A very rare acrofacialdyosotosis characterized by short stature, acrocephaly, ocular hypertelorism, ptosis of eyelids, ocular proptosis, downslanting palpebral fissures, high nasal bridge, anteverted nostrils, short philtrum, cleft palate, micrognathia, abnormal external ears, preauricular pits, mixed hearing loss, bulbous digits, metatarsus varus, pectus excavatum and various radiological abnormalities. Features of this syndrome were reported to overlap with otopalatodigital syndrome types 1 and 2. There have been no further descriptions in the literature since 1988.


A rare, genetic, chronic, recurrent, slowly progressive, epidermal disease characterized by small, sterile, pustular eruptions, involving the nails and surrounding skin of the fingers and/or toes, which coalesce and burst, leaving erythematous, atrophic skin where new pustules develop. Onychodystrophy is frequently associated and anonychia and osteolysis are reported in severe cases. Local expansion (to involve the hands, forearms and/or feet) and involvement of mucosal surfaces (e.g. conjunctiva, tongue, urethra) may be observed.


A rare inherited inborn error of metabolism resulting in a severe zinc deficiency and characterized by acral dermatitis, alopecia, diarrhea and growth failure.

Summary:
Epidemiology
The prevalence of Acrodermatitis enteropathica (AE) is unknown. It is more common in the North-West of Tunisia.
Clinical description
AE usually presents in the first 4-10 weeks of life in infants that are not breast-fed and at around the time of weaning in breast-fed infants, as cow's milk contains more zinc-binding phytates that impede zinc absorption. AE is characterized by eczematous pink scaly plaques that can become pustular, vesiculobullous, psoriasisform or crusted. Lesions usually involve the acral, periorificial and typically the anogenital areas. Skin lesions may evolve into erosions without treatment and are susceptible to secondary staphylococcal and candidal infections. Diarrhea, generalized alopecia and Beau-Reil lines on the nails are frequent manifestations. Paronychia, conjunctivitis, blepharitis and erythematous oral mucous membranes are also sometimes observed. Other features associated with severe and chronic zinc deficiency include failure to thrive, mental slowness, photophobia, hypogeusia, anemia, poor wound healing, hypogonadism in males, and delayed puberty.
Etiology
AE is due to a mutation in the SLC39A4 gene (8q24.3) that encodes a zinc transporter protein (called the Zip4 transporter). Zip4 is needed for the transcellular absorption of zinc into the enterocytes of the duodenum and jejunum where the ZnT-zinc transporters (that are not affected) allow for the transport of zinc into the bloodstream. Mutations in the SLC39A4 lead to zinc malapsorption. This can only be corrected by a high dietary intake of zinc that allows for a small fraction of zinc to be absorbed paracellularly, without the aid of Zip4.
Diagnostic methods
Diagnosis is based on clinical findings (diarrhea and acral dermatitis) as well as laboratory testing. Patients have low plasma zinc concentrations and low levels of serum alkaline phosphatase. Molecular genetic testing can identify a mutation in the SLC39A4 gene, confirming diagnosis of AE.
Differential diagnosis
Differential diagnoses include impetigo contagiosa, candidiasis, psoriasis, and other pathogen-related skin diseases. Sickle cell disease and related diseases, non-genetic or acquired causes of zinc deficiency such as glucagonoma (see these terms), chronic liver and renal diseases, nutritional deficiency, chronic inflammatory bowel diseases, AIDS, burn injuries, and excessive perspiration in hot climates should also be excluded.
Genetic counseling
AE is inherited autosomal recessively. Genetic counseling is recommended to identify other affected family members before the onset of symptoms.
Management and treatment
There is no cure for AE. In the majority of cases, zinc supplementation therapy results in the disappearance of AE symptoms, but this treatment is life-long and relapses can occur. Initial dosages of 5-10 mg/kg/day of elemental zinc, followed by maintenance doses of 1-2 mg/kg/day are recommended and are taken orally. Zinc sulphate is the best tolerated preparation, in most cases, but it can also be administered as acetate, gluconate and amino acid chelates. Zinc and copper levels should be monitored regularly. Dosages need to be increased during periods of growth, such as adolescence and during pregnancy, when relapses can occur.
Prognosis
With adherence to life-long zinc substitution therapy, the prognosis is good. Only when infants are left untreated can the disease be fatal.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Pr Brigitte DRÉNO


An acromelic dysplasia that is characterized by severe brachydactyly, peripheral dysostosis with facial dysostosis, nasal hypoplasia, and developmental delay.

Summary:
Epidemiology
Less than 80 cases of Acrodysostosis (ACRDYS) have been reported in the literature to date.
Clinical description
Typical clinical features include severe peripheral dysostosis (short stature and brachydactyly affecting metacarpals, metatarsals and phalanges), facial dysostosis (broad face, widely spaced eyes and maxillonasal hypoplasia), and developmental delay. Advanced skeletal maturation, decreased vertebral interpedicular distance, and obesity are also frequently observed. Several features of acrodysostosis are similar to those present in patients with Albright's hereditary osteodystrophy (AHO) such as short stature, obesity and brachydactyly (in AHO, only 4th and 5th metacarpals and metatarsals). Prenatal onset, and multiple hormonal resistance, most frequently to parathyroid hormone (PTH) and thyroid stimulating hormone (TSH), are reported in approximately half of ACRDYS patients. While patients with PRKAR1A mutations (referred to as ACRDYS type 1) constantly present with significant hormonal resistance, hormonal resistance in patients with PDE4D mutations (referred to as ACRDYS type 2) is rare, and when present, is relatively mild. Various degrees of intellectual disability and/or behavioral disorders have also been reported in ACRDYS patients.
Etiology
Acrodysostosis is caused by heterozygous mutations in either the PRKAR1A (17q24.2) or PDE4D (5q11.2-q12.1) genes. PRKAR1A mutations are gain-of-function leading to a constitutive loss of function in protein kinase A (by reducing the affinity of the protein subunits for cAMP, thereby hampering the dissociation from the catalytic subunit). A functional defect of PDE4D has not been characterized, but is expected to also be gain-of-function, leading to a constitutive loss of function in protein kinase A, at least in skeletal tissues.
Diagnostic methods
Diagnosis is based on the clinical, biochemical and radiological (i.e. cone-shaped epiphyses) characteristics. It is confirmed by the genetic screening of PRKAR1A or PDE4D genes. Basal urinary cAMP levels normalized by creatininuria, a reflection of PTH biological activity in the renal proximal tubule, have been found significantly increased in patients with PRKAR1A mutations, but not in patients with PDE4D mutations.
Differential diagnosis
Differential diagnosis includes brachydactyly type E, pseudohypoparathyroidism 1a or pseudopseudohypoparathyroidism.
Antenatal diagnosis
In families with a known disease causing mutation, prenatal diagnosis is possible.
Genetic counseling
Most cases occur sporadically but autosomal dominant inheritance has been reported in some families, and in these cases genetic counseling is possible.
Management and treatment
There is no specific treatment for acrodysostosis. Patients should be screened for hormonal resistances, in particular to PTH and TSH, and treated appropriately following the same criteria, doses, and follow-up as in any other form of hypoparathyroidism and hypothyroidism, and eventually treated for any associated endocrinopathy. Dietary and lifestyle measures to prevent obesity and supportive care for cognitive functions are recommended. Attention must be given in children to height, growth velocity, and pubertal development.
Prognosis
Prognosis is unknown due to a lack of long-term patient data. Functional consequences, however, can decrease a patient's quality of life.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Maria Luisa BRANDI


A rare, genetic dysostosis disorder characterized by brachydactyly and other finger/toe anomalies (short and/or wide metacarpals, abnormal or absent metatarsals, broad halluces), carpal synostosis, fused cervical vertebrae, scoliosis and spina bifida occulta. There have been no further descriptions in the literature since 1984.


