma or during summer). Palmoplantar involvement is seen in some patients and painful blisters tend to develop underneath. Digital contractures and pseudoainhum may occur. Skin is often itchy, smelly, and subject to infections. Other features may include hypohidrosis, scalp scaling, nail dystrophy and abnormal posture. Growth failure may be seen in severe cases. EI persists into adulthood, with hyperkeratosis of variable intensity and extension.
Etiology
The disease is caused by mutations in the genes coding for epidermal suprabasal keratins 1 (KRT1; 12q13.13) and 10 (KRT10; 17q21-q23) that impair keratin intermediate filament formation in the suprabasal keratinocytes. A genotype-phenotype correlation exists, with palmoplantar involvement being generally associated with KRT1, as KRT10 is less expressed in these locations. The position of the mutation may influence the severity of the phenotype
Diagnostic methods
Diagnosis is based on the clinical picture and on histological examination showing hyperkeratosis with orthokeratosis, hypergranulosis, and cytolysis in the upper stratum spinosum and granular layers with characteristic intracellular vacuolization (epidermolytic hyperkeratosis). Electron microscopy shows suprabasal keratinocytes with keratin intermediate filaments clumps and perinuclear keratin clumps in the upper epidermis. Genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis at birth includes other blistering diseases: toxic epidermal necrolysis, inherited epidermolysis bullosa, staphylococcal scalded skin syndrome, incontinentia pigmenti or herpetic infection. In later stages, blistering, ridges along skin lines, and histologic features help to differentiate it from other forms of ichthyoses. Superficial EI usually has a milder phenotype, lacks keratoderma, and has areas with characteristic superficial scaling. Annular epidermolytic ichthyosis is distinguished by the polycyclic and intermittent lesions.
Antenatal diagnosis
Genetic antenatal diagnosis is available.
Genetic counseling
The disease has an autosomal dominant mode of inheritance. Genetic counseling can be offered to affected families when a causing mutation has been identified.
Management and treatment
Treatment is symptomatic. Emollients are often used but have limited efficacy. Topical keratolytics and mechanical removal of scales can improve hyperkeratotic lesions, but may worsen blistering. Some patient, especially those with KRT10 mutation, may benefit from low dose acitretin. Antiseptic washes reduce the bacterial colonization and body odor. Antibiotic therapy is required in cases of bacterial infection.
Prognosis
The severity of the disease is variable. EI impacts the quality of life and social interactions due to skin aspect, pain, walking difficulties, pruritus, body odor, infections, malnutrition and hand contractures. EI can be life-threatening during the neonatal period due to infections and/or dehydration.

                            Last update:
                            February 2023

                            - Expert reviewer(s):
                            Dr Eulalia BASELGA TORRES | ERN-Skin*

                                * European Reference Network


Autosomal dominant epilepsy with auditory features

A rare, genetic, familial partial epilepsy disease characterized by focal seizures associated with prominent ictal auditory symptoms, and/or receptive aphasia, presenting in two or more family members and having a relatively benign evolution.

Summary:
Epidemiology
The prevalence of autosomal dominant epilepsy with auditory features (ADEAF) is unknown but likely to be very low. Fewer than 3% of persons with epilepsy have a significant family history of epilepsy and only a fraction of these have clinical features consistent with ADEAF.
Clinical description
ADEAF usually presents in adolescence or early adulthood (but can range from 4-50 years of age) with the onset of focal epilepsy originating predominantly in the lateral temporal lobe. Seizures may be precipitated by specific sounds (i.e. telephone ringing or speech) but in most cases there are no recognizable triggers. Ictal manifestations include auditory symptoms (such as humming, buzzing, ringing and, less frequently, more complex sounds such as voices, songs or volume changes) and receptive aphasia. Rarely, additional ictal manifestations, such as other sensory symptoms (e.g. visual or olfactory), as well as motor, psychic, and autonomic symptoms, have been reported. In many cases, focal seizures are followed by secondarily generalized seizures (e.g. generalized tonic-clonic seizures), which can manifest with loss of consciousness and convulsions (often during sleep). Disease course is usually benign with patients often being seizure free following treatment with anti-seizure medications.
Etiology
In approximately one-third of cases, ADEAF is caused by mutations in the LGI1 gene (10q23.33), encoding leucine-rich glioma-inactivated protein 1 and mutations in the RELN gene (7q22.1), encoding reelin. These proteins are thought to play key regulatory roles in both the developing and adult brain. In 50% of cases, the etiology is unknown.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical manifestations, a family history suggesting autosomal dominant inheritance, and normal brain imaging studies (using magnetic resonance imaging and computer tomography scans). Epileptiform interictal EEG abnormalities can be present in up to 2/3 of cases. Molecular genetic testing, identifying a causative mutation, confirms diagnosis.
Differential diagnosis
Differential diagnoses include other forms of focal epilepsy, such as autosomal dominant sleep-related hypermotor epilepsy and familial focal epilepsy with variable foci (FFEVF).
Antenatal diagnosis
Prenatal diagnosis is possible if a pathogenic variant has been previously identified in a family member. Variable penetrance is observed. In practice prenatal testing is not usually performed.
Genetic counseling
ADEAF is inherited in an autosomal dominant manner. Genetic counseling should inform parents with a pathogenic variant of the 50% risk of passing it on to their offspring. Due to the reduced and age-dependent penetrance seen in ADEAF, approximately 61% of patients who inherit the pathogenic variant will manifest symptomatology.
Management and treatment
ADEAF is treated with antiepileptic drugs that are routinely used in clinical practice (e.g. carbamazepine, phenytoin, valproate), with seizure control attained in the majority of cases. Evaluation of relatives is important in order to identify those who may be at risk and might benefit from early treatment initiation and/or measures to reduce risk in the event of seizure onset.
Prognosis
Although it is a life-long condition, the prognosis is generally good as ADEAF has a benign course and seizures are usually controlled with medication.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Pr Ruth OTTMAN


