A rare oligosaccharidosis characterized by facial dysmorphism, progressive intellectual disability and psychomotor deterioration due to accumulation of glycoasparagines in tissues and body fluids.

Summary:
Epidemiology
Aspartylglucosaminuria (AGU) is mainly found in Finland; the major pathogenic variants are approximately 50 times more frequent in Finns than non-Finnish Europeans. Outside of Finland, sporadic cases are observed, with > 50 known cases.
Clinical description
Clinical signs of AGU include slowly progressing neurodevelopmental disorder, beginning with clumsiness, delayed speech, and hyperkinesia. Patients also present with mild facial dysmorphism, and slight kyphoscoliosis. Hepatosplenomegaly is rare and has only been reported in non-Finnish cases.
Etiology
AGU is caused by pathogenic variants of the AGA gene located on 4q34.3. In Finland, two major mutations have been described (AGU-fin major and AGU-fin minor) and account for more than 98% of disease alleles; systematic screening for heterozygous individuals would thus be possible. Outside of Finland, the disease-causing variants are heterogeneous and often family-specific. The pathogenic variants lead to a deficiency of aspartylglucosaminidase (AGA), an enzyme that cleaves the N-acetylglucosamine-asparagine bond found in N-glycosyled proteins. AGA deficiency causes excess accumulation of glycoasparagines in the tissues and body fluids, with an increased excretion in urine.
Diagnostic methods
Most cases are detected by genetic analysis of the AGA gene or by exome sequencing. Biochemically, AGU is characterized by measuring the increased urinary excretion of aspartylglucosamine by liquid chromatography/mass spectrometry. A low activity of AGA enzyme can be measured in the serum, lymphocytes, fibroblasts, amniocytes or trophoblasts.
Differential diagnosis
As glycoasparagines can also be sporadically detected in the urine of patients with NGLY1 deficiency, genetic analysis and AGA activity measurement should be used to verify the diagnosis.
Antenatal diagnosis
Prenatal diagnosis by gene/exome sequencing or AGA enzyme activity measurement are possible.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant), informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Older patients may become severely handicapped due to cognitive and physical decline and will require special care. Attempts of curative treatment with allogenic bone marrow grafting showed limited results in five Finish patients. In addition, hematopoietic stem cell transplantation in three non-Finnish AGU patients showed that the intervention needs to be performed early in life to slow down cognitive decline. Treatment with a pharmacological chaperone (trimethylglycine) is currently under clinical evaluation.
Prognosis
Patients show a profound cognitive and physical decline after the age of 20-25 years. Death usually occurs before the age of 50, but the oldest Finnish patients have survived over 60 years.

                            Last update:
                            September 2023

                            - Expert reviewer(s):
                            Dr Minna LAINE  - Pr Ritva TIKKANEN


A rare infectious disease caused by inhalation of the opportunistic fungus aspergillus that can lead to the following manifestations: allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, chronic necrotizing pulmonary aspergillosis (CNPA), and invasive aspergillosis (IA). Aspergilloma occurs in patients with cavitary lung disease and results in a fungal mass with variable clinical presentations from asymptomatic to life-threatening (massive hemoptysis). CNPA manifests as subacute pneumonia in patients with underlying disease. IA is disseminated aspergillosis that eventually invades other organs. Cutaneous aspergillosis is usually the dermatological manifestation of IA that manifests as erythematous-to-violaceous plaques or papules, often characterized by a central necrotic ulcer or eschar.


A rare, lethal skeletal dysplasia characterized by short limbed dwarfism, osteogenesis imperfecta, and punctate calcification within cartilage. It has been described in less than ten cases.


A very rare glial neoplasm of the central nervous system, most often with an intra-axial peripheral supratentorial location in one hemisphere of the frontal or parietal lobes and usually presenting in infants and young adults with symptoms of vomiting, loss of consciousness, epileptic seizures and headaches.


A complex group of benign and malignant cerebral tumors arising at any age.

Summary:
Epidemiology
They are the most frequent cerebral tumors and represent more than half of all primary brain tumors. Incidence is estimated at 1/12,500.
Clinical description
The most frequent benign tumors are juvenile pilocytic astrocytomas (grade I) and diffuse low grade or fibrillary astrocytomas (grade II). The most frequent malignant tumors include anaplastic astrocytomas (grade III), glioblastomas (grade IV, the most severe form of astrocytoma; see this term), giant cell glioblastomas and gliosarcomas. Pleomorphic xanthoastrocytomas can be malignant or benign. These tumors occur at all ages although glioblastomas are more frequent in adults and in elderly people, while pilocytic astrocytomas are more frequent in children and adolescents. Age at diagnosis may influence tumor biology and evolution; the outcome generally being better in children. Speed of tumor growth is related to tumor grade. Symptom duration of less than three months is usually seen with malignant tumors.
Etiology
Apart from cranial irradiation, which may itself induce glioblastomas, the underlying causes of these tumors are not known. The principal genetic predisposing syndromes are: neurofibromatosis type 1, Turcot syndrome and Li-Fraumeni syndrome (see these terms). Familial cases of isolated astrocytomas are very rare.
Diagnostic methods
Diagnosis is made after MRI, which reveals an intraparenchymal lesion associated with a mass effect and compression of the normal structures.
Management and treatment
Treatment first consists of surgery, which aims at removing as much of the tumor as possible. If complete, surgical resection may be the only treatment required for benign astrocytomas. Adjuvant treatment is required for malignant tumors, whatever the quality of the resection. In case of incomplete resection of a benign tumor, adjuvant treatment may also be discussed. Radiation therapy is usually used in adults and in children over 10 years of age. Chemotherapy is preferred for younger children and may even be discussed for adults. The most chemosensitive tumors are pilocytic astrocytomas and anaplastic astrocytomas. Pilocytic tumors are highly curable, while malignant tumors are often fatal. The neurologic and intellectual sequelae of these tumors and their treatment may be severe, especially in young children, elderly people and patients requiring extended irradiation. Patient management requires multidisciplinary teams with expertise in the field of brain neoplasms. The relative rarity of these tumors calls for the management of patients in prospective trials aimed at improving prognosis and quality of survival.
Prognosis
Prognosis depends on tumor histology (benign or malignant) and location (operable or not).

                            Last update:
                            November 2007

                            - Expert reviewer(s):
                            Dr Jacques GRILL


A neurodegenerative disease belonging to the inherited cerebellar ataxias mainly characterized by progressive spino-cerebellar ataxia, loss of proprioception, areflexia, and is associated with a marked deficiency in vitamin E.

Summary:
Epidemiology
Global prevalence is not known but population-based studies have been performed and prevalence can be extrapolated at approximately 1/300,000. AVED is the second most frequently inherited cerebellar ataxia in North Africa. As vitamin E deficiency might bring protection against malaria (see this term), it could explain a higher prevalence of AVED in Plasmodium infested areas.
Clinical description
AVED presents generally between ages 5 and 20 years with variable phenotype and severity. Progressive spino-cerebellar ataxia, areflexia and loss of proprioception, mainly in distal joint position and of vibration sense, induce a noticeable clumsiness and imbalance. Patients may have a characteristic head titubation. Tendon reflexes are dramatically reduced and extensor plantar reflexes are frequent. Cerebellar impairment frequently manifests as dysmetria, dysdiadochokinesia and dysarthria. Decreased visual acuity with retinitis pigmentosa may be seen. In some cases, disease onset is late (> 30 years) and the course is milder. On the contrary, in early-onset cases, the course is more severe, with an increased risk of cardiomyopathy. Overall, the clinical picture of AVED is close to that of Friedreich's ataxia (see this term).
Etiology
AVED is caused by mutations in the tocopherol (alpha) transfer protein gene (TTPA; 8q13). This protein binds alpha-tocopherol (a vitamin E isomer) and very-low-density lipoproteins (VLDLs) in the liver. When mutated, TTPA prevents vitamin E linking to VLDLs, preventing it to pass into general circulation. Many mutations have been identified, but p.His101Gln and c.744delA are respectively responsible for the late-onset/mild and early-onset/severe forms of the disease.
Diagnostic methods
Diagnosis is based on physical examination, on vitamin E plasma dosage and on exclusion of known causes of malabsorption. Laboratory findings reveal a very marked deficiency of vitamin E in plasma but normal levels of lipid and lipoprotein profiles. Neuroimaging does not show an obvious cerebellar atrophy in the first stages of the disease. Electromyography usually reveals a pure sensory neuronopathy (ganglionopathy). Molecular analysis confirms the diagnosis.
Differential diagnosis
Differential diagnosis mainly includes Friedreich ataxia, sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) and abetalipoproteinemia (see these terms). Other autosomal recessive cerebellar ataxias may be considered as well (Refsum disease, ataxia telangiectasia, Charcot-Marie-Tooth disease 1A and ataxia with oculomotor apraxia types 1 and 2 (see these terms)).
Antenatal diagnosis
Antenatal diagnosis is feasible via molecular genetic testing when the mutation has been identified in the family.
Genetic counseling
The disease has an autosomal recessive mode of inheritance, with a subsequent recurrence risk of 25%.
Management and treatment
Treatment is based on a lifelong high-dose vitamin E supplementation, which should be taken every day. When treated early, some symptoms could be reversible; in older patients disease progression can be slowed. It remains unknown whether in families of index cases vitamin E preventive treatment can be administered in presymptomatic individuals to prevent development of AVED.
Prognosis
Even if treated, patients frequently have a poor prognosis and become wheelchair bound within 8 and 20 years of age.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Pr Mathieu ANHEIM


A rare genetic syndromic intellectual disability characterized by global developmental delay, intellectual disability, infantile or childhood onset of progressive ataxia, and bilateral sensorineural hearing impairment. Variable features include signs of upper and lower motor neuron disease, peripheral neuropathy, myopathic facies, lower limb muscle wasting, and heel contractures. There have been no further descriptions in the literature since 1993.


A very rare autosomal recessive, slowly progressive neurodegenerative disorder characterized by the triad of cerebellar ataxia (that generally manifests at adolescence or early adulthood), chorioretinal dystrophy, which may have a later onset (up to the fifth-sixth decade) leading to variable degrees of visual impairment, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). Ataxia-hypogonadism-choroidal dystrophy syndrome belongs to a clinical continuum of neurodegenerative disorders along with the clinically overlapping cerebellar ataxia-hypogonadism syndrome (see this term).