A rare congenital acrofacial dysostosis characterized by mild intrauterine growth retardation, postnatal short stature, microcephaly, intellectual disability, moderate mandibulofacial dysostosis (including dental anomalies and/or malpositioning, microretrognathia, and malar hypoplasia), and mild pre- and postaxial limb hypoplasia with generalized brachydactyly, mild interdigital webbing, single transverse palmar creases and clinodactyly. Reported facial features include high forehead, widow's peak, downslanted palpebral fissures, sparse lateral eyebrows, and small or dysplastic ears. Variably associated features include frequent caries, preauricular fistulae, inguinal hernia, spina bifida occulta, and cryptorchidism and hypospadias in males.


Acrofacial dysostosis, Kennedy-Teebi type

A rare acrofacial dysostosis due to the presence of manifestations not usually seen in Nager syndrome (NS) such as microcephaly, blepharophimosis, microtia, a peculiar beakednose, cleft lip and palate, symmetrical involvement of the thumbs and great toes and developmental delay. It has since been suggested that these features can also be a part of the NS phenotype.


A rare acrofacial dysostosis characterized by normal intelligence, shortness of stature, and mild acrofacial dysostosis (malar hypoplasia, micrognathia and webbing of digits with shortening of the fourth metacarpals) associated with oligodontia, normal or high arched palate, aplasia cutis verticis with pili torti, mild cutaneous syndactyly of digits 2-5, and unilateral cleft lip. Features are similar to those seen in Zlotogora-Ogur syndrome, although the latter shows no sign of acrofacial dysostosis. There have been no further reports in the literature since 1997.


A rare, severe, multiple congenital anomalies syndrome characterized by severe mandibular hypoplasia, upper limb phocomelia with olygodactyly, absent fibula, and a number of additional skeletal (hypoplastic scapula and ischii, 11 ribs, clubfeet), facial (hypertelorism, hypoplastic supraorbital ridges, wide nasal bridge, microtia with low-set ears) and variable internal organ abnormalities (including arhinencephaly, hypolobulated lungs, and congenital cardiac defects), which usually lead to perinatal death. Surviving patients show features similar to Nagel syndrome.


A rare ectodermal dysplasia syndrome with bone abnormalities characterized by onychodystrophy; anomalies of the lower jaw, oral vestibule and dentition; post-axialpolydactyly; moderately restricted growth with short limbs; and normal intelligence. Although it closely resembles Ellis-van Creveld syndrome (see this term), an allelic disorder and another type of ciliopathy, WAD is usually a milder disease without the presence of heart abnormalities and is inherited in an autosomal dominant manner.


A rare congenital malformation syndrome characterized by the association of facial and skeletal anomalies with severe intellectual deficit and occasional genitourinary anomalies.

Summary:
Epidemiology
Only 12 patients have been reported since the first description in 1985, 7 originate from Brazil.
Clinical description
The cranio-facial malformations are numerous and variable. They include brachycephaly or microbrachycephaly, prominent forehead with low frontal and occipital hairline, wide anterior fontanel, hypertelorism, large philtrum, broad notched nasal tip, cleft lip, highly-arched palate, small ears with prominent helix, hypoplasia of mid-face, and prognathism. Other skeletal malformations are also present, with syndactyly of fingers 3 and 4, hypoplastic 3rd, 4th and 5th toes, anomalies of feet structure and fibular hypoplasia. Short stature may be observed. Eye anomalies include bilateral ptosis, coloboma of the upper lids, cataract, congenital glaucoma and iris atrophy. In some male patients, hypospadias, with or without cleft glans, and bifid scrotum are reported. Patients suffer from potentially severe intellectual deficit and present with anomalies of the cortical gyration (without any corpus callosum abnormality). Encephalocele may occur.
Etiology
The etiology of acro-fronto-facio-nasal dysostosis is unknown.
Genetic counseling
Autosomal recessive transmission is probable.

                            Last update:
                            April 2012


A rare premature aging syndrome characterized by atrophy of the skin and subcutaneous tissue involving predominantly the distal parts of the extremities, resulting in prematurely aged appearance of the hand and feet. Another prominent feature is the characteristic facies with hollow cheeks, beaked nose, and owl-like eyes. Additional, non-dermatological manifestations, like bone anomalies have been described in some patients. Mode of inheritance has not been definitively established.


A rare punctate palmoplantar keratoderma characterized by multiple small, round to oval or rhomboid, yellowish, hyperkeratotic papules and plaques most commonly localized to the palms of the hands and soles of the feet, potentially extending to the dorsum of the hands and feet in severe cases. Histopathological analysis shows hyperkeratosis, epidermal hypertrophy, and fragmentation and rarefaction of elastic fibers. The condition can be sporadic or familial.


A rare, genetic, acrokeratoderma disease characterized by multiple, symmetrical, asymptomatic, skin-colored (rarely, brownish), flat-topped, wart-like papules located on the dorsal aspects of the hands and feet (occasionally found on other parts of the body, such as knees, elbows and forearms), typically associated with palmoplantar punctate keratosis and variable nail involvement (including leukonychia, thickening, ridging, longitudinal striations and splitting). Histology reveals undulating hyperkeratosis, papillomatosis, hypergranulosis, and acanthosis, creating a characteristic 'church spire' appearance, with no acantholysis nor dyskeratosis associated.


A rare acquired endocrine disease related to excessive production of growth hormone (GH) and characterized by progressive somatic disfigurement (mainly involving the face and extremities) and systemic manifestations.

Summary:
Epidemiology
Worldwide, the prevalence is 1/7,500 to 1/35,800. The annual incidence is 1/91,000 to 1/526,000.
Clinical description
Due to its insidious onset and slow progression, acromegaly is often diagnosed from four to more than ten years after its onset, and is most often diagnosed in middle age (average age 40-50 years). The main clinical features are broadened extremities (hands and feet), widened, thickened and stubby fingers, and thickened soft tissue. The facial aspect is characteristic and includes a widened and thickened nose, prominent cheekbones, forehead bulges, thick lips and marked facial lines. The forehead and overlying skin is thickened, sometimes leading to frontal bossing. There is a tendency towards mandibular overgrowth with prognathism, maxillary widening, tooth separation and jaw malocclusion. The disease also has rheumatologic, cardiovascular, respiratory and metabolic consequences which determine its prognosis.
Etiology
In the majority of cases, acromegaly is related to a pituitary adenoma, either purely GH-secreting (60%) or mixed. In very rare cases, acromegaly is due to ectopic secretion of growth hormone-releasing hormone (GHRH), responsible for pituitary hyperplasia. The gene aryl hydrocarbon receptor interacting protein, AIP (11q13.3), has been identified as a major susceptibility factor, particularly when acromegaly begins in childhood or adolescence. Acromegaly may also be part of multiple endocrine neoplasia syndromes such as MEN1 (MEN1; gene MEN1, 11q13), Carney complex (gene  PRKAR1A , 17q24.2) or familial isolated pituiatary adenoma (FIPA; gene AIP, 11q13.2). Very rarely it may be secondary to Xq26.3 chromosomal microduplications, responsible for X-linked acrogigantism due to Xq26 microduplication (XLAG), a very early-onset gigantism syndrome. Acromegaly may also be part of McCune-Albright syndrome.
Diagnostic methods
The clinical diagnosis is confirmed biochemically by detection of increased serum of insulin-like growth factor-I (IGF-I) concentrations (screening test) and an increased serum GH concentration not suppressed following an oral glucose tolerance test (OGTT; confirmation test). Assessment of tumor volume and extension is based on imaging studies. Echocardiography and sleep apnea testing are used to determine the clinical impact of acromegaly.
Differential diagnosis
Differential diagnosis includes other causes of acromegaly (FIPA, MEN1, Carney complex and XLAG) as well as pachydermoperiostosis and acromegaloid features of severe insulin resistance.
Genetic counseling
This form of acromegaly is sporadic; a causal genetic mutation has not been identified.
Management and treatment
Treatment is aimed at correcting (or preventing) tumor compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. Transsphenoidal surgery is often the first-line treatment. When surgery fails to correct GH/IGF-I hypersecretion, medical treatment with dopamine agonists and/or somatostatin analogs is proposed. The GH antagonist (pegvisomant) is used in patients that are resistant to somatostatin analogs. Radiotherapy may be discussed as a third line of treatment in cases of medical treatment failure.
Prognosis
Adequate hormonal disease control is achieved in most cases, allowing a life expectancy similar to that of the general population. However, even if patients are cured or well-controlled, sequelae (joint pain, deformities and altered quality of life) often remain.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Pr Philippe CHANSON


A rare pigmentation anomaly of the skin characterized by otherwise asymptomatic hyperpigmentation of the skin over the dorsal side of fingers and toes which may rapidly spread towards proximal regions, like genitals, abdomen, and thighs. It is mostly seen in newborns or during the first years of life.