Autosomal dominant focal dystonia, DYT25 type

A form of focal dystonia characterized by cervical, laryngeal and hand-forearm dystonia.


Autosomal dominant focal non-epidermolytic palmoplantar keratoderma with plantar blistering

A rare, genetic, isolated, focal palmoplantar keratoderma disease characterized by focal thickening of the skin of the soles, and often of the palms, associated with minimal or no nail involvement. Patients frequently present non-epidermolytic painful plantar blistering and, occasionally, subtle oral leukokeratosis or plantar hyperhidrosis.


Autosomal dominant generalized dystrophic epidermolysis bullosa

A rare dystrophic epidermolysis bullosa (DEB) characterized by generalized blistering, milia formation, atrophic scarring, and dystrophic nails.

Summary:
Epidemiology
The prevalence worldwide is unknown, in the USA prevalence at birth is estimated at 1/5,000,000.
Clinical description
The clinical picture of intermediate dominant dystrophic epidermolysis bullosa (DDEB-intermediate) is generally milder than that of the autosomal recessive generalized DEB forms. DDEB-intermediate manifests usually at birth with the development of blisters, primarily affecting the limbs. Blisters heal by developing numerous milia and atrophic scars with an onion-like appearance, particularly visible on the elbows, knees, and hands. Nail dystrophy, always present, can lead to loss of nail plates. Usually, fingers and toes are not affected by major cicatricial retractions. Blisters can develop in the mucosa, mainly in the oral cavity and, less commonly, in the esophagus, where they can cause strictures, often in sharp contrast with the scarce cutaneous involvement. Dental caries are relatively frequent. Corneal and genitourinary tract involvement, anemia, and growth delay are rare.
Etiology
DDEB-intermediate is caused by mutations in the collagen VII gene (COL7A1; 3p21.31) that lead to an alteration of function or a reduction in the amount of collagen VII. The molecular defect impairs collagen VII assembly into anchoring fibrils which fix the basement membrane to the underlying dermis, causing reduced skin resistance to minor trauma.
Diagnostic methods
Diagnosis is suspected at clinical examination and is confirmed by immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples showing a cleavage plane located below the lamina densa of the cutaneous basement membrane zone. Genetic testing confirms the diagnosis.
Differential diagnosis
The differential diagnosis includes other forms of EB. In the neonatal period, aplasia cutis congenita, herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, linear IgA bullous dermatosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, bullous impetigo, and staphylococcal scalded skin syndrome may need to be considered.
Antenatal diagnosis
Antenatal diagnosis is usually not recommended, but some people who are themselves affected, may request it.
Genetic counseling
Genetic counseling should be offered to all the patients and their parents. The disorder is autosomal dominant and therefore, for each pregnancy there is 50% risk of transmitting the pathogenic variant from an affected individual to offspring.
Management and treatment
Management is preventive: protective padding of the skin and appropriate lifestyle measures reduce blistering, and careful wound care prevents secondary infection and reduces scarring. Oral hygiene is important for the management of caries. When present, esophageal strictures can be treated by balloon dilatation with fluoroscopic guidance. In a minority of patients, a follow-up by a dietitian can be required to evaluate nutritional requirements.
Prognosis
Life expectancy is normal.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin* - Dr Gianluca TADINI | ERN-Skin*

                                * European Reference Network


Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form

Non-Dowling-Meara generalized epidermolysis bullosa simplex, formerly known as epidermolysis bullosa simplex, Köbner type (EBS-K) is a generalized basal subtype of epidermolysis bullosa simplex (EBS, see this term) characterized by non-herpetiform blisters and erosions arising in particular at sites of friction.