Ataxia-intellectual disability-oculomotor apraxia-cerebellar cysts syndrome

A rare neuro-ophthalmological disease characterized by nonprogressive cerebellar ataxia, delayed motor and language development and intellectual disability, in addition to ophthalmological abnormalities (e.g. oculomotor apraxia, strabismus, amblyopia, retinal dystrophy and myopia). Cerebellar cysts, cerebellar dysplasia and cerebellar vermis hypoplasia, seen on magnetic resonance imaging, are also characteristic of the disease.


A rare autosomal recessive cerebellar ataxia, characterized by progressive cerebellar ataxia associated with oculomotor apraxia, severe neuropathy, and hypoalbuminemia.

Summary:
Epidemiology
Ataxia-oculomotor apraxia type 1 (AOA1) represents 3.6% of all autosomal recessive cerebellar ataxia (ARCA) in Portugal; in Japan, AOA1 seems to be the most frequent cause of ARCA. In a cohort of 227 patients mostly of French origin with progressive cerebellar ataxia selected after exclusion of Friedreich ataxia, the relative frequency of AOA1 was of 5%.
Clinical description
Cerebellar ataxia is the first manifestation of AOA1 with a mean age of onset of 4.3 years (2-10 years) and is characterized by progressive gait imbalance followed by dysarthria, and limb dysmetria. Later, peripheral axonal motor neuropathy dominates the clinical picture. Oculomotor apraxia (OMA; inability to coordinate eyes ± head movements: when the head turns toward a lateral target; the head reaches the target before the eyes) is present in almost all individuals with AOA1. Chorea is present at onset in 80% of patients and upper limb dystonia (see this term) occurs in about 50% of individuals. Additional features include square wave jerks, saccadic pursuit and gaze-evoked nystagmus, areflexia followed by severe peripheral neuropathy. Variable intellectual disability is observed.
Etiology
AOA1 results from mutations in APTX gene (9p13.3) encoding aprataxin which plays a role in DNA-single-strand break repair. Most mutations identified so far are localized in exons 5, 6 and 7. Some correlations between genotype and phenotype have been established: for example severe and persistent choreic phenotype is associated with mutations A198V; truncating mutations are associated with earlier onset and deletions with more severe phenotype and intellectual disability.
Diagnostic methods
Diagnosis of AOA1 is based on the clinical features, the progressive evolution, the absence of extraneurologic findings and family history. Electromyography findings reveal severe axonal sensory-motor neuropathy. Oculographic recordings demonstrate normal latencies, hypometric saccades, decrease mean gain in amplitude and broken saccades into multiple successive saccades. Cerebral magnetic resonance imagery displays cerebellar atrophy. Hypoalbuminemia and hypercholesterolemia are usual (disease duration is positively correlated with cholesterol and negatively correlated with albumin levels). Diagnosis is confirmed by molecular analysis of APTX gene.
Differential diagnosis
Differential diagnosis includes Friedreich ataxia, ataxia with vitamin E deficiency, AOA2, ataxia-telangiectasia, ataxia-telangiectasia-like disorder, autosomal recessive spastic ataxia of Charlevoix-Saguenay (see these terms).
Antenatal diagnosis
Carrier testing for at-risk family members and prenatal testing are possible if both disease-causing alleles in a family are known.
Genetic counseling
Transmission of AOA1 is autosomal recessive. Genetic counseling is recommended as each sib of an affected individual has 25% risk of being affected, 50% risk of being an asymptomatic carrier, and 25% risk of being neither affected nor a carrier.
Management and treatment
No specific treatment exists for AOA1 and management is mainly supportive. It includes physical therapy for cerebellar ataxia and disabilities resulting from peripheral neuropathy; educational support for reading and writing difficulties, speech therapy for dysarthria and cognitive impairment. Low-cholesterol diet and hypolipemiant treatment are recommended. Routine follow-up with a neurologist or neurogenetician is suggested. Some therapeutic trials are on the way such as the evaluation of efficacy of Coenzyme Q10 in evolution of the disease.
Prognosis
AOA1 is a progressive neurodegenerative disorder and most patients usually become wheelchair bound from seven to ten years after onset of the disease.

                            Last update:
                            May 2020

                            - Expert reviewer(s):
                            Dr Perrine CHARLES


A rare autosomal recessive cerebellar ataxia characterized by onset of dystonia and other extrapyramidal signs, ataxia, oculomotor apraxia, and progressive sensorimotor polyneuropathy in the first decade of life. Patients present distal muscle weakness and atrophy, decreased vibratory sensation, and areflexia, and usually become wheelchair-bound by the third decade. Variable cognitive impairment may also be seen.


A rare genetic disease characterized by cerebellar ataxia, cytopenias and predisposition to bone marrow failure and myeloid leukaemia. Neurologic features variably include slowly progressive cerebellar ataxia or balance impairment with cerebellar atrophy and periventricular white matter T2 hyperintensities in brain MRI, horizontal and vertical nystagmus, dysmetria, dysarthria, pyramidal tract signs and reduced nerve conduction velocity. Hematological abnormalities are variable and may be intermittent and include cytopenias of all cell lineages, immunodeficiency, myelodysplasia and acute myeloid leukemia.


A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by cerebellar-like ataxia, photosensitivity (mainly of the face and trunk), short stature and intellectual disability. Additonal features include clinodactyly, single palmar transverse crease, high-arched palate, pseudohypertrophy of the calves and aortic valve lesions. There have been no further descriptions in the literature since 1983.


A rare hereditary ataxia characterized by simultaneous onset and development of cerebellar ataxia and chorioretinal degeneration (including macular degeneration, advancing choroidal sclerosis, punctata albescens, and retinitis pigmentosa). There have been no further descriptions in the literature since 1963.


A rare, genetic, persistent combined dystonia characterized by clinical signs similar to ataxia-telangiectasia but with a later (usually adulthood) onset and slower progression. Patients typically present extrapyramidal signs, such as resting tremor, choreathetosis, and dystonia, as the initial symptoms and later often develop mild cerebellar ataxia (with gait usually preserved). Telangiectasia and immunodeficiency may be absent but secondary features of ataxia-telangiectasia, such as risk of malignancy, dysarthria and peripheral neuropathy, are frequently present.


A rare genetic disease characterized by slowly progressive cerebellar degeneration resulting in ataxia, oculomotor apraxia, and other cerebellar symptoms. There is an increased frequency of spontaneous chromosomal aberrations, as well as hypersensitivity to ionizing radiation, while telangiectasia is absent.


A rare autosomal recessive cerebellar ataxia due to a DNA repair defect characterized by progressive neurological impairment with cerebellar syndrome, oculocutaneous telangiectasia, defects in B and T cell-mediated immunity, and increased susceptibility to malignancies (mainly lymphoid neoplasms). High sensitivity to ionizing radiation limits patient treatments.

Summary:
Epidemiology
Prevalence is estimated to be 1/100,000 live births.
Clinical description
The first manifestations usually occur at 1-2 years of age with progressive walking difficulties, balance disorders followed by slurred speech, drooling and oculomotor apraxia. Choreoathetosis may appear around 9-10 years of age and worsen progressively. Intelligence is normal although slurred speech and drooling may be interpreted as intellectual deficiency. Cutaneo-mucosal telangiectasias (especially of the conjunctivae) usually appear around 3-6 years of age, or later. Immunodeficiency causes recurrent airway infections (otitis, sinusitis, bronchitis, pneumonia) which can lead to bronchiectasis and autoimmune/inflammatory features such as granulomas (mostly of the skin but also other organs); its severity varies widely between patients, from severe lymphopenia (including severe combined immune deficiency and/or severe hypogammaglobulinemia) to no overt biological abnormality. There is a high risk of malignancy, particularly of lymphoma and leukemia (in childhood and adolescence mostly), and carcinomas (in adulthood). Patients are highly sensitive to ionizing radiation, that are forbidden. X-rays imaging must be avoided. Other features include growth delay, infertility, glucose intolerance, non-alcoholic steatohepatitis.
Etiology
Ataxia-telangiectasia (A-T) is caused by loss of function biallelic (homozygous or compound heterozygous) pathogenic variants (PVs) of the ATM gene (11q22.3) which encodes a protein kinase involved in double-strand-break DNA repair, notably in the Purkinje cells of the cerebellum and cutaneous and conjunctival endothelial cells. PVs induce stop codons or directly inactivate the kinase domain; some are hypomorphic and lead to an attenuated disease with late onset symptoms and dystonia.
Diagnostic methods
Early diagnosis is difficult. Quasi-constant very high serum level of alpha-fetoprotein is a useful clinical sign. Cytogenetic analysis may help confirm the diagnosis (7;14 translocations) but few laboratories still perform it. Molecular analysis of the ATM gene confirms the diagnosis. Multigene panels for ataxias or immune deficiencies have now greatly facilitated A-T diagnosis and other differential diagnoses.
Differential diagnosis
The differential diagnosis includes ataxia-telangiectasia-like disorder and ataxia-oculomotor apraxia types 1 and 2.
Antenatal diagnosis
Antenatal and preimplantation genetic diagnosis are possible when pathogenic variants have been identified in a family.
Genetic counseling
Genetic counseling should be discussed due to the severity and incurability of the disease. Siblings of an affected individual have a 25% chance of being affected. The risk for couples with one PV carrier to have an affected child is estimated at 1/600-800. PV carriers are estimated to represent 1/150-200 of the general population. Genetic testing of the spouse may be discussed.
Management and treatment
There is no curative therapy. Management is symptomatic and involves physiotherapy, speech therapy and treatment of the infection and pulmonary complications (chronic antibiotic prophylaxis and/or human polyvalent normal Immunoglobulin long-term replacement therapy). The cells of A-T patients show increased susceptibility to ionizing radiation; X-rays, radiotherapy, and some forms of chemotherapy should be used with caution or avoided. Affected children with classical A-T are often wheelchair bound by 10-11 years old. Beta-blockers may reduce trembling and improve fine movements performance. Nicotinamide riboside brings minor improvements of some neurological symptoms. Dexamethasone administration through autologous erythrocytes has shown promising results on neurologic features in clinical trials. Gene therapy using antisense oligonucleotides is currently under trial.
Prognosis
The prognosis is severe due to the occurrence of respiratory infections, neurodegeneration, accelerated cutaneo-mucosal ageing and an increased risk of cancer (35% of patients develop cancer by the age of 20).