A rare frontonasal dysplasia characterized by distinct craniofacial (large fontanelle, hypertelorism, bifid nasal tip, nasal clefting, brachycephaly, median cleft face, carp-shaped mouth), brain (interhemispheric lipoma, agenesis of the corpus callosum), and limb (tibial hypoplasia/aplasia, club foot, symmetric preaxial polydactyly of the feet and bilateral clubbed and thickened nails of halluces) malformations as well as intellectual disability. Other manifestations sometimes reported include absent olfactory bulbs, hypopituitarism and cryptorchidism.


A rare autosomal recessive acromesomelic dysplasia characterized by severe dwarfism at birth, abnormalities confined to limbs, severe shortening and deformity of long bones, fusion or absence of carpal and tarsal bones, ball shaped fingers and, occasionally, polydactyly and absent joints. As seen in acromesomelic dysplasia, Hunter-Thomson type and acromesomelic dysplasia, Maroteaux Type, facial features and intelligence are normal.


Acromesomelic dysplasia, Hunter-Thompson type

A rare autosomal recessive acromesomelic dysplasia characterized by severe dwarfism (adult height approximately 120 cm) with abnormalities limited to the limbs (affecting the lower limbs more than upper limbs, with middle and distal segments being the most affected), severe shortening, absence or fusion of tubular bones of hands and feet and large joint dislocations. As seen in acromesomelic dysplasia, Grebe type and acromesomelic dysplasia, Maroteaux type, facial features and intelligence are normal.


A rare autosomal recessive acromesomelic dysplasia characterized by severe dwarfism (adult height <120 cm), both axial and appendicular involvement (shortening of the middle and distal segments of limbs and vertebral shortening), and with normal facial appearance and intelligence. It is a less severe form than acromesomelic dysplasia, Grebe type and acromesomelic dysplasia, Hunter-Thomson type .


A rare bone dysplasia characterized by short stature, short hands and feet, mild facial dysmorphism, and characteristic X-ray abnormalities of the hands.

Summary:
Epidemiology
The prevalence is unknown. Fewer than 60 patients with this condition have been reported to date.
Clinical description
Length is usually normal at birth but postnatal height falls progressively below the normal percentiles. The mean adult height is 130 cm (133 cm in males, 129 cm in females). The hands, feet, and limbs are short and occipitofrontal circumference is normal. There is no intellectual deficit. Mild dysmorphic features have been noted, including a round face, narrow palpebral fissures, well-defined eyebrows, long eyelashes, a bulbous nose with anteverted nostrils, a long and prominent philtrum, and thick lips with a small mouth. Other features include well-developed muscles, a hoarse voice, generalized joint limitations in some patients, frequent ear, tracheal, and respiratory complications, and spine abnormalities. Long-term follow-up shows that facial dysmorphism becomes less obvious in adults and that carpal tunnel syndrome is frequent in older patients. The entity known as Moore-Federman syndrome (see this term) characterized by short stature (with disproportionately short legs), joint stiffness, ocular abnormalities (hypermetropia, glaucoma) and thickened skin on the forearms, is believed to represent a variable clinical expression of acromicric dysplasia.
Etiology
The disease is caused by heterozygous mutations in the FBN1 gene. Mutations are all located in exon 41-42, encoding TGFβ binding protein-like domain 5.
Diagnostic methods
Diagnosis of acromicric dysplasia can be suspected on association of severe postnatal short stature, short hands and feet, normal intelligence and mild facial dysmorphism. X-rays show delayed carpal bone age, cone shaped epiphyses, short metacarpals and phalanges with an internal notch of the second metacarpal, an external notch of the fifth metacarpal, as well as an internal notch of the femoral heads. Notches of the hands disappear in adulthood.
Differential diagnosis
Overlapping syndromes include geleophysic dysplasia, Weill-Marchesani syndrome, and Myhre syndrome (see these terms). Geleophysic dysplasia can be distinguished from acromicric dysplasia by the presence of cardiac abnormalities (e.g. cardiac valvular thickening), Weill-Marchesani syndrome by the presence of microspherophakia, and Myhre syndrome by the presence of prognathism, deafness, developmental delay, and a thick calvarium.
Genetic counseling
Transmission is autosomal dominant. Affected individuals have a 50% risk of transmitting the disease to their offspring.
Management and treatment
Orthopedic management may be needed for hip dysplasia during childhood and for carpal tunnel syndrome in older patients. Physical therapy is required to prevent progressive joint limitation. In a few cases, children have been treated with growth hormone therapy. Regular multidisciplinary follow-up is required, especially for respiratory abnormalities.
Prognosis
The prognosis for affected individuals is usually good with a normal life expectancy. However, complications may occur, such as respiratory disorders, which may worsen the prognosis.

                            Last update:
                            June 2012

                            - Expert reviewer(s):
                            Pr Valérie CORMIER-DAIRE


Acroosteolysis-keloid-like lesions-premature aging syndrome

A rare, genetic, progeroid syndrome disorder characterized by a prematurely aged appearance (including lipoatrophy, thin, translucent skin, sparse, thin hair, and skeletal muscle atrophy), delayed tooth eruption, keloid-like lesions on pressure regions, and skeletal abnormalities including marked acroosteolysis, brachydactyly with small hands and feet, kyphoscoliosis, osteopenia, and progressive joint contractures in the fingers and toes. Craniofacial features include a thin calvarium, delayed closure of the anterior fontanel, flat occiput, shallow orbits, malar hypoplasia and narrow nose.


A very rare disorder associating pseudopapilledema (optic disc swelling not secondary to increased intracranial pressure), mixed hearing loss, facial dysmorphism and limb extremity anomalies.

Summary:
Epidemiology
Only 4 cases have been reported in the literature from 3 inbred sibships.
Clinical description
Facial dysmorphism is characterized by small head, downslanting palpebral fissures, broad base of the nose, micrognathia and malformed ears. Hand anomalies include short fingers, hypoplasia of thenar and hypothenar eminences and cutaneous syndactyly. Feet are small with a peculiar shape, wide space between toes 1 and 2 and syndactyly type 1 (see this term). The affected patients have no intellectual deficit.
Genetic counseling
The condition is most probably hereditary, transmitted as an autosomal recessive trait.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


A rare syndrome characterized by a combination of distal limb abnormalities (syndactyly of all fingers and toes, preaxial polydactyly in the feet and/or hands) and upper sternum malformations.


A rare skeletal dysplasia characterized by fusion of the carpal and tarsal bones, with complex anomalies of the fingers and toes (preaxial polydactyly of the hands and/or feet, syndactyly of fingers and toes, hypoplasia and dysgenesis of metatarsal bones).

Summary:
Epidemiology
It has been described in less than 30 patients from three unrelated families.
Clinical description
Other manifestations include prominence of the sternum with variable pectus excavatum, lumbosacral spina bifida occulta, minor craniofacial anomalies and mild intellectual deficit.
Etiology
The causative gene has been mapped to chromosome region 2q36.
Genetic counseling
This syndrome is transmitted as an autosomal dominant trait with full penetrance.

                            Last update:
                            January 2007

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


A spectrum of congenital malformative disorders characterized by the co-occurrence of distal limb anomalies (usually bilateral cleft feet and/or hands) and renal defects (e.g. unilateral or bilateral agenesis), that can be associated with a variety of other anomalies such as those of genitourinary tract (genital anomalies, ureteral hypoplasias, vesicoureteral reflux), abdominal well defects, intestinal atresias, and lung malformations. Familial cases have been reported in which an autosomal recessive inheritance was suspected.