Summary:
Epidemiology
Worldwide prevalence is unknown but in Scotland reported overall prevalence of non-Dowling-Meara generalized EBS and localized EBS is 1/35,000.
Clinical description
Onset of the disease is usually at birth. Blistering tendency usually worsens in summertime (or in warm weather). The frequency of milia, mild atrophic scarring, focal plantar hyperkeratosis and nail dystrophy is intermediate between that of localized EBS and EBS-DM (see these terms), and extracutaneous findings, other than occasional intraoral blistering, are rare. Given the considerable overlap between non-Dowling-Meara EBS and localized EBS within some kindreds, some experts prefer to group both subtypes together.
Etiology
Non-Dowling-Meara EBS is caused by dominant negative mutations within either the KRT5 (12q13.13) or KRT14 (17q12-q21) genes, encoding keratin 5 and keratin 14, respectively.
Genetic counseling
Transmission is autosomal dominant and sporadic cases are frequent.
Prognosis
Although the disease can be severely disabling, life-expectancy is normal.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


Autosomal dominant generalized epidermolysis bullosa simplex, severe form

Epidermolysis bullosa simplex, Dowling-Meara type (EBS-DM) is a basal subtype of epidermolysis bullosa simplex (EBS, see this term) characterized by the presence of generalized vesicles and small blisters in grouped or arcuate configuration.

Summary:
Epidemiology
Worldwide prevalence is unknown but reported prevalence in Scotland is 1/1,700,000.
Clinical description
Onset is usually at birth with large, frequently hemorrhagic blisters. After the neonatal period, the lesions take the typical herpetiform (or herpes-like) clustering with central healing pattern. Blister formation gradually reduces starting from late childhood. By childhood, most patients begin to develop confluent thickening and hyperkeratosis (keratoderma) of the palms and soles which may partially resolve in some patients during mid- to late-adulthood. Along with blisters, skin findings commonly include mild atrophic scarring and post-inflammatory pigmentation, nail shedding and nail dystrophy, as well as occasional milia formation. Lesions may improve in some patients in case of fever, unlike other forms of EB in which warmer weather exacerbates disease activity. The reason for this is unknown. Extracutaneous complications can occur including oral cavity blistering, constipation and, rarely, tracheolaryngeal compromise.
Etiology
EBS-DM is caused by dominant negative mutations within either the KRT5 (12q13.13) or KRT14 (17q12-q21) genes, encoding keratin 5 and keratin 14, respectively.
Genetic counseling
Transmission is autosomal dominant and sporadic cases are frequent.
Prognosis
EBS-DM is frequently associated with marked morbidity in infancy and early childhood and, in rare cases, may result in death during early infancy. Patients also have a markedly increased risk of basal cell carcinoma by mid-adulthood (cumulative risk of 44% by age 55).

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency

A very rare primary immunodeficiency disorder characterized by the clinical triad of high serum IgE (>2000 IU/ml), recurring staphylococcal skin abscesses, and recurrent pneumonia with formation of pneumatoceles.