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Dr Jessica LE GALL  - Dr Nizar MAHLAOUI | RITA* - Pr Dominique STOPPA-LYONNET

                                * European Reference Network


A Pierre Robin syndrome associated with bone disease characterized by severe short-limbed dwarfism, joint dislocations, club feet along with distinctive facies and radiographic findings.

Summary:
Epidemiology
Atelosteogenesis I (AOI) is a very rare infrequently described disorder.
Clinical description
Affected neonates are stillborn or die rapidly after birth and present clinically with severe short-limbed dwarfism, dislocated hip, knee and elbow joints, club feet and if born alive have cardiorespiratory failure. Craniofacial dysmorphism describes a prominent forehead, hypertelorism, a depressed nasal bridge with a grooved tip, micrognathia and frequently a cleft palate. There is a continuum with overlapping clinical findings between atelosteogenesis I, atelosteogenesis III and boomerang dysplasia.
Etiology
Atelosteogenesis I results from heterozygous mutations in exons 2-5 and 27-33 of the gene encoding filamin B (FLNB) located to 3p14.
Diagnostic methods
Diagnosis can be confirmed from skeletal radiographs, chondro-osseous histopathology and genetic testing. Distinctive radiographic findings comprise severe platyspondyly, distally tapered; shortened, incomplete or absent humeri and femurs; shortened or bowed radii, ulnas, and tibias; hypoplastic pelvis and fibulas; and deficient ossification of the metacarpals, middle and proximal phalanges.
Differential diagnosis
Differential diagnosis comprises other skeletal dysplasias with severe short-limbed dwarfism such as campomelic dysplasia, Ellis-van Creveld syndrome, achondroplasia, metatropic dysplasia, Roberts syndrome, short rib-polydactyly syndrome, and thanatophoric dysplasia. Other, differential diagnosis includes achondrogenesis, hypophosphatasia, and osteogenesis imperfecta.
Antenatal diagnosis
Prenatal ultrasound can detect bone dysplasia and other manifestation and plays an important role in early detection and diagnosis. Prenatal ultrasound findings for AOI may include severe limb shortening and deficient ossification of the long bones, shortened flaring or absent humeri and femurs from 18 weeks onwards. Other skeletal abnormalities as well as some facial dysmorphic features may be detectable.
Genetic counseling
All cases have been autosomal dominant and sporadic resulting from de novo mutations in FLNB.
Management and treatment
Palliative care is offered to newborns suffering from AOI.
Prognosis
Prognosis is poor. Death is often due to a combination of pulmonary hypoplasia and tracheobronchomalacia early in life.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Stephen ROBERTSON  - Dr Emma WADE


A rare, lethal perinatal bone dysplasia characterized by limb shortening, normal sized skull with cleft palate, hitchhiker thumbs, distinctive facial dysmorphism and radiographic skeletal features, caused by mutations in the diastrophic dysplasia sulfate transporter gene.


A rare skeletal dysplasia characterized by short limbs dysmorphic facies and diagnostic radiographic findings.

Summary:
Epidemiology
The prevalence of AOIII is unknown. Less than 25 affected patients have been reported.
Clinical description
AOII, like AOI, is characterized by rhizomelic limb shortness, dislocated hip, knee and elbow joints, broad hands and feet with broad digits, club feet, facial dysmorphism (midface hypoplasia, micrognathia, cleft palate). Feeding problems and cardiorespiratory insufficiency are often seen in newborns. Clinical manifestations due to secondary complications past early infancy include learning and language problems and a gross motor developmental delay.
Etiology
Atelosteogenesis III results from missense mutations or small in-frame deletions in the FLNB gene reported in exons 2-5, 13 and 27-33 resulting in the translation of filamin B protein with altered biochemical properties.
Diagnostic methods
The diagnosis is established after a full skeletal x-ray survey and confirmed with genetic testing. AOIII demonstrates less delay of normal ossification compared to AOI.
Antenatal diagnosis
Prenatal diagnosis is possible by ultrasound from 20 weeks onward and by prenatal genetic testing in case of family history.
Genetic counseling
Most cases of AOIII are sporadic, but AOIII may be transmitted in an autosomal dominant manner. Affected individuals of which one of the parents presents with a milder phenotype (like Larsen syndrome) (see this term) have been reported. This is likely to be related to a somatic mosaicism in the parents for a mutation that is germline in the offspring.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Pr Stephen ROBERTSON


Athabaskan brainstem dysgenesis syndrome

A rare, genetic, neurological disorder characterized by horizontal gaze palsy, sensorineural deafness, central hypoventilation, developmental delay, and intellectual disability, described in persons of Athabascan American Indian heritage. Swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, internal carotid artery, and cardiac outflow tract anomalies may be additionally observed. No dysmorphic facial features are associated.


A rare, severe, circulatory system disease characterized by premature, diffuse, severe atherosclerosis (including the aorta and renal, coronary, and cerebral arteries), sensorineural deafness, diabetes mellitus, progressive neurological deterioration with cerebellar symptoms and photomyoclonic seizures, and progressive nephropathy. Partial deficiency of mitochondrial complexes III and IV in the kidney and fibroblasts (but not in muscle) may be associated. There have been no further descriptions in the literature since 1994.


A rare form of thyroid dysgenesis characterized by complete absence of thyroid tissue that results in primary congenital hypothyroidism, a permanent thyroid deficiency that is present from birth.

Summary:
Epidemiology
Prevalence is estimated at around 1/28,000. Athyreosis and thyroid hypoplasia (see this term) combined account for one-third of cases of thyroid dysgenesis.
Clinical description
Clinical manifestations of athyreosis are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone. More specific symptoms and signs do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age.
Etiology
Around 2% of cases have been shown to be familial and may be caused by mutations in the FOXE1,  NKX2-1, NKX2-5 or PAX8 genes (9q22, 14q13, 5q34 and 2q12-q14). Mutations that result in complete inactivation of the TSHR gene (14q31) can present with athyreosis.
Diagnostic methods
Imaging studies are required to confirm the diagnosis of athyreosis.
Genetic counseling
Athyreosis is generally thought to be sporadic. However, recent evidence points to the possibility of a genetic component.
Prognosis
Without treatment athyreosis results in severe intellectual deficit and short stature.

                            Last update:
                            August 2010

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


A rare X-linked syndromic intellectual disability characterized by variable intellectual deficit, macrocephaly, short stature, and facial dysmorphism (such as prominent forehead, prominent supraorbital ridges, hypertelorism, downslanting palpebral fissures, broad nasal tip, anteverted nostrils, thick lower lip, and localized microdontia). Additional reported features include seizures, post-pubertal macroorchidism, obesity, and short, broad hands with tapered fingers.


A rare, chronic allergic disease of the cornea and conjunctiva occurring in all age groups, characterized by severe itching and burning sensation, conjunctival injection, photophobia and edema with serious cases leading to ulceration of the cornea which can result in blindness. It is often associated with atopic dermatitis.


A rare fetal lower urinary tract obstruction (LUTO) characterized by closure or failure to develop an opening in the urethra and resulting in obstructive uropathy presenting in utero as megacystis, oligohydramnios or anhydramnios, and potter sequence.

Summary:
Epidemiology
Prevalence is unknown, but is higher in males than females.
Clinical description
Atresia of urethra often presents on routine antenatal ultrasound with megacystis, oligohydramnios or anhydramnios and sometimes urinary ascites. It may cause fetal death. In cases that survive to birth, additional symptoms include respiratory insufficiency due to pulmonary hypoplasia, megaureter, hydronephrosis and enlarged often cystic and functionally impaired/non-functional dysplastic kidneys as well as abdominal distention. Furthermore, a Potter sequence can be found due to oligo- or anhydramnios. Patients may present with patent urachus or vesicocutaneous fistula.
Etiology
The etiology of atresia of the urethra is unknown. Common clinical features arise from the inability of urine to pass out of the body of the fetus, resulting in oligohydramnios which in turn affects the development of the lungs and causes features of Potter sequence. Congenital obstruction of the urinary tract at a critical time in organogenesis has a profound and lifelong effect on kidney, ureteral and bladder function. In rare cases, there is an abnormal opening between the bladder and the rectum which may allow the urine to drain.
Diagnostic methods
Antenatal diagnosis is based on ultrasound. By then it is not possible to clearly distinguish between different forms of LUTO. If megacystis occurs in early pregnancy (around 17 weeks of gestation) atresia of the urethra is more likely to be a possible underlying cause then in later gestation. Postnatally, micturating cysto- urethrography and/or cystoscopy can be used for final diagnosis and differentiation between atresia of the urethra and other forms of LUTO as differential diagnosis.
Differential diagnosis
Differential diagnoses include other causes of megacystis including posterior urethral valve, anterior urethral valve, urethral stenosis, urethral agenesis, double urethra, cloacal malformation and, in rare and severe cases, different forms of voiding dysfunction or megacystis megaureter syndrome. Atresia of urethra can occur in combination with several other conditions including caudal dysplasia, cloacal extrophy, DiGeorge syndrome, prune belly syndrome, Fraser syndrome, cryptophtalmus, Johnson-Munson, Meckel-Gruber, Sirenomelia, and Townes-Brocks syndrome.
Antenatal diagnosis
Antenatal diagnosis is based on ultrasound evidence of megacystis and oligohydramnios. Fetal MRI can be used to attempt confirmation of the diagnosis.
Genetic counseling
If atresia of the urethra occurs together with other birth defects, genetic counselling should be considered. For isolated atresia of the urethra no genetic causes are known so far.
Management and treatment
Antenatal treatment involves urinary decompression with a vesico-amniotic shunt. If the antenatal period is survived, postnatal treatment depends on the pulmonary and renal function. All cases with remaining renal function require a suprapubic urine drainage until reconstructive surgery. Successful treatment of severe cases (obstructive uropathy, kidney failure and pulmonary hypoplasia) with extra corporal membrane oxygenation (ECMO) therapy and hemofiltration/peritoneal dialyses has been described.
Prognosis
The malformation usually results in fetal death without surgical intervention. Prenatal decompression allows survival and may even lead to normal bladder and renal function. Nevertheless, progression into kidney failure is common. Extensive surgical reconstruction is to be expected.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Alina HILGER


A rare congenital non-syndromic heart malformation characterized by an abnormal protrusion of the interatrial septum into the right or left atrium, or both, during the cardiorespiratory cycle. The defect may be limited to the fossa ovalis or involve the entire septum. It can present as an isolated finding but is more often associated with interatrial shunts, in particular patent foramen ovale. Clinically it increases the risk of peripheral arterial embolism and stroke.