A group of endogenous Cushing syndrome (CS) caused by abnormal production of ACTH due, in 80% of cases, to adrenocorticotropic hormone (ACTH) oversecretion by a pituitary adenoma (Cushing disease, CD) and in 20% of cases to ectopic ACTH secretion (CS due to EAS) by an extrapituitary tumor or very rarely due to a tumor secreting both ACTH and corticotrophin-releasing hormone (CRH).


A rare cutaneous lichen planus characterized by the development of photo-distributed lichenoid lesions.

Summary:
Epidemiology
The exact prevalence is unknown. It is extremely rare in Caucasians but it is more common in dark-skinned populations, particularly in young adults.
Clinical description
Indurated plaques or papules erupt on the face, neck, and the dorsal surface of hands after exposure to ultraviolet (UV) light. Different morphological subtypes have been described: the classic form (violaceous papules), a granuloma annular-like form (annular erythematous hyperpigmented plaques), a dyschromic form (white angular coalescent papules on the neck and dorsa of the hands), and a pigmented melasma-like form (dark patches on the face and neck). There is no mucosal or nail involvement. Histology is characterized by more marked melanin incontinence than in classical lichen planus; there may also be a lighter inflammatory cell infiltrate and focal areas of parakeratosis.
Etiology
Etiology is unknown.

                            Last update:
                            May 2011

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


A rare, chronic, photodermatosis disease characterized by intensely pruritic, polymorphic, erythematous, excoriated and/or lichenified papules, macules, plaques and nodules, occurring on sun-exposed areas of the skin (particularly face, nose, lips, and ears), frequently associating cheilitis (especially of the lower lip) and conjuctivitis, which are present year-round or only in the spring/summer (depending on geographic location), observed mainly in Native Americans and Mestizos. Cheilitis may be the sole clinical presentation. Histologically, the presence of lymphoid follicles in mucosa is pathognomonic.


A rare bacterial infectious disease characterized by a chronic granulomatous infection by Actinomyces species which are commensals in the human gastrointestinal and urogenital tract and oropharynx. Corresponding to the affected site, the disease presents as cervicofacial, respiratory tract, genitourinary tract, digestive tract, central nervous system, or cutaneous actinomycosis and leads to the formation of abscesses and fistulae in the respective region.


A rare epilepsy syndrome characterized by progressive myoclonus epilepsy in association with primary glomerular disease. Patients present with neurologic symptoms (including tremor, action myoclonus, tonic-clonic seizures, later ataxia and dysarthria) that may precede, occur simultaneously or be followed by renal manifestations including proteinuria that progresses to nephrotic syndrome and end-stage renal disease. In some patients, sensorimotor peripheral neuropathy, sensorineural hearing loss and dilated cardiomyopathy are associated symptoms.


A rare, genetic, primary immunodeficiency disease characterized by increased susceptibility to recurrent and/or severe bacterial and viral infections (in particular, sinopulmonary bacterial and herpesvirus infections), chronic benign lymphoproliferation (manifesting as lymphadenopathy, hepatosplenomegaly and focal nodular lymphoid hyperplasia), and/or autoimmune disease (including immune cytopenias, juvenile arthritis, glomerulonephritis and sclerosing cholangitis). Immunophenotypically, variable degrees of agammaglobulinemia with increased IgM levels, increased circulating transitional B cells, decreased naïve CD4 and CD8 T-cells with increased CD8 effector/memory T cells are observed.


A rare disorder due to poisoning caused by the ingestion of unripe Blighia sapida fruits, clinically characterized by toxic hypoglycaemia and inhibition of neoglucogenesis.

Summary:
Epidemiology
The true incidence is unknown and most likely underreported. It is relatively frequent in the Caribbean and Western Africa where the fruit is consumed. In contrast, it is rare in France and other Western countries.
Clinical description
The clinical manifestations are severe and rapidly progressing (delirium, toxic hepatitis, acute dehydration and a state of shock, convulsions, coma) and may lead to death.
Etiology
The hypoglycaemia is caused by the effect of hypoglycin A, which is found in the arils of the Blighia sapida fruit. When ingested, hypoglycin A is metabolized into (methylenecyclopropyl)acetyl-CoA, which inhibits several enzymes required for beta oxidation of fatty acids and gluconeogenesis.
Diagnostic methods
Diagnosis is based on clinical presentation following consumption of ackee fruit.
Differential diagnosis
Other acute poisonings and acute gastritis are among the differential diagnoses.
Management and treatment
Treatment is symptomatic (administration of glucose, IV or per os)
Prognosis
Although the intoxication is generally benign or has a favourable outcome, ingestion of large doses may lead to death: ackee fruit intoxication lead to 29 deaths in 1998 and more than 50 in 2001.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Pr Bruno MÉGARBANE  - Pr Dabor RÉSIÈRE


A primary adrenal insufficiency caused by a sudden defective production of adrenal steroids (cortisol and aldosterone). It represents an emergency, thus the rapid recognition and prompt therapy are critical for survival even before the diagnosis is made.

Summary:
Epidemiology
Acute adrenal insufficiency (AAI) exact prevalence is unknown.
Clinical description
The disease may occur at any age. The onset is often sudden. The initial presentation may be non specific and may be limited to abdominal pain, nausea, vomiting, weight loss, tachycardia, and fever. Asymptomatic hypoglycemia, Hypoglycemic seizures or symptoms of dehydration are common manifestations seen in children. If untreated, shock and bilateral adrenal hemorrhage can rapidly lead to death.
Etiology
Steroid withdrawal is the most common cause of AAI in patients with chronic adrenal insufficiency. A precipitating illness (severe infection, acute myocardial infarction, stroke), surgery without adrenal support, pregnancy, any acute or chronic disease, or acute trauma are other potential causes of an acute adrenal crisis. AAI may result from an acute exacerbation of chronic primary adrenal insufficiency (CPAI). Adrenal destruction may be associated with autoimmune adrenalitis (Addison disease), isolated or in the context of autoimmune polyendocrinopathy type 1, 2 or 4. It can also be caused by medications that reduce steroid metabolism for patients with tuberculosis, opportunistic mycoses and viral infections in immunocompromised patients and adrenal metastases. Adrenal destruction may occur in the absence of CPAI history and may be due to bilateral massive adrenal hemorrhage (BMAH) as seen in Waterhouse-Friderichsen syndrome. AAI may also result from corticotroph insufficiency, either isolated or more often resulting from complete anterior pituitary insufficiency. Chronic glucocorticoid therapy (exogenous steroid such oral prednisolone or inhaled steroid) is also a cause of adrenal insufficiency (secondary adrenal insufficiency). Abrupt withdrawal of treatment may result in acute adrenal insufficiency.
Diagnostic methods
The clinical signs are nonspecific but the diagnosis of AAI is suspected if a patient presents with hypotonia or shock that responds poorly to catecholamines. Laboratory exams show signs of adrenal insufficiency (hypoglycemia, hyponatremia and elevated natriuresis, hyperkaliemia, hemoconcentration, metabolic acidosis and functional renal failure) confirmed by hypocortisolemia, increased ACTH (Adreno CorticoTropic Hormone), and an insufficient response to rapid ACTH stimulation testing that leads to the diagnosis of absolute and peripheral AAI. The mineralocorticoid insufficiency, when present, can be confirmed by low aldosterone levels and high plasma renin activity (PRA). The etiological diagnosis is based on various imaging exams (CT-scan, ultrasound, or MRI). In case of anterior pituitary insufficiency, ACTH is low.
Differential diagnosis
Secondary adrenal insufficiency needs to be eliminated. Peritonitis is often a differential diagnosis as well as other causes of adrenal destruction such as bilateral adrenalectomy, Waterhouse-Friderichsen syndrome, autoimmune adrenalitis, infectious adrenalitis.
Management and treatment
Immediate treatment in an intensive care unit is necessary. Administration of 100 mg hydrocortisone i.v. (followed by 100-200 mg over 24 hours) combined with fluid resuscitation (1L saline solution during first hour, 500ml during second hour) is the standard treatment for an adrenal crisis. In children the dosage is based on 2 mg/kg/every 6 hours and hydroelectrolytic re-equilibration based on 3l/m2/d. During this time cardiac monitoring is essential. Antibiotics, vasopressors, heparin, packed red blood cells, platelets, cryoprecipitates and fresh frozen plasma are also administered if needed. Preventive strategies include dosage increase of oral steroid hormones during times of stress in those with CPIA or intramuscular, intraveinous or sub cutaneous injection. Patients and their families should also be educated on what to do during an adrenal crisis.
Prognosis
Prognosis varies depending on the etiologies, but is generally correlated with the rapidity of diagnosis and medical assistance. Death is rare when the patients receive appropriate medical assistance.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Pr Juliane LEGER


A rare, acquired retinal disorder characterized by unilateral, acute onset, rapidly progressive visual field loss. Sometimes patients have photopsia and complain of floaters. Typical ophthalmoscopic finding is a unilateral, yellowish-white annular intraretinal line, splitting the retinal field to affected outer retina with thinning, and normal retina. Gradual spontaneous visual recovery has been observed.