Summary:
Epidemiology
Annual incidence is estimated at around 1/1,000,000. The syndrome affects males and females equally.
Clinical description
AD-HIES typically first manifests with neonatal rash but it affects the immune system, connective tissue, skeleton, and dental development, with variations in severity. Eczema, recurrent skin abscesses, pneumonia with pneumatocele formation, mucocutaneous candidiasis, elevated serum IgE levels, and eosinophilia are the most common features of immune deficiency/dysregulation. Severe recurrent respiratory infections that may lead to chronic respiratory insufficiency are frequent. A distinctive facial appearance is described (rough skin, facial asymmetry, a prominent forehead, deep-set eyes, broad nasal bridge and a fleshy nasal tip, prognathism), along with midline anomalies. Recurrent pathological fractures occur in about 50% of patients (long bones and ribs). Scoliosis of varying degrees of severity is seen in more than 60%. Anomalies of dentinogenesis are a consistent feature. Reduced resorption of primary tooth roots may lead to prolonged retention of primary teeth, which in turn prevents the appropriate eruption of permanent teeth. Vascular features (coronary and aortic aneurysms, thrombosis of the cerebellar artery and congenital patent ductus venosus) have also been reported. Ocular complications may include xanthelasmas, giant chalasias, eyelid nodules, strabismus, and retinal detachment with complicated cataracts. There is also an increased risk of autoimmune and lymphoproliferative diseases.
Etiology
In 70% of patients, the phenotype is associated with heterozygous mutations of the signal transducer and activator of transcription 3 gene (STAT3; 17q21.31). STAT3 plays a key role in the signal transduction of a broad range of cytokines (control of infections caused by fungi and extracellular bacteria). The etiology in the remaining 30% is unknown.
Diagnostic methods
The diagnostic hallmark is increased serum immunoglobulin E (IgE) levels exceeding 2000 U/ml, often higher than 5000 U/ml. A clinical scoring sheet has been defined to assess the probability of diagnosis. Total IgE concentration > 1000 IU/ml and weighted score of clinical features > 30 indicates AD-HIES due to STAT3 deficiency, and a dominant-negative heterozygous mutation in STAT3 provides a definitive diagnosis.
Differential diagnosis
The differential diagnosis should include cystic fibrosis and chronic granulomatous disease (see these terms), as well as severe atopic dermatitis and HIV-infection. A clinically distinct autosomal recessive hyper-IgE syndrome has also been described (AR-HIES; see this term).
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.
Genetic counseling
The majority of AD-HIES cases are caused by de novo mutations and are therefore sporadic but autosomal dominant transmission is characteristic for STAT3 mutations.
Management and treatment
The therapeutic approach involves prevention and management of infections with long-term administration of systemic antibiotics and antifungals. Lung abscesses may require surgery but possible complications require close attention. The role of hematopoietic stem cell transplantation (HSCT) has to be evaluated further.
Prognosis
Although HIES is associated with significant morbidity and mortality, adequate care, close monitoring, and patient compliance improve the prognosis and can lead to survival of 50 years of age or over.

                            Last update:
                            June 2012

                            - Expert reviewer(s):
                            Pr Bodo GRIMBACHER  - Dr Cristina WOELLNER


A form of diazoxide-sensitive diffuse hyperinsulinism (DHI) characterized by hypoglycemic epiosodes that are usually mild, escaping detection during infancy, and usually a good clinical response to diazoxide, (but some are diazoxide resistant). Autosomal dominant hyperinsulinism due to Kir6.2 deficiency usually has a milder phenotype when compared to that resulting from recessive K+ (K-ATP) channel mutations (Recessive forms of diazoxide-resistant hyperinsulinism).


Autosomal dominant hyperinsulinism due to SUR1 deficiency

A form of congenital diazoxide-sensitive diffuse hyperinsulinism due to ABCC8 variants and characterized by hypoglycemic episodes that are usually mild, escaping detection during infancy, and usually have a good clinical response to diazoxide. The autosomal dominant hyperinsulinism usually has a milder phenotype when compared to that resulting from recessive potassium (K-ATP) channel mutations.


A rare disorder of calcium homeostasis characterized by variable degrees of hypocalcemia with disproportionately low/normal levels of parathyroid hormone (PTH) and persistent normal or elevated renal calcium excretion.