Atrial septal defect-atrioventricular conduction defects syndrome

An extremely rare genetic congenital heart disease characterized by the presence of atrial septal defect, mostly of the ostium secundum type, associated with conduction anomalies like atrioventricular block, atrial fibrillation or right bundle branch block.


A rare cardiac rhythm disease characterized by a transient or permanent absence of electrical and mechanical atrial activity. Electrocardiographic findings include bradycardia, ectopic supraventricular rhythms, lack of atrial excitability and absent P waves.


A rare inherited form of alopecia characterized by irreversible hair loss during the neonatal period on all hear-bearing areas of the body, later associated with the development of papular lesions all over the body and preferentially on the face and extensor surfaces of the extremities.


Atrioventricular defect-blepharophimosis-radial and anal defect syndrome

A rare, genetic multiple congenital anomalies syndrome characterized by atrioventricular septal defects and blepharophimosis, in addition to radial (e.g. aplastic radius, shortened ulna, fifth finger clinodactyly, absent first metacarpal and thumb) and anal (e.g. imperforate or anteriorly place anus, rectovaginal fistula) defects.


A rare variant of cutaneous lichen planus characterized by the development of pale papules or plaques with an atrophic center.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Lesions develop on the trunk or lower extremities on skin areas previously affected by classic lichen planus.
Etiology
Etiology is unknown.

                            Last update:
                            May 2011

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


A rare genetic skin disease characterized by childhood onset of follicular keratotic papules slowly progressing to characteristic ''honeycomb'' atrophy on the cheeks, preauricular area, and forehead. Less frequently, the condition may affect also the upper lip, ears, or limbs. Additional features include facial erythema, milia, and follicular plugs.


A very rare and atypical form of Chédiak-Higashi syndrome (CHS), a genetic disorder characterized by partial oculocutaneous albinism, severe immunodeficiency, mild bleeding, neurological dysfunction and lymphoproliferative disorder.

Summary:
Epidemiology
Fewer than 100 cases have been reported to date but the disorder is likely underdiagnosed. The atypical form may account for 10-15% of CHS patients who do not develop the accelerated phase.
Clinical description
Mild adolescent- or adult-onset attenuated CHS is characterized by subtle or absent oculocutaneous albinism, a characteristic feature of classic CHS, as well as minor to severe infections during childhood but a lower frequency of infections in adolescence and adulthood, mild bleeding manifestations, and progressive neurological findings including intellectual deficit, peripheral neuropathy, parkinsonism, balance abnormalities, and tremor.
Etiology
Missense mutations in the LYST lysosomal trafficking regulator gene (1q42.1-q42.2) appear to cause this form of CHS.
Genetic counseling
Attenuated Chédiak-Higashi syndrome is inherited in an autosomal recessive manner.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Dr Wendy INTRONE


Attenuated familial adenomatous polyposis

A mild form of familial adenomatous polyposis characterized by the presence of fewer than 100 adenomatous colonic polyps, a more proximal colonic location, a delayed age of colorectal cancer onset and a more limited expression of the extracolonic features.


A rare hereditary Transthyretin (TTR)-related systemic amyloidosis (ATTR) with predominant cardiac involvement resulting from myocardial infiltration of abnormal amyloid protein.

Summary:
Epidemiology
Global prevalence is unknown. The prevalence of the Val122Ile variant has been estimated to be 3.5% in American population of African descent, corresponding to potentially 1.6 million carriers in the USA. However, the actual penetrance in this population is unknown, with estimates as low as 10%.
Clinical description
Patients present during late adulthood with restrictive cardiomyopathy (with varying degrees of chronic heart failure and possible brady/tachyarrhythmias). Cardiomyopathy may be accompanied by sensorimotor/autonomic polyneuropathy but in many patients carrying this variant the phenotypic expression may remain exclusively cardiac.
Etiology
Several specific TTR mutations are associated with predominant cardiac involvement. Among these, V122I is particularly common among African-Americans (3.5% of the population).
Diagnostic methods
The gold standard for diagnosis of amyloidosis is histological analysis and Congo red staining of biopsy specimens. Detection of the specific TTR mutation allows confirmation of the diagnosis. A high level of diagnostic suspicion of cardiac amyloidosis can be generated by characteristic echocardiographic and ECG findings, and confirmed by bone tracer scintigraphy and/or magnetic resonance imaging with late enhancement. A family history of cardiac disease may suggest hereditary ATTR amyloidosis etiology.
Differential diagnosis
The differential diagnosis should include other infiltrative/storage myocardial diseases, including other types of cardiac amyloidosis, such as AL amyloidosis. Hypertrophic cardiomyopathy should also be included in the differential diagnosis.
Antenatal diagnosis
Considering the late-onset phenotype and the increasing availability of disease-modifying therapies, antenatal diagnosis has a very limited role in this specific condition.
Genetic counseling
Hereditary ATTR amyloidosis is dominantly transmitted. Genetic counseling is generally highly recommended to at-risk patients' relatives, informing them there is a 50% risk of inheritance in siblings and offspring. For the Val122Ile variant in African-Americans, it is particularly important to discuss the low penetrance and possible gender-related variations, with a higher disease rate observed in males over the age of 70. Factors affecting penetrance are still unknown. In general, pre-symptomatic testing is increasingly offered in hereditary ATTR amyloidosis due to emerging disease-modifying therapies.
Management and treatment
Close monitoring of cardiac function and symptoms by an expert cardiologist is recommended. Supportive therapy plays a major role. Disease modifying therapy is available for hereditary V122I amyloidosis. Patient with exclusive cardiomyopathy can be treated with the TTR stabilizer tafamidis at the dose of 61 mg/day. Patients presenting with a mixed phenotype (cardiomyopathy associated with polyneuropathy) are eligible to a gene-silencing treatment, including the RNAi agent patisiran (or vutrisiran, where already available) and the antisense oligonucleotide inotersen.
Prognosis
Prognosis is driven by the severity of cardiomyopathy. A validated prognostic staging system for patients with hereditary ATTRV122I amyloidosis is the NAC staging system, in which survival correlates with NT-proBNP concentration and eGFR at diagnosis.

                            Last update:
                            May 2023

                            - Expert reviewer(s):
                            Dr Laura OBICI | RITA*

                                * European Reference Network


A rare hereditary ATTR amyloidosis (hATTR) characterized by a progressive, length-dependent sensorimotor axonal polyneuropathy and/or autonomic neuropathy in adulthood. Renal, ocular and cardiac involvement also frequently occurs. Two different phenotypes are associated with this mutation, namely early-onset V30M and late-onset V30M, that differ in terms of age on onset (<50 years or >50 years, respectively), presenting features, histopathological characteristics, rate of disease progression and response to therapy.

Summary:
Epidemiology
ATTRV30M is the most common hATTR. The worldwide prevalence is unknown, although data is available for countries like Portugal, Japan and Sweden where the disease is relatively frequent. In Portugal the estimated incidence is 1/115,000 people a year, and the estimated prevalence is 1/4,360 adults.
Clinical description
Early-onset V30M manifests usually from the fourth decade of life. Inaugural symptoms are consistent with a small fibre neuropathy and typically include pain and temperature sensation loss in lower limbs. Motor neuropathy occurs later. Autonomic features include postural hypotension, gastrointestinal and genitourinary disorders. Rhythm disturbances, including atrioventricular nodal block requiring pacemaker implantation, are also frequent at disease onset. Proteinuria progressing to nephrotic syndrome may be an early clinical finding as well. In late-onset V30M, small and large nerve fibres are usually affected since the early stages of the disease, manifesting with a rapidly progressing sensory and motor polyneuropathy. Carpal tunnel syndrome may anticipate peripheral neuropathy in lower limbs. Infiltrative cardiomyopathy frequently develops, leading to heart failure.
Etiology
The disease is caused by a methionine for valine substitution at residue 30 of the mature TTR protein, which is encoded by the TTR gene located on chromosome18q12.1. It leads to misfolding and dissociation of the TTR tetramer and monomer aggregation as amyloid in tissues and organs.
Diagnostic methods
Detection of V30M TTR variant by genetic testing and tissue biopsy (preferably a non-invasive biopsy like minor labial salivary gland, subcutaneous fat tissue or rectal mucosa) are required for a complete diagnosis. Green birefringence on polarized light microscopy after Congo red staining reveal amyloid deposits. Amyloid deposits are typed by immunohistochemistry or mass spectrometry for definite diagnosis when a patient also presents with a serum and/or urinary monoclonal gammopathy.
Differential diagnosis
The differential diagnosis includes diabetic neuropathy, chronic inflammatory demyelinating polyneuropathy, AL, AGel and AApoAI amyloidosis.
Antenatal diagnosis
Prenatal/pre-implantation diagnosis is possible and should be discussed in the context of genetic counseling. It is more relevant in families with early-onset V30M, depending also on local regulations. The emerging availability of effective disease-modifying therapies is reducing the request for pre-implantation diagnosis. Antenatal diagnosis is usually not an option in late-onset V30M, due to advanced age of onset and reduced penetrance.
Genetic counseling
The pattern of inheritance is autosomal dominant. Genetic counselling should be offered to affected individuals and their at-risk relatives, informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Management of the disease should be multidisciplinary, involving neurologist, geneticist, cardiologist, nephrologist, ophthalmologist and gastroenterologist. Liver transplantation is no longer a first-line treatment. Presently, patients that are able to walk unassisted (FAP stage 1) can be treated with a gene-silencing agent (RNAi patisiran, vutrisiran or ASO inotersen) or with the TTR stabilizer tafamidis 20 mg/day. Patients that require support for walking (FAP stage 2) can be treated with a gene-silencing agent only.
Prognosis
This neurological disease is progressive and highly disabling if untreated. Severe cardiac, renal and ocular manifestations may develop. Before disease-modifying treatment availability, death occurred within a mean interval of 10.8 years after onset of the inaugural symptoms.