A rare acute myeloid leukemia characterized by primary differentiation to basophils. Microscopically, peripheral blood and bone marrow blasts contain coarse cytoplasmic basophilic granules which are positive with metachromatic staining (toluidine blue). Electron microscopy confirms that granules show features characteristic of basophil precursors. Mature basophils are usually sparse. Patients may present with manifestations related to bone marrow failure, as well as hepatosplenomegaly, cutaneous involvement, lytic lesions, and hyperhistaminemia. The disease is associated with a poor prognosis.


A rare neurologic disease characterized by lethargy, hypotonia, poor feeding, opisthotonus, and a typical high-pitched cry due to bilirubin accumulation in the globus pallidus, sub-thalamic nuclei, and other brain regions, resulting from severe neonatal unconjugated hyperbilirubinemia. Onset of symptoms is typically within the first three to five days of life. Additional features include fever, apnea, seizures, and coma. Especially respiratory failure or refractory seizures may lead to a fatal outcome.


A demyelinating disorder of the central nervous system.

Summary:
Epidemiology
The incidence rate has been estimated at 1 in 125,000-250,000 per year.
Clinical description
Children younger than 10 years are predominantly affected. A seasonal winter and spring peaks have been registered. The disease usually develops after acute viral or bacterial infection or vaccination, with a sudden onset of irritability and lethargy after a prodromal period of 1-4 weeks. Major symptoms include fever, headache, drowsiness, changes in mental status, seizures and coma. Weakness, vomiting, weight loss, stiff neck, ataxia, bilateral optic neuritis and delirium are common. Peripheral nervous system involvement (paralysis of a single limb or hemiplegia) occurs in 5-45% of cases, according to literature data. Although initially the symptoms of ADEM may be mild, they worsen rapidly within several hours to four days. Pathologically, ADEM is characterized by bilateral large and confluent lesions in cerebral and cerebellar white matter; basal ganglia and gray matter may also be involved. ADEM lesions in the spinal cord are continuous and extending to multiple levels. Some authors consider the disease as a variant or borderline form of multiple sclerosis (MS) (see this term).
Etiology
ADEM is considered as an immune-mediated disorder of the central nervous system. It can arise spontaneously but in most cases the disease is triggered by infectious disease or vaccinations. Links between the Pasteur rabies vaccine and ADEM have been documented. Immunizations less frequently associated with ADEM include pertussis, measles, Japanese B virus, tetanus, influenza.
Diagnostic methods
Diagnosis is based on the clinical history and magnetic resonance imaging, which is the diagnostic modality of choice.
Differential diagnosis
MS is the main differential diagnosis. The differentiation between ADEM and a first episode of MS can be very difficult but has important prognostic and treatment implications. Differential diagnosis also includes infectious encephalitis, Guillain-Barré syndrome, glioblastoma multiforme, Schilder's disease (see these terms), psychotic disorders with acute onset, toxic/metabolic encephalopathy, vasculitis, nonvasculitic autoimmune encephalopathy, meningitis, metastatic tumor.
Management and treatment
Currently, immunosuppression with corticosteroids for the acute events is the mainstay of treatment. In patients refractory to steroid therapy, plasmapheresis or intravenous immunoglobulin therapy can be used. Symptomatic and supportive treatments are recommended.
Prognosis
ADEM is typically a monophasic (single episode) disease with generally favorable outcome. Average time to recover is one to six months. Relapses may occur in 5-25% of cases, generally 6-18 months after the onset. Fulminant presentation with cerebral edema requiring critical intensive care is rare.

                            Last update:
                            July 2009


Acute encephalopathy with biphasic seizures and late reduced diffusion

A rare childhood-onset epilepsy syndrome associated with infection and characterized by a biphasic clinical course. The initial symptom is a prolonged febrile seizure on day 1 (the first phase). Afterwards, patients have variable levels of consciousness from normal to coma. Irrespective of the consciousness levels, magnetic resonance imaging (MRI) during the first 2 days shows no abnormality. During the second phase (usually days 4 - 6), patients show a cluster of seizures and deterioration of consciousness. Diffusion-weighted images (DWI) on MRI reveal the brain lesions with reduced diffusion predominantly in the subcortical white matter. After the second acute phase, consciousness levels improve with the emerging focal neurological signs. Neurological outcomes of AESD vary from normal to mild or severe sequelae including cerebral atrophy, mental retardation, paralysis and epilepsy.


A rare unclassified acute myeloid leukemia characterized by a proliferation of immature cells exclusively of the erythroid lineage without a significant myeloblastic component. Microscopically, the cells may be undifferentiated or proerythroblastic in appearance. Patients may present with pancytopenia with fatigue, infections, and mucocutaneous bleedings, as well as weight loss, fever, and night sweats. Prognosis is poor.


A rare, severe complication occurring in the third trimester of pregnancy or in early postpartum period bearing a risk for perinatal and maternal mortality and characterized by jaundice, rise of hepatic injuries and evolving to acute liver failure and encephalopathy.


Acute generalized exanthematous pustulosis

A rare hypersensitivity reaction characterized by the rapid development of numerous, nonfollicular, sterile, pinhead-sized pustules on an erythematous base, predominantly occurring on the trunk, intertriginous and flexural areas, with rare, mostly oral, mucosal involvement. Fever, peripheral blood leukocytosis, and mild eosinophilia are accompanying features. Systemic involvement, with hepatic, renal or pulmonary dysfunction, occasionally occurs. Onset usually occurs 1-12 days after administration of the causal medication and is most frequently associated with beta‐lactam antibiotics, macrolides (including pristinamycin and clindamycin), diltiazem, terbinafine, (hydroxy‐)chloroquine but many other medications have also been implicated. Histology reveals spongiform, subcorneal and/or intraepidermal, pustules but this pattern is not specific (same in pustular psoriasis).


A subgroup of porphyria characterized by the occurrence of neurovisceral attacks with or without cutaneous signs. They encompass four diseases: acute intermittent porphyria (PAI; the most common), variegate porphyria (VP), hereditary coproporphyria (HC), and hereditary delta-aminolevulinic acid dehydratase deficiency (ADP; extremely rare).