Summary:
Epidemiology
Prevalence is unknown, but the disease is likely to be underdiagnosed as the hypocalcemia may remain asymptomatic.
Clinical description
Clinical expression and age of onset are extremely variable (depending on the degree of hypocalcemia), ranging from completely asymptomatic patients (in whom the diagnosis is made by chance during a routine exam) to patients with limited symptoms (cramps, asthenia, paresthesias) and patients with severe symptoms (i.e. recurrent seizures). In addition to hypocalcemia, hypercalciuria or relative hypercalciuria (hypercalciuria within the normal range, but relatively high in the presence of hypocalcemia) is present. Hyperphosphatemia, hypomagnesemia and hypermagnesuria are also common. Nephrocalcinosis and impaired renal function have been reported and cases of autosomal dominant hypocalcemia (ADH) with classical features of Bartter syndrome (BS) have been described (referred to as BS with hypocalcemia). Serum levels of PTH are normal or low. In addition to regulation by PTH, environmental factors also influence calcium homeostasis and may explain why an initially well-controlled hypocalcemia may become symptomatic at various stages of life.
Etiology
ADH is caused by activating mutations of the gene CASR (3q21.1), encoding the calcium-sensing receptor (CaSR). CaSR is expressed by cells in several tissues and plays a key role in the regulation of calcium-phosphate metabolism by controlling PTH secretion and renal calcium excretion in response to variations in serum calcium levels. Gain-of-function CASR mutations result in increased sensitivity of parathyroid and renal cells to calcium levels, leading to hypocalcemia being perceived as normal. Activating mutations in GNA11 (19p13.3) have also been described.
Diagnostic methods
Diagnosis is made through analysis of serum calcium and PTH levels. Molecular analysis of CASR followed by GNA11 confirms diagnosis.
Differential diagnosis
Differential diagnosis includes all other causes of hypoparathyroidism as well as BS in patients with renal salt wasting.
Antenatal diagnosis
Antenatal diagnosis is possible.
Genetic counseling
Genetic counseling may be proposed but patients should be informed about the wide variability in clinical presentation.
Management and treatment
Treatment to normalize calcemia levels should be considered with caution, as any increase in calcium levels (even within the normal range) will be perceived by renal cells as hypercalcemia and lead to increased urinary calcium excretion, with increased risk of nephrocalcinosis and renal failure. Treatment should aim towards finding a balance between the clinical signs of hypocalcemia and (near-)normal serum calcium levels. Urine calcium levels should be monitored in order to avoid hypercalciuria rather than adapting treatment towards hypocalcemia. In asymptomatic and mildly symptomatic patients, treatment may not be necessary. Special care must be given to children as chronic hypocalcemia has deleterious effects on intellectual development. Treatment is based on administration of 1-alpha hydroxylated vitamin D (doses ranging from 0.5 to 1.5 micrograms/day, but higher doses are sometimes required). Careful monitoring of calciuria and regular kidney ultrasound are recommended. In cases where calcium homeostasis is difficult to achieve, exogenous PTH can be attempted.
Prognosis
The prognosis is variable, depending on the severity of the hypocalcemia /hypercalciuria and the possible consequences of treatment. In adults, it is associated with a reduced quality of life.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Pr Lars REJNMARK | Endo-ERN*

                                * European Reference Network


A rare hereditary renal phosphate-wasting disorder characterized by hypophosphatemia, rickets and/or osteomalacia.

Summary:
Epidemiology
Autosomal dominant hypophosphatemic rickets (ADHR) is extremely rare, to date approximately 50 cases have been reported in the literature.
Clinical description
Clinical manifestations depend on the age of onset (childhood, adolescence, even adulthood) and on the severity of hypophosphatemia. During childhood, the disease manifests with signs and symptoms of rickets. When the disease manifests during adolescence or adulthood, clinical findings include bone pain, muscle weakness, and pseudo fractures. Some patients are asymptomatic throughout life, some patients alternate between symptomatic and non-symptomatic.
Etiology
The disease is caused by activating mutations in the FGF23 gene (12p13) encoding fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone. These mutations render FGF23 resistant to cleavage and thus cause an increase in circulating levels. Increased FGF23 levels leads to reduced renal phosphate reabsorption and decreased intestinal phosphate and calcium absorption, consequently leading to abnormal bone mineralization.
Diagnostic methods
Diagnosis is based on clinical findings, and biochemical and X-ray examination. Biochemical findings can include significant hypophosphatemia, hyperphosphaturia (that can disappear with age), elevated circulating levels of FGF23 associated with normal serum levels of calcium, increased plasma levels of alkaline phosphatase. Radiological findings include typical signs of rickets and/or osteomalacia. Molecular genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia (ARHP), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), fibrous dysplasia of bones, renal Fanconi syndrome, vitamin D deficiency, and tumor-induced osteomalacia.
Genetic counseling
Transmission is autosomal dominant with incomplete penetrance.
Management and treatment
Treatment aims at improving growth, bone or joint pain, enhancing mineralization of bones, and preventing skeletal deformities caused by rickets. It consists of daily oral administration of phosphate and calcitriol and is associated with frequent monitoring of height, calcium, alkaline phosphatase, parathyroid hormone, and phosphate serum concentrations, as well as urinary calcium and creatinine. Corrective surgery of skeletal deformities may be required in some cases. Sometimes, nephrocalcinosis and hyperparathyroidism can be observed as complications of the therapy; frequent follow-up is therefore necessary. The efficacy of burosumab (an anti-FGF23 humanized antibody), a recently developed therapy that lowers circulating FGF-23 levels and thus corrects renal phosphate wasting, has not yet been evaluated in ADHR patients.
Prognosis
With treatment, prognosis is very good: growth is normalized and skeletal deformities can be corrected.