                            Last update:
                            May 2023

                            - Expert reviewer(s):
                            Dr Laura OBICI | RITA*

                                * European Reference Network


A rare, pervasive developmental disorder that does not fit the diagnosis for the other specific autistic spectrum disorders (autism, Asperger syndrome, Rett syndrome or childhood disintegrative disorder) and is characterized by usually milder developmental and social delay and less stereotypical autistic behavior.


A rare myelodysplastic/myeloproliferative neoplasm characterized by peripheral blood leukocytosis due to increased numbers of morphologically dysplastic neutrophils and their precursors, hypercellular bone marrow with granulocytic proliferation and dysplasia (with or without dysplasia in the erythroid and megakaryocytic lineages), and prominent dysgranulopoiesis, but no or minimal absolute basophilia or monocytosis. Blasts account for less than 20% of leukocytes in the blood and bone marrow. BCR-ABL1 fusion is absent, as well as PDGFRA, PDGFRB or FGFR1 rearrangement, or PCM1-JAK2. Patients may present with signs and symptoms related to splenomegaly, anemia, or thrombocytopenia. Prognosis is generally poor.


Atypical dentin dysplasia due to SMOC2 deficiency

A rare, genetic, dentin dysplasia disease characterized by extreme microdontia, oligodontia, and abnormal tooth shape (including globular teeth, incisal notches and double tooth formation). Short roots with a variable pulp phenotype (including taurodontia and flame-shaped pulp), enamel hypoplasia and anterior open bite may also be associated.


Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome

A rare genetic disease characterized by the association of Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. Patients display a phenotype of proximal tubulopathy characterized by generalized aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricemia, and additional features not normally seen in Fanconi syndrome (apart from nephrocalcinosis), namely renal impairment, hypercalciuria with relative hypocalcemia, and hypermagnesemia.


A rare form of glycine encephalopathy presenting disease onset or clinical manifestations that differ from neonatal or infantile glycine encephalopathy.

Summary:
Epidemiology
The prevalence of atypical glycine encephalopathy is not known. Approximately 20 cases have been reported to date.
Clinical description
Symptoms are mostly non-specific and are not similar to the severe neurological symptoms observed in neonatal and infantile GE (see these terms). Some patients have milder disease with onset from late infancy to adulthood, while others have rapidly progressive severe disease often of late onset. It also includes patients with transient hyperglycinemia, whose symptoms in neonatal period resemble those of neonatal form. Manifestations include cognitive decline, behavioral disorders, ataxia, peripheral neuropathy and optic atrophy.
Etiology
Etiology of atypical glycine encephalopathy remains largely unknown. It was reported that some patients had mutations in genes encoding GCS components.
Genetic counseling
Mode of inheritance has not been identified in most of patients with atypical glycine encephalopathy

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                             Shigeo KURE


A rare, genetic thrombotic microangiopathy due to dysregulation of the alternative complement pathway and characterized by the triad of hemolytic anemia, thrombocytopenia, and acute renal dysfunction.

Summary:
Epidemiology
The estimated prevalence in Europe is 1/100,000. Atypical hemolytic uremic syndrome (aHUS) accounts for 5-10% of hemolytic uremic syndrome (HUS) cases in children, and most cases in adults.
Clinical description
Disease onset may occur at any age. Presentation is typically of acute onset, nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The episode is usually preceded by a triggering event such as upper respiratory infection or viral gastroenteritis. In 20% of patients, onset is insidious with relapsing subclinical anemia, thrombocytopenia, decreased or rarely preserved renal function, and nonspecific symptoms (e.g.fatigue, and anorexia). The renal manifestations are variable across patients and can range from acute anuric kidney injury requiring dialysis to chronic kidney disease or chronic proteinuria. Approximately half of the cases progress to end-stage kidney disease. Extra-renal manifestations occur in approximately 20% of patients and include neurological symptoms (10%; e.g. irritability, drowsiness, seizures, diplopia, cortical blindness, hemiparesis or hemiplegia, stupor, or coma), myocardial infarction (3%), pulmonary hemorrhage, ischemic colitis, pancreatitis, hepatocellular injury, and peripheral vascular disease.
Etiology
Most of the cases present with uncontrolled complement activation that results in endothelial damage. Pathogenic mutations have been identified in several genes coding proteins and regulators of complement cascade. The most frequent include CFH (1q31.3), CFI (4q25), CD46 (1q32.2), C3 (19p13.3) and CFB (6p21.33). Rearrangements in CFH gene and CFH related genes also cause similar phenotype. An acquired form caused by factor H antibodies exists. Approximately 10% of the aHUS patients have these auto-antibodies identified. There is a possible link to CFHR1 and CFHR3 gene deletions that increase the risk of developing these antibodies in an individual.
Diagnostic methods
Diagnosis is suspected on presentation of thrombotic microangiopathy with renal involvement, and the exclusion of the main differential diagnoses. Diagnosis is confirmed by genetic testing (sequencing and multiplex ligation-dependent probe amplification (MLPA), complement cascade proteins functional tests and screening for factor H auto-antibodies. Tests should evaluate C3, C4, Complement factor H, I and B, membrane cofactor protein, as well as copy number variations by MLPA in CFHR genes and their hybrids with CFH.
Differential diagnosis
The main differential diagnoses includes HUS due to Shiga toxin Escherichia coli, thrombotic thrombocytopenic purpura (both congenital and acquired type) and HUS secondary to immunological or external factors (drugs). Cobalamin C deficiency can present in a similar fashion.
Antenatal diagnosis
There are no specific anatomical prenatal markers. Genetic prenatal diagnosis is theoretically possible when there is a known familial genetic risk.
Genetic counseling
Approximately 20-25% of cases are familial, usually with autosomal dominant patterns of predisposition. Autosomal recessive pedigrees can be seen less often. Variable penetrance in autosomal dominant pedigrees is common.
Management and treatment
The recommended first line targeted therapy is with eculizumab which blocks complement terminal pathway, thus halting endothelial damage and ensuing thrombotic microangiopathy. Eculizumab should be administered within 24 hours of presentation and is recommended as a lifelong treatment, although trials are ongoing regarding the safe discontinuation. Targeted therapy is accompanied by symptomatic support of acute renal injury by renal replacement therapy (dialysis) and red blood cell transfusions. Plasma exchange (or plasma infusion) is less effective. However, it might still have some relevance in countries with limited resources and no access to eculizumab. For anti-CFH antibody-mediated disease, immunosuppressive regimens (steroids, rituximab and cyclophosphamide) targeting auto-antibody production combined with plasma exchange are also utilized, particularly when eculizumab is unavailable. All patients on eculizumab treatment require prophylactic N. meningitits vaccination and antibiotic prophylaxis.
Prognosis
Prognosis is significantly improved with eculizumab treatment; however, time-to-treatment is a significant factor in recovery of renal function. Without treatment, there is a significant risk of developing end-stage kidney disease.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Dr Michal MALINA | ERKNet*

                                * European Reference Network


A form of hypotonia-cystinuria type 1 syndrome characterized by mild to moderate intellectual disability in addition to classic hypotonia-cystinuria syndrome phenotype (cystinuria type 1, generalised hypotonia, poor feeding, growth retardation, and minor facial dysmorphism).


A complex form of young-onset Parkinson disease that manifests with pyramidal signs, eye movement abnormalities, psychiatric manifestations (depression, anxiety, drug-induced psychosis, and impulse control disorders), intellectual disability, and other neurological symptoms (such as ataxia and epilepsy) along with classical parkinsonian symptoms.

Summary:
Epidemiology
To date, only six families (from Iran, Italy, The Netherlands, Pakistan, and Turkey) have been reported.
Clinical description
The disease has a juvenile onset (usually in the early teens or early twenties) and manifests with pyramidal signs, dystonia, psychiatric (depression, anxiety, drug-induced psychosis, dementia, and impulse control disorders) and other neurological (such as ataxia and epilepsy) symptoms along with classical parkinsonian symptoms (bradykinesia, postural instability, rigidity, involuntary movements, dysarthria, supranuclear gaze, hypomimia, gait impairment, and myoclonic jerks). Intellectual disability is also observed.
Etiology
Mutations in the genes ATP13A2 (1p36), PLA2G6 (22q13.1), FBXO7 (22q12.3), DNAJC6 (1p31.3), SPG11 (15q13-q15), SPG15 (14q24.1) and SYNJ1 (21q22.2) are associated with Atypical juvenile parkinsonism (AJP).
Genetic counseling
AJP usually occurs in an autosomal recessive manner. However, sporadic cases have also been reported and the majority of these cases are born from consanguineous parents.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Coro PAISAN-RUIZ


An intermediate form of lichen myxedematosus (LM) (a form of mucin dermal deposit) which does not meet the criteria for either scleromyxedema or the localized form. Three clinical subtypes have been described and include scleromyxedema without monoclonal gammopathy; localized forms with monoclonal gammopathy and/or systemic symptoms; localized forms with mixed features of the 5 subtypes of localized LM (discrete form, acral persistent papular mucinosis, self-healing papular mucinosis, papular mucinosis of infancy, and a pure nodular form). The course of atypical LM is unpredictable because only a few cases have been reported.


A rare benign ovarian tumor characterized by a benign pelvic mass associated with right-sided pleural effusion, but without ascites. The pleural effusion resolves after resection of the tumor.