Summary:
Epidemiology
In most European countries, the prevalence of acute hepatic porphyria (AHP) is about 1/75,000.
Clinical description
In 80% of cases, patients are women between 20 and 45 years old. In all acute hepatic porphyrias, neurovisceral attacks may occur and manifest by intense abdominal pain (85-95% of cases) lasting one to two weeks, neurological disorders (muscle weakness, sensory disturbance or convulsions), and psychological disturbances (irritability, anxiety, auditory or visual hallucinations, mental confusion). The episodes are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low caloric diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle). In the majority of VP patients and in less than 15% of HC patients, skin lesions are present.
Etiology
Each of the acute hepatic porphyrias is due to a deficiency of one of the enzymes in the heme biosynthesis pathway. These deficiencies lead to an accumulation of porphyrin precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver, and also, in the case of VP and HC, to an accumulation of porphyrins inducing cutaneous symptoms.
Diagnostic methods
Diagnosis is based on the demonstration of significantly elevated ALA levels, and above all, PBG (pathognomonic of acute porphyria attack) and, occasionally, porphyrins in urine, stool and/or plasma. Biochemical and enzymatic assays followed by characterization of mutations in the corresponding gene help defining the type of porphyria.
Differential diagnosis
The differential diagnosis includes Guillain-Barré syndrome and all causes of acute abdominal pain. For VP and HC, the differential diagnosis also includes photodermatoses. For ADP, the differential diagnosis must include type I tyrosinemia and lead poisoning.
Antenatal diagnosis
Antenatal diagnosis may be proposed in families at risk of homozygous acute hepatic porphyrias.
Genetic counseling
Acute hepatic porphyrias are monogenic disorders with autosomal dominant pattern of inheritance (except for ADP, which is autosomal recessive). There is a 50% risk of transmitting the pathogenic variant from an affected individual to their offspring. Genetic counseling is recommended to patients and families to identify individuals at risk of developing or transmitting the disease.
Management and treatment
Acute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes attacks prevention (avoidance of triggers) and skin protection against light in the case of cutaneous symptoms.
Prognosis
In most cases, acute attacks do not recur throughout adult life, and the disease is rarely progressive. However, in some patients, episodes can reoccur necessitating repeated injections of human hemin. A new treatment based on ALAS1 siRNA, which prevents the recurrence of crippling acute episodes, may be proposed, thus removing the need for liver transplantation. AHP is a risk factor for the long-term development of hepatocellular carcinoma and chronic renal failure. Annual monitoring is proposed to detect these chronic complications.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                            Dr Neila TALBI | MetabERN*

                                * European Reference Network


Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

A rare mitochondrial respiratory chain deficiency due to TRMU deficiency leading to mitochondrial tRNA synthesis defect and characterized clinically by transient, but life-threatening acute liver failure episodes.

Summary:
Epidemiology
To date, more than 30 cases have been reported.
Clinical description
Clinical presentation is typically with acute liver failure (hepatomegaly, jaundice, irritability, feeding difficulties, vomiting, coagulopathy) occurring between 1 and 6 months of age. Patients present with hypoglycemia and hyperlactatemia, consistent with a defect in mitochondrial respiratory chain function. Uncommon clinical features including muscular involvement, mainly cardiac, have also been reported.
Etiology
This disease is due to biallelic pathogenic variants in the (TRMU, 22q13.31) gene. This gene encodes for the tRNA mitochondrial 2-thiouridylase that is responsible for the 2-thiolation of uridine at the first anticodon position of the mitochondrial tRNALys, tRNAGlu, and tRNAGln. Mutations in this gene impair the translation of mtDNA-dependent complexes and cause combined respiratory chain defects.
Diagnostic methods
Diagnosis is based on the clinical evaluation of liver failure symptoms and on metabolic tests evaluating the mitochondrial function. Abdominal ultrasound usually disclosed hyperechogenic liver. When performed, liver biopsy analysis showed microvesicular steatosis and oncocytic hepatocytes, suggesting mitochondrial disease. Molecular genetic analysis searching for mitochondrial diseases establishes the diagnosis by identifying pathogenic TRMU variants.
Differential diagnosis
Differential diagnoses include mainly: other mitochondrial respiratory chain diseases involving the liver, especially hepatocerebral depletion syndromes (POLG, DGUOK, MPV17); adenosine kinase deficiency; recurrent acute liver failure triggered by infections or hyperthermia (NBAS, SCYL1, RINT1); aminoacyl-tRNA synthetase deficiencies (LARS, MARS, IARS). Molecular genetic testing rules out the diagnosis of these diseases.
Antenatal diagnosis
Prenatal testing is possible if pathogenic variants have been previously identified in the family.
Genetic counseling
The disorder follows an autosomal recessive inheritance pattern. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Non-specific supportive care including treatment and prevention of hypoglycemia is provided to patients undergoing an episode of acute liver failure. While cysteine supplementation efficacy is not demonstrated, supplementation with N-acetylcysteine or L-cysteine should be considered. Given the absence of significant neurological involvement reported so far, when indicated, a liver transplantation could be considered in these patients.
Prognosis
According to published data, 8 out of 32 patients (25%) died during the first year of life. In patients who survive the acute liver failure episodes, a full recovery occurs within months. Currently, no prognostic factor has been identified.

                            Last update:
                            December 2021

                            - Expert reviewer(s):
                            Dr Pauline GAIGNARD  - Pr Emmanuel GONZALES | RARE-LIVER*

                                * European Reference Network


Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome

A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by infantile onset of recurrent episodes of acute liver failure (resulting in chronic liver fibrosis and hepatosplenomegaly), delayed motor development, cerebellar dysfunction presenting as gait disturbances and intention tremor, neurogenic stuttering, and motor and sensory neuropathy with muscle weakness especially in the lower legs, and numbness. Mild intellectual disability was reported in some patients. MRI of the brain shows non-progressive atrophy of the cerebellar vermis and thinning of the optic nerve.


Acute infantile liver failure-multisystemic involvement syndrome

A rare, genetic, parenchymal hepatic disease characterized by acute liver failure, that occurs in the first year of life, which manifests with failure to thrive, hypotonia, moderate global developmental delay, seizures, abnormal liver function tests, microcytic anemia and elevated serum lactate. Other associated features include hepatosteatosis and fibrosis, abnormal brain morphology, and renal tubulopathy. Minor illness exacerbates deterioration of liver failure.


Acute inflammatory demyelinating polyradiculoneuropathy

A rare inflammatory neuropathy belonging to the clinical spectrum of Guillain-Barré syndrome (GBS).

Summary:
Epidemiology
Overall annual incidence of GBS is estimated at between 1/91,000 and 1/55,000. AIDP accounts for around 90% of GBS cases in Europe and North America and thus the term GBS is often synonymous with AIDP in Western countries. The disease occurs in patients of all ages and men are affected about 1.5 times more often than women.
Clinical description
The clinical course of AIDP is divided into three phases. The first phase (lasting a few weeks) is characterized by rapidly progressive muscle weakness (usually appearing first in the feet and progressing upwards). It is symmetrical and may cause acute neuromuscular paralysis. Sensory disturbances (tingling and numbness), intense pains, and cramps may also occur. Other sites involved may include the respiratory muscles (leading to acute respiratory failure, with 20-30% of patients needing mechanical ventilation), the deglutition muscles (leading to life-threatening aspiration) and the eye muscles (leading to ophthalmoplegia). Deep-tendon reflexes may be decreased or absent. During the second phase (variable duration), symptoms become stable but other manifestations (cardiac arrhythmias, hyper/hypotension and gastric dysmotility) may occur. During the third (recovery) phase, lasting a few months or longer, symptoms slowly regress. Many patients have residual findings (weakness, sensory disturbances, fatigue or pain) for many months or even years.
Etiology
In the majority of cases, an infectious disease precedes the onset of limb weakness, with Campylobacter jejuni infection being the most frequent initiating event. Cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, and Haemophilus influenza have also been implicated. Onset of AIDP has also been reported after vaccination and surgical intervention. Although the exact pathological mechanisms remain to be discovered, AIDP is associated with activated macrophage infiltration of myelin sheaths, leading to myelin damage and demyelination. Other immunological mechanisms are also likely to play a role.
Diagnostic methods
Diagnosis is based on the clinical picture and can be difficult to establish. Lumbar puncture and cerebrospinal fluid (CSF) examination should be performed and electromyography can be helpful for confirming the diagnosis and identifying the GBS subtype: AIDP, or the axonal (AMAN, AMSAN) forms (see these terms).
Differential diagnosis
The differential diagnosis is wide and includes drug-induced neuropathy, critical illness polyneuropathy, carcinomatosis, metabolic disturbances, acute rhabdomyolysis, and cord and spinal nerve root compression or inflammation. Porphyria, vasculitis, diphtheria,, myasthenia gravis, botulism, polymyositis, dermatomyositis, brainstem encephalitis, meningitis, transverse myelitis, poliomyelitis (see these terms) as well as vitamin B1 deficiency may also be considered.
Management and treatment
Optimal care from a multidisciplinary team providing intensive-care facilities is essential for management. Treatment consists of rapid administration of intravenous immunoglobulin (IVIg) or plasma exchange. Physiotherapy and rehabilitation are important.
Prognosis
GBS patients have a variable prognosis: it is estimated that around 50% of patients recover completely or have only minor sequelae, 20% are unable to walk after 6 months and 3% die. Multiple clinical, electrophysiological, serological and laboratory factors have been identified as predictors of a poor outcome. Fatigue and endurance intolerance may persist for years.