                            Last update:
                            August 2022

                            - Expert reviewer(s):
                            Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*

                                * European Reference Network


Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome

A rare genetic neurodevelopmental disorder characterized by global developmental delay (DD) and variable degrees of intellectual disability (ID) with delayed or limited/absent speech development associated with neonatal hypotonia, feeding difficulties, cardiac anomalies and dysmorphic facial features, predominantly broad nasal tip and thin, tented upper lip. Microcephaly, frequent infections, gastrointestinal and/or ocular anomalies have also been described.

Summary:
Epidemiology
About 76 patients are reported in the scientific and medical literature; however, more than 300 are known to patient organizations.
Clinical description
Most patients present with neonatal hypotonia and feeding difficulties, often requiring nasogastric intubation. The developmental delay and intellectual disability are of variable severity. All patients reported presented with language delay/deficits (mostly expressive limitations) and some patients are non-verbal into adulthood. About half of the patients are diagnosed with a cardiac abnormality (atrial septal defects, ventricular septal defect, patent foramen ovale and/or persistent ductus arteriosus). Other frequent problems are gastroesophageal reflux, constipation and eye abnormalities (strabismus, amblyopia and less frequently refractory errors). A facial gestalt might be recognized with a broad nasal tip, thin tented upper lip and bi-temporal narrowing. Microcephaly occurs in a minority of the patients. Other less common features are autism spectrum disorders, sleep disturbances, craniosynostosis, seizures, increased susceptibility to infections, haematological and immunological abnormalities and bowel obstruction.
Etiology
The disorder is caused by heterozygous pathogenic variants affecting the KAT6A gene (8p11.21) which encodes for a lysine (K) acetyltransferase 6A that forms part of a histone acetyltransferase complex regulating transcriptional activity and gene expression. Genotype-phenotype correlations suggest that variants affecting the last two exons of the gene (16 and 17) are associated with a more severe phenotype.
Diagnostic methods
The diagnosis is established by whole exome or genome sequencing or multi-gene panel including the KAT6A gene. Cases due to copy number variants might be identified by array-comparative genomic hybridization.
Differential diagnosis
The syndrome has an extensive differential diagnosis in the context of syndromic DD/ID.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disorder is autosomal dominant. Most cases are sporadic due to de novo variants, but familial and germinal mosaicism cases have been reported. For the affected individual, the risk of transmission is 50% for each pregnancy.
Management and treatment
Management is symptom-based and requires a multidisciplinary approach. Early speech and language therapy can improve oro-motor dyspraxia and articulation deficits. Augmentative and alternative communication tools are important aids. All patients require early cardiac evaluation with electrocardiogram and echocardiogram. Tube feeding might be required in infants, and all patients should be monitored for signs and symptoms of gastroesophageal reflux. Older patients might need long term medication with laxatives. Bowel obstruction should be considered in case of abdominal pain, and increased vomiting/reflux. Follow-up should include evaluation of behavioural/social difficulties, complete blood count and immune profile for recurrent infections, and regular assessment of vision. For sleep disorder, study of obstructive apnoea is recommended and melatonin supplementation might be considered.
Prognosis
Long term prognosis of the disorder is unknown.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Patricia DIAS | ITHACA* - Dr Mariana NEVES | ITHACA*

                                * European Reference Network


Autosomal dominant intermediate Charcot-Marie-Tooth disease type A

A rare hereditary motor and sensory neuropathy characterized by intermediate motor median nerve conduction velocities (usually between 25 and 45 m/s) and signs of both demyelination and axonal degeneration in nerve biopsies. It presents with usual clinical features of Charcot-Marie-Tooth disease (progressive muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, and feet deformities) in the first to second decade of life with steady progression until the fourth decade, severe progression and stabilization afterwards.


Autosomal dominant intermediate Charcot-Marie-Tooth disease type B

A rare hereditary motor and sensory neuropathy characterized by intermediate motor median nerve conduction velocities (usually between 25 and 45 m/s) and signs of both demyelination and axonal degeneration in nerve biopsies. It presents with mild to moderately severe, slowly progressive usual clinical features of Charcot-Marie-Tooth disease (muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, and feet deformities). Other findings include asymptomatic neutropenia and early-onset cataracts.


Autosomal dominant intermediate Charcot-Marie-Tooth disease type C

A rare hereditary motor and sensory neuropathy characterized by intermediate motor median nerve conduction velocities (usually between 25 and 60 m/s). It presents with moderately severe, slowly progressive usual clinical features of Charcot-Marie-Tooth disease (muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, feet deformities, extensor digitorum brevis atrophy). Findings in nerve biopsies include age-dependent axonal degeneration, reduced number of large myelinated fibres, segmental remyelination, and no onion bulbs.