Atypical Norrie disease due to Xp11.3 microdeletion

A rare chromosomal anomaly syndrome, resulting from the partial deletion of the short arm of chromosome X, principally characterized by classical Norrie disease (bilateral, severe retinal malformations and opacity of the lens leading to congenital blindness, on occasion associated with progressive sensorineural deafness and intellectual disability), microcephaly, hypotonia, psychomotor and growth delay, moderate to severe mental handicap and disruptive behaviour. Clinical phenotype is highly variable and immunodeficiency, epilepsy and hypogonadism have also been reported.


A very rare type of choroid plexus tumor that, contrary to papilloma of the choroid plexus, has an increased likelihood of progression to carcinoma and of recurrence. It displays brisk mitoses, nuclear pleomorphism, raised cellular density, obscurity of the papillary growth pattern, and cell necrosis.


Atypical progressive supranuclear palsy syndrome

A form of progressive supranuclear palsy syndrome (PSP), a rare late-onset neurodegenerative disease, characterized by an underlying PSP-tau pathology, that does not conform to the classic presentation of PSP. The clinical phenotype is variable and comprises PSP with predominant Parkinsonism (PSP-P), PSP with progressive gait freezing (PSP-PGF), PSP with predominant corticobasal syndrome (PSP-CBS), PSP with predominant speech/language disorder (PSP-SL), PSP with predominant frontal presentation (PSP-F), PSP with predominant ocular motor dysfunction (PSP-OM), and PSP with predominant postural instability (PSP-PI).


A rare genetic neurological disorder characterized by the presence of two or more of the main criteria for classic Rett syndrome (loss of acquired purposeful hand skills, loss of acquired spoken language, gait abnormalities, stereotypic hand movements), a period of regression followed by recovery or stabilization, and five out of eleven supportive criteria (breathing difficulties, bruxism, impaired sleep pattern, abnormal muscle tone, peripheral vasomotor disturbances, scoliosis/kyphosis, delayed growth, small cold hands and feet, inappropriate laughter or screaming spells, decreased pain sensation, and intense eye communication). Like classic Rett syndrome, it almost exclusively affects girls, while the disease course may be either milder or more severe.

Summary:
Epidemiology
Based on reports that up to 32% of RTT cases show an atypical phenotype, the prevalence of atypical RTT is estimated at around 1/45,000. Like classic RTT, atypical RTT syndrome predominantly affects girls.
Clinical description
Atypical forms may present with either a milder or more severe clinical picture than that seen in typical RTT. Several subvariants of atypical RTT have been defined. i) The early-onset seizure type (Hanefeld variant) is characterized by seizures in the first months of life with subsequent development of RTT features. ii) The congenital variant (Rolando variant) is the most severe form of atypical RTT, with onset of classic RTT features during the first three months of life. iii) The 'forme fruste' is a milder variant with onset in early childhood and an incomplete and protracted course. iv) The late childhood regression form is characterized by a normal head circumference and by a more gradual and later onset (late childhood) regression of language and motor skills. v) The preserved speech variant (PSD or Zappella variant) is marked by recovery of some verbal and manual skills.
Etiology
The early-onset seizure type (Hanefeld variant) is frequently caused by mutations in the X-linked CDKL5 gene (Xp22). A translocation involving the NTNG1 gene (1p13.2-p13.1) has also been identified in a patient with early seizures and atypical RTT. The congenital variant (Rolando variant) is generally caused by mutations in the FOXG1 gene (14q11-q13). A microdeletion syndrome involving a 14q12 interstitial deletion has also been described with a similar phenotype but with the additional feature of facial dysmorphism. The preserved speech variant (PSD or Zappella variant) is caused in at least some cases by mutations in the MECP2 (Xq28) gene, which is also responsible for the majority of cases of classic RTT.
Diagnostic methods
Diagnosis relies on clinical evaluation using the diagnostic criteria for atypical RTT originally defined by Hagberg in 1994: an atypical case must meet at least three of the six main criteria and at least five of the eleven supportive criteria. Molecular analysis may allow confirmation of the diagnosis.
Differential diagnosis
Differential diagnoses include Angelman syndrome, autism, cerebral palsy, inborn errors of metabolism and severe intellectual deficit (see these terms).
Genetic counseling
Genetic counseling should be proposed and prenatal testing is available for female relatives of an index case, who may asymptomatic due to skewed X-inactivation.
Management and treatment
At present, there is no specific cure for atypical RTT. Treatment is symptomatic and supportive. Medication may be needed for breathing irregularities, sleep disturbances (melatonin), agitation (risperidone), rigidity (carbidopa, levodopa) and motor difficulties, and antiepileptic drugs may be used to control seizures. Anti-reflux agents may also be required.
Prognosis
The course of atypical Rett syndrome, including the age of onset and the severity of symptoms, varies from child to child. Despite the range of symptoms, most individuals with RTT continue to live well into middle-age and beyond.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Pr Thierry BIENVENU


A rare, highly malignant central nervous system (CNS) rhabdoid tumor (RT) found almost exclusively in children.

Summary:
Epidemiology
The prevalence of ATRT is estimated to be 1- 2% among all pediatric CNS tumors and 10-20% of CNS tumors in patients less than 3 years. The age-standardized incidence rate is estimated to be 1/72,500 persons/year in Austria.
Clinical description
Onset of primary ATRT occurs from birth to adulthood, with the highest incidence in the first 2 years of life. Only single cases have been reported in adults. Manifestations of ATRT include macrocephaly, vomiting, irritability, headache, apathy/lethargy, ataxia, neck stiffness, and seizures. ATRT can occur in the posterior fossa, fourth ventricle, cerebellar vermis (with intraventricular extension), cerebellum (alone or in combination with a supratentorial tumor), cerebral hemisphere, pineal region, frontal lobe, brainstem, spinal cord or result from metastases of renal RT. ATRT can involve the cerebellopontine angle (CPA), resulting in acute cranial nerve deficits (such as acute facial nerve palsy) as the presenting sign.
Etiology
The vast majority of ATRT tumors show biallelic somatic inactivation of SMARCB1, a gene suppressor which encodes a core member of the adenosine triphosphate (ATP)-dependent SWI/SNF chromatin remodeling complex and which is a key regulator of cell proliferation and differentiation. In rare cases, mutations in the SMARCA4 gene, which encode another SWI/SNF chromatin-remodeling complex member, are observed.
Diagnostic methods
Diagnosis is based on imaging findings (magnetic resonance and computed tomography scan) showing large and hyperdense solid tumors with marked tumor necrosis, intratumoral hemorrhage, patchy pattern of enhancement and association with moderate to marked adjacent parenchymal edema. Intratumoral calcification may be observed. Histological examination of the tumor shows a diffuse growth pattern of predominantly polygonal cells, vesicular nuclei with prominent nucleoli, high mitotic index, multiple necrosis or cystic foci and scattered cells that contain a cytoplasmic hyaline globular inclusion adjacent to the nucleus (rhabdoid cells). ATRT may be composed only of rhabdoid cells or, more commonly, may contain areas of rhabdoid cells juxtaposed to areas of primitive neuroepithelial cells and/or mesenchymal tissue and/or epithelial tissue. Tumor cells are immunopositive for vimentin, epithelial markers (cytokeratin, epithelial membrane antigen), rarely positive for the mesenchymal marker S-100 and immunonegative for desmin, GFAP, synaptophysin and neurofilaments. Diagnosis is confirmed by loss of nuclear staining of SMARCB1 (or SMARCA4) protein by immunohistochemistry.
Differential diagnosis
Differential diagnosis includes medulloblastoma, ependymoblastoma, primitive neuroectodermal tumor, choroid plexus carcinoma, Ewing sarcoma (see these terms), undifferentiated chordoma, anaplastic meningioma and small cell sarcoma.
Genetic counseling
ATRT can occur sporadically or as part of a RT predisposition syndrome (familial RT; see this term).
Management and treatment
No standard of care exists for ATRT. Treatment includes the maximal resection of the tumor mass and postoperatively, chemotherapy with radiotherapy as long as it is compatible with the age of the patient.
Prognosis
ATRT is highly aggressive and the prognosis is exceedingly dismal compared with other malignant brain tumors. Reported survival times have ranged from 0.5 to 11 months, with a particularly poor outcome for infants.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Franck BOURDEAUT


An heterogeneous group of cases that are clinically diagnosed as Werner syndrome (WS) but do not carry WRN gene mutations. Similar to classical WS caused by WRN mutations, patients generally exhibit an aged appearance and common age-related disorders at earlier ages compared to the general population.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Atypical WS shows accelerated aging characterized by short stature, thinning/graying of hair, a ''bird-like'' facial appearance, skin atrophy, lipodystrophy, myopathy along with other age-related disorders such as osteoporosis and atherosclerosis. Compared to WS, it has an earlier age of onset (early 20s or earlier) and a more rapid rate of progression. Cataracts are often not present.
Etiology
A subset of atypical WS is caused by the mutation of the LMNA gene, the same causal gene seen in Hutchinson-Gilford progeria syndrome (HGPS; see this term) that codes for the nuclear intermediate filament, lamin A/C. The LMNA type of atypical WS follows an autosomal dominant pattern of inheritance. Additional causes of atypical WS are being discovered, and their inheritance patterns elucidated.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Fuki HISAMA  - Dr George MARTIN  - Dr Junko OSHIMA


A rare neurologic disease characterized by seizures that are triggered by acoustic stimulation, which can be simple (as in startle epilepsy) or complex (e.g. musicogenic seizures, seizures triggered by the voice).


Auditory neuropathy-optic atrophy syndrome

A rare mitochondrial disease characterized by bilateral auditory neuropathy and optic atrophy. Patients present hearing and visual impairment in the first or second decade of life, while psychomotor development is normal. Bilateral retinitis pigmentosa has been reported in association.


Auricular abnormalities-cleft lip with or without cleft palate-ocular abnormalities syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of auricular abnormalities (such as external ear abnormalities and postauricular pits) and cleft lip with or without cleft palate. Additional manifestations include myopia, nystagmus, and retinal pigment abnormalities.


A rare, genetic dysostosis with predominant craniofacial involvement characterized by bilateral external ear malformations, mandibular condyle hypoplasia, microstomia, micrognathia, microglossia and facial asymmetry. Additional manifestations include hypotonia, ptosis, cleft palate, full cheeks, developmental delay, hearing impairment and respiratory distress. Significant intra- and interfamilial phenotypic variation has been reported.