                            Last update:
                            December 2009

                            - Expert reviewer(s):
                            Pr P.A. [Pieter] VAN DOORN


A form of acute hepatic porphyria characterized by the occurrence of neurovisceral attacks without cutaneous symptoms.

Summary:
Epidemiology
This is the most frequent and severe form of acute hepatic porphyria. Its prevalence in Europe is about 1/75,000. The disease generally manifests after puberty, predominantly affecting women (80% of cases).
Clinical description
Patients suffer intermittent neurovisceral attacks lasting several days and repeat over several weeks. They manifest as severe abdominal pain (>95% of patients), neurological disorders, and/or psychological disturbances. Abdominal pain is very often associated with low back pain irradiating to the legs, nausea, vomiting, and severe constipation. Several psychological disturbances can be observed: irritability, emotional sensitivity, depressive disorder, anxiety and, more rarely, auditory or visual hallucinations, disorientation, and mental confusion. Neurological manifestations can affect both the central and peripheral nervous systems (myalgia, paresis, ascending flaccid paralysis of the limbs or convulsions), and can lead to severe complications such as motor paralysis. Tachycardia and hyponatremia are common during attacks. In the rare case of cardiac arrhythmia or respiratory paralysis, the attacks can be fatal. The attacks are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low caloric diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle).
Etiology
The disease is caused by a deficiency in porphobilinogen deaminase (PBG-D, the third enzyme in the heme biosynthesis pathway), which leads to an accumulation of porphyrins and their precursors (aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver. The enzyme deficiency is due to mutations of the HMBS gene (11q23.3; NM_000190.4) coding for PBGD.
Diagnostic methods
Reddish or brown coloration of urine following exposure to warm light is suggestive of the disease. Diagnosis is based on significantly elevated concentrations of PBG (pathognomonic of acute porphyria) and ALA in urine, and 50% residual PBGD activity in red blood cells (but not always found during attacks). Identification of a causal mutation of the HMBS gene confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes other acute hepatic porphyrias, and is based on porphyrin analysis in urine, stool, and plasma.
Antenatal diagnosis
Antenatal diagnosis may be offered in families at risk of homozygous acute intermittent porphyria (AIP).
Genetic counseling
Transmission is autosomal dominant, with very low penetrance. Genetic counselling is recommended to patients and their families to identify individuals at risk of developing or transmitting the disease.
Management and treatment
Acute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes elimination of one or more triggers, relief of pain (opioids), vomiting, and anxiety, and prevention of attacks (avoidance of triggers, particularly drugs).
Prognosis
In most cases, acute attacks of AIP do not recur throughout adult life, and the disease is rarely progressive. However, in some patients, attacks can reoccur, necessitating repeated injections of human hemin. A new ALAS1 siRNA-based treatment to prevent the recurrence of crippling acute attacks may be proposed, thereby delaying the need for liver transplantation. AIP is a risk factor for the long-term development of hepatocellular carcinoma and chronic renal failure. Annual monitoring is proposed to detect these chronic complications.

                            Last update:
                            March 2024

                            - Expert reviewer(s):
                            Dr Neila TALBI | MetabERN*

                                * European Reference Network


A rare, rapidly progressive, and histologically distinct, form of idiopathic interstitial pneumonia.

Summary:
Epidemiology
Prevalence of acute interstitial pneumonia (AIP) is estimated at 1 in 25,000.
Clinical description
AIP occurs over a wide age range, with a mean age of approximately 50 years. There is no sex predominance or association with smoking. The onset is acute/subacute (1±3 weeks), with dyspnoea and cough followed by rapid development of respiratory failure and the need for mechanical ventilation in the vast majority of the patients. Fever is present in almost half of the patients on presentation and a history of viral-like symptomatology exists in most cases but extensive investigations for bacterial and viral agents are negative.
Etiology
No etiology is known for AIP. There is no genetic predisposition identified.
Diagnostic methods
The chest radiograph and high-resolution computed tomography (HRCT) scan is abnormal; chest CT manifestations of AIP are bilateral, extensive, and sometimes patchy. They show alveolar densities associated with areas of ground glass attenuation. Consolidation is seen in the majority of cases, but is not as common as ground glass attenuation. Lung biopsies from patients with AIP show histologic features of the acute and/or organising phases of diffuse alveolar damage (DAD). The exudative phase shows oedema, hyaline membranes, and microvascular thrombi. The organising phase shows loose organising fibrosis, mostly within alveolar septa, and type II pneumocyte hyperplasia. The diagnosis of AIP is made in the appropriate clinical setting in a patient who has a clinical, radiological and histopathological presentations compatible with acute respiratory distress syndrome (ARDS) but without a clear etiology.
Differential diagnosis
The differential diagnosis, histologically and clinically, includes acute exacerbation of pulmonary fibrosis, DAD in patients with collagen vascular diseases, DAD of known cause (ARDS), infection (especially Pneumocystis jiroveci pneumonia and legionellosis) and drug-induced pneumonitis, as well as hypersensitivity pneumonitis and acute eosinophilic pneumonia.
Management and treatment
There is no proven treatment, however supportive care with mechanical ventilation, occasionally extracorporeal membrane oxygenation, high-dose corticosteroids, and often intravenous pulse cyclophosphamide, are usually provided.
Prognosis
The prognosis is severe and early mortality is high, with a mortality rate over 50% within six months after onset.

                            Last update:
                            January 2023

                            - Expert reviewer(s):
                            Pr Vincent COTTIN


A rare hepatic disease characterized by acute onset of severe liver dysfunction without evidence of underlying chronic liver disease. Patients present with nonspecific symptoms like jaundice, upper right abdominal pain, nausea, vomiting, pruritus, fatigue, and fever. The condition may rapidly progress to hepatic encephalopathy, coagulopathy, and life-threatening multiorgan failure. Liver biopsy typically shows massive hepatic necrosis.


A rare disease characterized by malignant proliferation of lymphoid cells blocked at an early stage of differentiation and accounts for 75% of all cases of childhood leukaemia.

Summary:
Epidemiology
About 3,000 children in the United States and 5,000 children in Europe are diagnosed with ALL per year.
Clinical description
The peak incidence occurs between 2 and 5 years of age. ALL may be either asymptomatic or acute with a life-threatening haemorrhage, infection, or episode of respiratory distress. Although ALL primarily affects the bone marrow and peripheral blood, any organ or tissue may be infiltrated by the abnormal cells. The most frequent signs are lymphadenopathies, hepatosplenomegaly, fever, signs of haemorrhage, and bone pain.
Etiology
Most cases show chromosomal and genetic abnormalities, occurring spontaneously in genes playing important regulatory roles in controlling the lymphoid cell population. The most common ALL translocation, the t(12;21), appears to have good prognostic implications.
Diagnostic methods
ALL is biologically heterogeneous and morphologic, immunologic, cytogenetic, biochemical, and molecular genetic characterisation of leukaemia lymphoblasts is needed to establish the diagnosis or to exclude other possible causes of bone marrow failure and, finally, to classify ALL subtypes. Biological findings include hyperleukocytosis due to circulating lymphoblasts, anaemia and thrombocytopaenia. Diagnosis is established by bone marrow biopsy revealing leukaemic cell infiltration.
Management and treatment
The chemotherapy protocols adopted by international cooperative groups have four main objectives: induction with the aim of complete remission, preventative therapy to avoid central nervous system involvement, consolidation/re-induction, and maintenance therapy. Although management of relapse remains largely controversial, high dose chemotherapy blocks and stem cell transplantation are approaches increasingly adopted in most cases. In 2006, clofarabine obtained EU marketing authorisation as an Orphan drug for second line treatment of paediatric ALL patients. A novel tyrosine-kinase inhibitor, dasatinib, has been shown to be a safe and effective treatment option for adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia and resistance or intolerance to imatinib. Clinical trials with this inhibitor are ongoing in the paediatric population. With the need to stratify patients into risk groups and to provide risk-adapted therapy, treatment requires high levels of organisation, expertise and knowledge.
Prognosis
The increase in the survival rate for children younger than 15 years of age has been dramatic, moving from less than 10% in the early 60's to about 75% in the late 90's. Unfortunately, however, results are still rather poor in countries with limited resources, which are home to around 80% of the child population.