Autosomal dominant intermediate Charcot-Marie-Tooth disease type D

A rare hereditary motor and sensory neuropathy characterized by intermediate motor median nerve conduction velocities (usually between 25 and 45 m/s) and signs of both axonal degeneration and demyelination without onion bulbs in nerve biopsies. It presents with usual Charcot-Marie-Tooth disease clinical features of variable severity (progressive muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, and feet deformities). Other findings in some of the families include debilitating neuropathic pain and mild postural/kinetic upper limb tremor.


Autosomal dominant intermediate Charcot-Marie-Tooth disease type E

A rare hereditary motor and sensory neuropathy disorder characterized by the typical CMT phenotype (slowly progressive distal muscle weakness and atrophy in upper and lower limbs, distal sensory loss in extremities, reduced or absent deep tendon reflexes and foot deformities) associated with focal segmental glomerulosclerosis (manifesting with proteinuria and progression to end-stage renal disease). Mild or moderate sensorineural hearing loss may also be associated. Nerve biopsy reveals both axonal and demyelinating changes and nerve conduction velocities vary from the demyelinating to axonal range (typically between 25-50m/sec).


Autosomal dominant intermediate Charcot-Marie-Tooth disease type F

A rare hereditary motor and sensory neuropathy disorder characterized by the typical CMT phenotype (slowly progressive distal muscle atrophy and weakness in upper and lower limbs, distal sensory loss in extremities, reduced or absent deep tendon reflexes and foot deformities) with nerve biopsy demonstrating demyelinating and axonal changes and nerve conduction velocities varying from the demyelinating to axonal range.


Autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain

A rare subtype of autosomal dominant intermediate Charcot-Marie-Tooth disease characterized by debilitating neuropathic pain associated with mild, distal, symmetrical lower limb sensory loss and mild or absent motor dysfunction. Patients typically manifest with burning, aching, shooting, or throbbing pain and intermittent paraesthesia in toes, heels and ankles.


Autosomal dominant Kenny-Caffey syndrome

A rare, primary bone dysplasia characterized by severe growth retardation, short stature, cortical thickening and medullary stenosis of long bones, delayed closure of the anterior fontanelle, absent diploic space in the skull bones, prominent forehead, macrocephaly, dental anomalies, eye problems (hypermetropia and pseudopapilledema), and hypocalcemia due to hypoparathyroidism, sometimes resulting in convulsions. Intelligence is normal.


A rare genetic inflammatory corneal disorder characterized by anterior stromal corneal opacification and vascularization of the peripheral cornea with potential central progression and subsequent reduction in visual acuity. Variable features include abnormalities of the iris, such as stromal defects and ectropion uveae, as well as foveal hypoplasia.


Autosomal dominant limb-girdle muscular dystrophy type 1A

A rare subtype of autosomal dominant limb girdle muscular dystrophy characterized by an adult onset of proximal shoulder and hip girdle weakness (that later progresses to include distal weakness), nasal speech and dysarthria. Other frequent findings include tightened heel cords, reduced deep-tendon reflexes and elevated creatine kinase serum levels. Respiratory failure, as well as mild facial weakness and dysphagia, may also be observed.


A rare isolated constitutional thrombocytopenia characterized by abnormally large platelets.

Summary:
Epidemiology
To date less than 10 cases are reported.
Clinical description
Autosomal dominant macrothrombocytopenia is caused by mutations in the integrin, beta 3 ITGB3, tubulin, beta-1TUBB1 and actinin, alpha1 ACTN1 genes. These mutations lead to abnormal proplatelets and thrombocytopenia.
Etiology
Transmission is autosomal dominant.

                            Last update:
                            May 2013


Autosomal dominant mendelian susceptibility to mycobacterial diseases due to a partial deficiency

A group of variants of mendelian susceptibility to mycobacterial diseases (MSMD) due to dominantly inherited partial deficiencies in interferon gamma receptor 1 (IFN-gammaR1), IFN-gammaR2, signal transducer and activator of transcription 1 (STAT1) or interferon regulator factor 8 (IRF8).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The clinical disease seen in all of these variants is relatively mild. Weakly virulent bacillus Calmette-Guérin (BCG) and Mycobacterium avium complex infections are most commonly seen in patients with these diseases.
Etiology
AD MSMD due to a partial deficiency is caused by a mutation in one of the following genes: IFNGR1, IFNGR2, STAT1 or IRF8, depending on the variant. These mutations affect the IFN-gamma pathway and lead to susceptibility to infections with BCG and other environmental mycobacteria.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency

A rare, genetic variant of mendelian susceptibility to mycobacterial diseases (MSMD) characterized by a partial deficiency leading to impaired IFN-gamma immunity and, consequently, recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).