A very rare condition characterized by multiple osseous dysplasia, characteristic ear shape (elongation of the lobe that is attached and accompanied by a small, slightly posterior lobule) and somewhat short stature.

Summary:
Epidemiology
The disorder has been observed in numerous members of two families.
Clinical description
Dysplasia of the radiocapitellar joint was a constant finding in all affected individuals.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            March 2008


Autism spectrum disorder due to AUTS2 deficiency

A rare genetic syndromic intellectual disability characterized by global developmental delay and borderline to severe intellectual disability, autism spectrum disorder with obsessive behavior, stereotypies, hyperactivity but frequently friendly and affable personality, feeding difficulties, short stature, muscular hypotonia, microcephaly, characteristic dysmorphic features (hypertelorism, high arched eyebrows, ptosis, deep and/or broad nasal bridge, broad/prominent nasal tip, short and/or upturned philtrum, narrow mouth, and micrognathia), and skeletal anomalies (kyphosis and/or scoliosis, arthrogryposis, slender habitus and extremities). Other clinical features may include hernias, congenital heart defects, cryptorchidism and seizures.


Autism spectrum disorder-epilepsy-arthrogryposis syndrome

A form of congenital disorders of N-linked glycosylation characterized by distal arthrogryposis (mild flexion contractures of the fingers, deviation of the distal phalanges, swan-neck deformity), retromicrognathia, general muscle hypotonia, delayed psychomotor development, autism spectrum disorder (speech delay, abnormal use of speech, difficulties in initiating, understanding and maintaining social interaction, limited non-verbal communication and repetitive behavior), seizures, microcephaly and mild to moderate intellectual disability that becomes apparent with age.


Autism-epilepsy syndrome due to branched chain ketoacid dehydrogenase kinase deficiency

A rare disorder of branched-chain amino acid metabolism characterized by childhood-onset epilepsy, autism and intellectual disability with reduced levels of plasma branched chain aminoacids.


A rare autoimmune disease with skin involvement characterized by recurrent episodes with isolated or multiple painful edematous inflammatory skin lesions progressing to ecchymoses within 24 hours, due to autosensitization to a stromal component of the patient's own erythrocytes. The development of the lesions is usually preceded by emotional or physical stress, followed by a prodromal stage with fatigue or malaise. Lower limbs and trunk are the most frequently involved sites. Accompanying features may include fever, arthralgia, myalgia, headache, gastrointestinal problems, or hematuria and epistaxis, among others. The disease occurs predominantly in women.


Autoimmune encephalopathy with parasomnia and obstructive sleep apnea

A rare neurologic disorder characterized by a unique non-REM and REM parasomnia with sleep breathing dysfunction, gait instability and repetitive episodes of respiratory insufficiency, as well as autoantibodies against IgLON5. Patients may present stridor, chorea, limb ataxia, abnormal ocular movements, and bulbar symptoms (i.e. dysphagia, dysarthria, episodic central hypoventilation) with normal brain MRI. Excessive day sleepiness and cognitive deterioration have also been reported.


Cold autoimmune hemolytic anemia comprises two types of autoimmune hemolytic anemia (AIHA; see this term) defined by the presence of cold autoantibodies (autoantibodies which are active at temperatures below 30°C): cold agglutinin disease (CAD), which is the more common, and paroxysmal cold hemoglobinuria (PCH; see these terms).

Summary:
Clinical description
CAD is more common in people over the age of 55 years, while PCH typically presents in young children.
Etiology
CAD is caused by IgM autoantibodies while PCH is caused by an IgG immunoglobulin.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Pr Marc MICHEL


Warm autoimmune hemolytic anemia is the most common form of autoimmune hemolytic anemia (see this term) defined by the presence of warm autoantibodies against red blood cells (autoantibodies that are active at temperatures between 37-40°C).

Summary:
Epidemiology
Warm auto-antibodies are responsible for 60/70% of AIHA, whose annual incidence is estimated to be between 1/35,000-1/80,000 in North America and Western Europe.
Clinical description
Warm AIHA is more common in women (female to male ratio approximately 2:1 in adults). The disease is characterized by symptoms due to the anemia including fatigue, exertional dyspnea, and, more rarely, jaundice and dark urine in case of severe hemolysis. If the disease is severe, fever, chest pain, syncope or heart failure may occur. Hemolysis occurs mainly in the spleen, so mild splenomegaly is relatively common.
Etiology
Approximately half of cases of warm AIHA are primary (idiopathic) while the other half are secondary to an underlying condition, frequently chronic lymphocytic leukemia or an autoimmune systemic disease such as systemic lupus erythematosus (SLE; see this term).
Diagnostic methods
Diagnosis is based on clinical and laboratory evidence of hemolytic anemia and the detection of autoantibodies with the direct anti-globulin test (DAT). Typically in warm AIHA, the DAT pattern is IgG alone or IgG with complement C3.
Differential diagnosis
The differential diagnosis of warm AIHA includes a post-transfusional alloimmune hemolytic anemia and, when the DAT is negative (less than 5% of all warm AIHAs), every other cause of either hereditary or acquired hemolytic anemia.
Management and treatment
The most common therapy and the cornerstone of treatment for warm AIHA are corticosteroids. If these are ineffective, splenectomy can be considered. Rituximab has become an option in refractory disease and the use of immunosuppressors can be helpful in chronic severe refractory cases.
Prognosis
Warm AIHA is often severe but death is usually a rare outcome, except in elderly patients who have a higher risk of cardiovascular manifestations (in cases with severe anemia) and also of severe treatment-induced infections. Prognosis depends on the underlying condition.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Pr Marc MICHEL


Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome due to TPP2 deficiency

A rare genetic immune disease characterized by infantile or childhood onset of combined immunodeficiency with recurrent viral, bacterial, and fungal infections, severe autoimmunity mainly manifesting as antibody-mediated destruction of red blood cells, platelets, and neutrophils, and mild to moderate developmental delay. Laboratory findings include decreased circulating T-, B-, and natural killer cells, and hypergammaglobulinemia.


A rare, autoimmune disorder in which various types of auto-antibodies are directed against red blood cells causing their survival to be shortened and resulting in hemolytic anemia.

Summary:
Epidemiology
The annual incidence of AIHA is estimated at 1/35,000-1/80,000 in North America and Western Europe. Warm autoantibodies (active at temperatures between 37-40°C) cause 60-70% of cases, cold autoantibodies (active at temperatures below 30°C) account for 13-15% of cases, mixed type occurs in less than 10% of cases and the annual incidence of drug-induced AIHA is estimated at 1/1,000,000.
Clinical description
The disease can appear at any age and there is a slight predominance of cases in females (60%). AIHA is characterized by hemolytic anemia, which is most often revealed by an unusual weakness and fatigue with tachycardia and exertional dyspnea, and also in some cases by jaundice, dark urine and/or splenomegaly.
Etiology
AIHA can be primary (idiopathic), secondary to infection or associated with diseases such as B-cell lymphomas, other systemic or organ-specific autoimmune diseases, Hodgkin's disease, hepatitis or primary immunodeficiencies, or, in the case of drug-induced AIHA, caused by a reaction to drugs. The condition may develop gradually or occur suddenly. There are different subtypes of AIHA according to the temperature reactivity of the autoantibody: warm AIHA, cold AIHA (which includes cold agglutinin disease, CAD and paroxysmal cold hemoglobinuria or PCH), mixed-type AIHA and drug-induced AIHA (see these terms). Half of warm AIHA cases are idiopathic whereas almost all cold AIHA are secondary.
Diagnostic methods
Diagnosis is based on clinical or laboratory evidence of hemolysis and the detection of autoantibodies by means of the direct anti-globulin test (DAT).
Differential diagnosis
Biological differential diagnoses include other non-autoimmune causes of hemolytic anemia.
Management and treatment
Treatment is dependent on correct diagnosis. Cases of drug-induced AIHA should be investigated to determine if stopping a drug will induce remission. For warm AIHAs, corticosteroids are used, followed by splenectomy if necessary. Some targeted therapies, such as rituximab (anti-CD20 monoclonal antibody), have shown promising results. Other immunosuppressive treatments may be suggested. For cold AIHA, keeping the patient warm may be sufficient, and corticosteroids and splenectomy must be avoided as they are known to be ineffective. Rituximab has been demonstrated as a relatively effective and safe option for treating patients with symptomatic chronic cold agglutinin disease. Transfusion may be necessary in cases with inadequate response to therapy and life-threatening worsening anemia. However, transfusion can be complicated because of the presence of the autoantibodies, which can, in addition, increase destruction of the donor red blood cells.
Prognosis
Prognosis depends on the underlying cause of the disease and whether symptoms are managed appropriately and in a timely manner, but death is a rare outcome.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Pr Marc MICHEL


A form of autoimmune hepatitis characterized by clinical presentation as cryptogenic hepatitis, interface hepatitis on histological examination, elevated serum aminotransferase levels, hypergammaglobulinemia/elevated immunoglobulin G, and presence of circulating autoantibodies, specifically antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), and/or anti-soluble liver antigen/liver pancreas antigen antibodies (anti-SLA/LP). The disease predominantly develops at a post-pubertal age and most commonly takes a chronic course, although acute or acute severe presentation may also be observed. Typical concurrent autoimmune diseases are autoimmune thyroiditis and rheumatic diseases.


A form of autoimmune hepatitis characterized by clinical presentation as cryptogenic hepatitis, interface hepatitis on histological examination, elevated serum aminotransferase levels, hypergammaglobulinemia/elevated immunoglobulin G, and presence of circulating autoantibodies, specifically antibodies to liver kidney microsome type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) antibodies. The disease typically manifests in childhood or adolescence with an acute onset, often with acute liver failure. Long-term immunosuppression is usually required. Reported concurrent autoimmune diseases are autoimmune thyroiditis, diabetes mellitus, and vitiligo.