Summary:
Epidemiology
The prevalence is unknown. Since it was first reported in 1999, more than 70 patients bearing heterozygous mutations in IFNGR1 gene have been reported.
Clinical description
Patients present with moderately severe mycobacterial infections at around the age of 13 years. These infections are recurrent but less severe than those seen in MSMD due to complete IFN-gammaR1 and IFN-gammaR2 deficiencies (see these terms). Infections with Mycobacterium bovis BCG or Mycobacterium avium often lead to multifocal or unifocal osteomyelitis in patients with this variant. Salmonellosis has been reported in 5% of cases and infections with other pathogens such as Histoplasma capsulatum and varicella-zoster virus have also been reported in single patients.
Etiology
AD MSMD due to partial IFN-gammaR1 deficiency is caused by heterozygous mutations in the IFNGR1 gene on chromosome 6q23-q24 that encodes the IFN-gamma receptor ligand binding chain. Microdeletion 818del4 is by far the most common mutation and it corresponds to the first documented hotspot for a microdeletion in the human genome. It leads to the expression of IFN-gamma receptor on the cell surface with no signal transduction and therefore patients only show a partial response to IFN-gamma.
Diagnostic methods
Diagnosis is made by laboratory analysis. Cells of patients show a residual response to IFN-gamma in terms of Stat-1 DNA-binding (GAS-binding activity) and HLA-II induction. Genetic testing reveals mutations in IFNGR1.
Differential diagnosis
Other genetic etiologies of MSMD should be excluded.
Antenatal diagnosis
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
Genetic counseling
Transmission is autosomal dominant and genetic counseling is possible.
Management and treatment
BCG vaccination should be avoided in those with a known mutation in the IFNGR1 gene. Patients should be treated with antibiotics and, if necessary, with recombinant IFN-gamma.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency

A rare, genetic variant of mendelian susceptibility to mycobacterial diseases (MSMD) characterized by a partial deficiency in IFN-gammaR2, leading to impaired response to IFN-gamma and, consequently, to recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).

Summary:
Epidemiology
The prevalence is unknown. It was recently discovered in two patients.
Clinical description
The first reported patient with this deficiency presented with moderate mycobacterial infections secondary to BCG vaccination. She developed no other severe infections. The father of this patient was a heterozygous carrier of the mutation, but remained healthy.
Etiology
AD MSMD due to partial IFN-gammaR2 deficiency is caused by a heterozygous mutation in the IFNGR2 gene on chromosome 21q22.1-22.2 that encodes the IFN-gamma receptor ligand binding chain 2. The 186delC mutation corresponds to the first mutation conferring an AD partial IFN-gammaR2 deficiency.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Autosomal dominant mitochondrial myopathy with exercise intolerance

A rare mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies characterized by onset of slowly progressive proximal lower limb weakness and exercise intolerance in the first decade of life, followed by weakness of neck flexor, shoulder, and distal leg muscles. Facial muscles become involved still later in the disease course. Additional manifestations are restrictive pulmonary function and short stature. Laboratory studies reveal lactic acidemia and increased serum creatine kinase.


Autosomal dominant multiple pterygium syndrome

A rare distal arthrogryposis syndrome characterized by multiple pterygia (typically involving the neck, axilla and popliteal areas), joint contractures, ptosis, camptodactyly of the hands with hypoplastic flexion creases, vertebral fusions, severe scoliosis and short stature.


A rare metabolic myopathy characterized by episodic myalgia with myoglobinuria which is induced by fever, viral or bacterial infection, prolonged exercise or alcohol abuse, and could, on occasion, lead to acute renal failure. Between episodes, patients may be asymptomatic or could present elevated creatine kinase levels and mild muscle weakness. There have been no further descriptions in the literature since 1997.


Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome

A rare primary bone dysplasia characterized by micromelia with rhizomelic shortening, metaphyseal widening of the long bones, brachydactyly, small scapulae, micrognathia and thoracic insufficiency requiring tracheostomy and ventilation, and severe myopia and sensorineural hearing loss. Further dysmorphic craniofacial features include frontal bossing, proptosis, epicanthal folds, short nose, flat nasal bridge, anteverted nares, midfacial retrusion, and cleft palate.