A rare liver disease characterized by immune-mediated, acute or chronic liver inflammation, clinically presenting as cryptogenic hepatitis, with interface hepatitis on histological examination, elevated serum aminotransferase levels, and hypergammaglobulinemia / elevated immunoglobulin G, in the presence or absence of specific circulating autoantibodies. Patients may be asymptomatic, chronically ill, or present with acute liver failure. Concurrent autoimmune diseases are frequently observed.

Summary:
Epidemiology
The incidence and prevalence of autoimmune hepatitis (AIH) varies across different age groups, ethnicities and geographical region. In Caucasian Europeans and North Americans, the prevalence is approximately 1/6,000. Although possibly under recognized, a lower occurrence is reported in Asian countries. All ages and both genders may be affected, although there is a clear female preponderance.
Clinical description
The disease occurs in both pediatric and adult patients. Presentation is highly variable; approximately 25% of patients present with an acute onset or an acute- on-chronic disease process. A subset has severe disease at presentation and may rapidly progress to liver failure. The most common clinical phenotype (two-thirds of patients) is characterized by an insidious onset either without any apparent symptom or with non-specific symptoms (including fatigue, general ill health, right upper quadrant pain, lethargy, malaise, anorexia, weight loss, nausea, pruritus, fluctuating jaundice and polyarthralgia of the small joints without arthritis). Half of patients have liver fibrosis at diagnosis, and one third have cirrhosis irrespective of the presence of symptoms. AIH subtypes are classed based on presence of auto-antibodies. AIH type 1 accounts for 90% of cases, occurs at any age and is defined by detection of either antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), or anti-soluble liver antigen/liver pancreas antigen antibodies (anti-SLA/LP). AIH type 2 is defined by the presence of anti-liver kidney microsome type 1 (anti-LKM1), anti-liver cytosol (anti-LC1) and, rarely, anti-liver-kidney microsomal antibody type 3 (anti-LKM3), onset is in childhood or young adulthood, and is typically of severe acute disease with frequent failure of treatment and frequent relapses after steroid withdrawal. Antibodies may be absent in up to one third of patients, particularly in severe, acute AIH, and is defined as seronegative AIH. Concurrent autoimmune or immune-mediated diseases in the patient are common.
Etiology
Environmental factors, genetic susceptibility, and impaired immunoregulatory networks are thought to play a role.
Diagnostic methods
AIH should be considered in any patient with acute or chronic liver disease. Diagnosis is very challenging, and is based in diagnostic scores comprised of typical, but mostly non-specific, findings of autoantibodies (for which testing is not currently standardized), hypergammaglobulinemia/elevated IgG, histological pattern of interface hepatitis, exclusion of other liver diseases and, eventually, the treatment response to steroids.
Differential diagnosis
The differential diagnosis is of other causes of acute or chronic liver failure such as the rare disorder Wilson disease as well as viral hepatitis, hepatotoxic drugs, and excessive alcohol consumption.
Management and treatment
The standard treatment is with a steroid-based induction and followed by thiopurine-based maintenance regime (typically prednisolone and azathioprine). Immunosuppressive treatment tends to be life-long. The aim of treatment is complete biochemical remission defined as normalized liver enzymes and gammaglobulins / IgG. Some patients require second- or third-line treatment due to intolerance or insufficient response to standard treatment. Repeated liver histology can be used to guide therapy. Therapy withdrawal can be considered where patients have stable biochemical remission for at least 24-36 months; however, relapses are common. Untreated autoimmune hepatitis can lead to cirrhosis, complications of cirrhosis, and eventually to liver failure.
Prognosis
Morbidity largely relates to treatment side effects. The risk of mortality is determined by disease progression to liver cirrhosis under insufficient treatment response and by acute severe presentation. Patients with AIH-onset under the age of 18 seem to be more prone to recurrent flares.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Marcial SEBODE | RARE-LIVER*

                                * European Reference Network


A rare parathyroid disease and phosphocalcic metabolism anomaly characterized by hypocalcemia, hyperphosphatemia, hypercalciuria, and low serum parathyroid hormone levels, in the presence of autoantibodies against parathyroid tissue. Clinical signs and symptoms are of variable severity and include paresthesia, seizures, laryngospasm, tetany, cardiac dysrhythmias, calcifications of the basal ganglia, and neuropsychological manifestations such as anxiety, depression, confusion, or hallucination. The condition may occur as an isolated disease or in association with other autoimmune diseases.


Autoimmune interstitial lung disease-arthritis syndrome

A rare genetic systemic or rheumatologic disease characterized by interstitial lung disease (often with pulmonary hemorrhage) and inflammatory arthritis, associated with high-titer autoantibodies (including anti-nuclear and anti-neutrophil cytoplasmic antibodies, and rheumatoid factor). Patients present from infancy to adolescence with tachypnea, cough, hemoptysis, and/or joint pain. Some patients may also develop glomerular disease.


Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency

A rare, primary immunodeficiency characterized by variable combination of enteropathy, hypogammaglobulinemia, recurrent respiratory infections, granulomatous lymphocytic interstitial lung disease, lymphocytic infiltration of non-lymphoid organs (intestine, lung, brain, bone marrow, kidney), autoimmune thrombocytopenia or neutropenia, autoimmune hemolytic anemia and lymphadenopathy.


Autoimmune lymphoproliferative syndrome-recurrent viral infections due to CASP8 deficiency

A rare genetic disorder characterized by lymphadenopathy and/or splenomegaly and recurrent infections due to herpes viruses.

Summary:
Epidemiology
Prevalence of this disorder is not known. It is extremely rare with four individuals in one family identified to date.
Clinical description
Development is reported to be normal in affected patients. Clinical signs include lymphadenopathy and splenomegaly, and development of recurrent sinopulmonary and significant mucocutaneous infections with the Herpes zoster and Herpes simplex viruses. Patients are also poorly responsive to immunization and seem to benefit from IVIG supplementation.
Etiology
The disorder is caused by germline homozygous mutations in the CASP8 gene (2q33-q34) involved in the execution phase of cell apoptosis. Carriers with a normal copy of the gene are asymptomatic.
Diagnostic methods
Biologically, autoimmune lymphoproliferative syndrome with recurrent viral infections is characterized by slightly elevated double-negative T cells (DNTs), and defective Fas-mediated apoptosis of B, T, and NK lymphocytes.
Genetic counseling
The pattern of inheritance appears to be autosomal recessive.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Koneti RAO


A rare, inherited disorder characterized by non-malignant lymphoproliferation, multilineage cytopenias, and a lifelong increased risk of Hodgkin's and non-Hodgkin's lymphoma.

Summary:
Epidemiology
The prevalence of ALPS is unknown. It has been characterized in more than 500 patients to date and has been reported worldwide in various ethnic groups.
Clinical description
ALPS is clinically heterogeneous with the following primary clinical signs: lymphoproliferation, manifesting as lymphadenopathy and hepatosplenomegaly with or without hypersplenism, often improving with age, autoimmune disease, mostly involving blood cells, and an increased risk of lymphoma lifelong. Many patients develop non-malignant lymphoproliferation during the first years of life. Clinical manifestations of autoimmunity in the form of hemolytic anemia, thrombocytopenia, neutropenia, or autoimmune hepatitis are of variable severity but these signs are often absent at the time of diagnosis. Autoimmunity has been reported to potentially affect almost any organ, leading to uveitis, pulmonary fibrosis, gastritis, colitis, nephritis, urticaria, arthritis, or rarely autoimmune neurological complications. The disease course is also variable. Several genetic subtypes based on the causative genes and types of mutations have been proposed and result in often similar clinical presentations and outcomes. These include ALPS-FAS, ALPS-FASLG (FASgene), ALPS-CASP10 (CASP10), and ALPS-U (undetermined genetic defect).
Etiology
ALPS is caused by defective lymphocyte homeostasis. Germline mutations in the FAS (10q24.1), FASLG (1q23), or CASP10 (2q33-q34) genes are known to be associated with ALPS. 75% of cases are associated with heterozygous mutations in FAS. The second largest group (10%) has somatic mutations in FAS, while CASP10 (2-3%) and FASLG (<1%) mutations are extremely rarely reported. Some patients do not have mutations in any of these genes (ALPS-U). More recently one case of an ALPS-like disorder due to mutation in the PRKCD gene (3p21.31) was reported. This patient however did not have elevated DNT cells and hence does not fit the diagnostic criteria.
Diagnostic methods
Diagnosis is based on clinical, laboratory and genetic findings. A definitive diagnosis is established in the presence of both of the required diagnostic criteria, i.e. chronic non-malignant, non-infectious lymphadenopathy and/or splenomegalyand elevated TCR alpha/beta-double-negative T cells (DNTs) with normal or elevated lymphocyte counts, along with one primary accessory criterion, including defective lymphocyte apoptosis, and germline or somatic mutations in FAS, FASLG or CASP10.
Genetic counseling
Depending on the specific genetic mutation, inheritance may be autosomal dominant or autosomal recessive.
Management and treatment
Some patients may require chronic immunosuppressive therapies with sirolimus and mycophenolate mofetil.
Prognosis
The prognosis for ALPS patients remains guarded. ALPS-FAS patients have a significantly increased risk of non-Hodgkin's and Hodgkin's lymphoma which can occur at any age and responds to conventional chemotherapy.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Koneti RAO


Type 1 autoimmune pancreatitis is a form of autoimmune pancreatitis seen in elderly males (>60 years) and presenting with abdominal pain, steatorrhea, obstructive jaundice and other organ (bile duct, kidneys and retroperitoneum) involvement. It is thought to be due to an immunoglobulin G4 (IgG4)-associated systemic disease.


Type 2 autoimmune pancreatitis is a form of autoimmune pancreatitis (see this term) affecting both sexes and having a younger age of onset (<60 years) and presenting with abdominal pain, steatorrhea and obstructive jaundice.


A rare pancreatic disease characterized by chronic non-alcoholic pancreatitis that presents with abdominal pain, steatorrhea, obstructive jaundice and responds well to steroid therapy and is seen in two subforms: type 1, which affects elderly males, involves other organs and has increased immunoglobin G4 (IgG4) levels and type 2, which affects both sexes equally but presents at a younger age and has no other organ involvement or increased IgG4 levels.