                            Last update:
                            August 2007

                            - Expert reviewer(s):
                            Pr Andrea BIONDI  - Dr Roberto CHIESA  - Dr C CITTERIO  - Dr Valentino CONTER  - Pr Carmelo RIZZARI  - Dr Arturo SALA


A rare, acquired retinal disorder characterised by transient or permanent visual impairment accompanied by the presence of reddish-brown, wedge-shaped lesions in the macula, the apices of which tend to point towards the fovea. The lesions usually appear in a petalloid or tear-drop configuration. Patients tend to be young, Caucasian, and female.


A rare systemic mastocytosis characterized by the presence of at least 20% usually immature and atypical mast cells in bone marrow aspirate smears. In classic mast cell leukemia, mast cells account for at least 10% of peripheral white blood cells, although the aleukemic variant with less than 10% mast cells is more common. C-findings (cytopenias, hepatomegaly, ascites, portal hypertension, splenomegaly, skeletal lesions, malabsorption), indicative of organ damage due to mast cell infiltration, are usually present at diagnosis, while skin lesions are absent in most cases. Prognosis is generally poor.


A rare acute myeloid leukemia that occurs predominantly in childhood and particularly in children with Down syndrome (DS-AMKL). Nonspecific symptoms may be irritability, weakness, and dizziness while specific symptoms include pallor, fever, mucocutaneous bleeding, hepatosplenomegaly, neurological manifestations and rarely lymphadenopathy. Acute panmyelosis with myelofibrosis may also be associated with AMKL. In contrast to DS-AMKL (around 80 % survival), non-DS-AMKL is an AML subgroup associated with poor prognosis.


A form of acute myeloid leukemia that is either comprised of more than 80% of monoblasts or 30-80% monoblasts with (pro)monocytic differentiation. It presents with asthenia, pallor, fever, and dizziness. Specific features include hyperleukocytosis, propensity for extramedullary infiltrates, coagulation abnormalities including disseminated intravascular coagulation and neurological disorders. Leukemia cutis and gingival infiltration can also be seen. A characteristic translocation observed is t(9;11).


Acute motor and sensory axonal neuropathy

A rare motor-sensory, axonal form of Guillain-Barré syndrome (GBS).

Summary:
Epidemiology
The overall annual incidence of GBS is estimated at between 1/91,000 and 1/55,000. The axonal (AMSAN and acute motor axonal neuropathy, AMAN; see this term), forms account for only 3-5% of cases of GBS in Western countries but are much more frequent (30%-50% of GBS cases) in Asia and Latin America.
Clinical description
Patients present with a clinical picture (muscle weakness and sensory deficits) similar to that of the more frequent demyelinating form of GBS, acute inflammatory demyelinating polyradiculoneuropathy (AIDP; see this term) but the disease course in AMSAN tends to be more severe. As in other types of GBS, an infectious disease precedes the onset of limb weakness in the majority of cases.
Etiology
Although the exact pathological mechanism is poorly understood, both AMAN and AMSAN are associated with the presence of antiganglioside antibodies (anti-GM1/GD1a/GM1b/GalNAc-GD1a) and may be caused by antibody-mediated primary axonal degeneration or antibody-mediated inhibition of voltage-gated sodium channels.
Prognosis
AMSAN is generally a severe form of GBS and recovery is often poor.

                            Last update:
                            December 2009

                            - Expert reviewer(s):
                            Pr P.A. [Pieter] VAN DOORN


A rare pure motor axonal form of Guillain-Barré syndrome (GBS).

Summary:
Epidemiology
The overall annual incidence of GBS is estimated at between 1/91,000 and 1/55,000. The axonal forms (AMAN and acute motor-sensory axonal neuropathy, AMSAN; see this term) account for only 3-5% of cases in Western countries but are much more frequent (30%-50% of GBS cases) in Asia and Latin America.
Clinical description
AMAN presents with rapid onset of muscle weakness and absent reflexes. The clinical course in AMAN tends to be more severe than in the more frequent, demyelinating form of GBS, acute inflammatory demyelinating polyradiculoneuropathy (AIDP; see this term), with an increased number of patients requiring artificial ventilation due to respiratory involvement. However, there is no sensory deficit in AMAN and cranial nerve involvement is rare.
Etiology
In the majority of cases, AMAN occurs following Campylobacter jejuni infection, in particular following infection with strains of C jejuni that cause enteritis. Although the exact pathological mechanism is not fully understood, AMAN is associated with the presence of antiganglioside antibodies (primarily, anti-GM1/GD1a) and may be caused by antibody-mediated primary axonal degeneration or antibody-mediated inhibition of voltage-gated sodium channels.
Prognosis
Although the clinical course initially can be severe in AMAN, recovery can be rapid. However, recovery may be significantly prolonged in patients with extensive axonal degeneration.

                            Last update:
                            December 2009

                            - Expert reviewer(s):
                            Pr P.A. [Pieter] VAN DOORN


Acute myeloblastic leukemia with maturation

A rare, acute myeloid leukemia characterized by evidence of granulocytic maturation and more than 20% of blast cells in the bone marrow and/or peripheral blood. The maturing non-blast granulocytic cells account for greater than or equal to 10% and monocytic cells less than or equal to 20% of the bone marrow cells. Various degrees of anemia, thrombocytopenia, or pancytopenia are present. Frequent clinical manifestations include fatigue, fever, bleeding disorders, and organomegaly, especially hepatosplenomegaly.


Acute myeloblastic leukemia without maturation

A rare, acute myeloid leukemia characterized by no significant myeloid maturation and more than 90% blast cells in the non-erythroid population. Various degrees of anemia, thrombocytopenia, or pancytopenia are present. Frequent clinical manifestations include fatigue, fever, bleeding disorders, and organomegaly, especially hepatosplenomegaly.


Acute myeloid leukaemia with myelodysplasia-related features

A rare acute myeloid leukemia (AML) characterized by the presence of acute leukemia with at least 20% peripheral blood or bone marrow blasts with morphological features of myelodysplasia, or occurrence in patients with a prior history of a myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm, with MDS-related cytogenetic abnormalities, in the absence of specific genetic abnormalities characteristic of AML with recurrent genetic abnormalities. Prior cytotoxic or radiation therapy for an unrelated disease must be excluded. The condition occurs mainly in elderly patients and is rare in children. Patients often present with severe pancytopenia. Prognosis is generally poor.


Acute myeloid leukemia and myelodysplastic syndromes related to alkylating agent

A subgroup of therapy-related myeloid neoplasms (t-MN), associated with a treatment of an unrelated neoplastic or autoimmune disease with cytotoxic agents, like cyclophosphamid, platins, melphalan and others. The neoplastic cells typically harbor unbalanced aberrations of chromosomes 5 and 7 (monosomy 5/del(5q) and monosomy 7/del(7q)) or a complex karyotype. It usually presents with multilineage dysplasia and cytopenias 5-10 years after exposure, with symptoms related to the degree of bone marrow failure and the corresponding cytopenia (fatigue, bleeding and bruising, recurrent infections, bone pain).


Acute myeloid leukemia and myelodysplastic syndromes related to radiation

A subgroup of therapy-related myeloid neoplasms (t-MN), associated with treatment of an unrelated neoplastic disease with radiation. The neoplastic cells typically harbor unbalanced aberrations of chromosomes 5 and 7 (monosomy 5/del(5q) and monosomy 7/del(7q)) or a complex karyotype. Patients frequently present with multilineage dysplasia and cytopenias 5-10 years after exposure.


Acute myeloid leukemia and myelodysplastic syndromes related to topoisomerase type 2 inhibitor

A subgroup of therapy-related myeloid neoplasms (t-MN), associated with treatment of an unrelated neoplastic disease with cytotoxic agents, like etoposid, doxorubicin, daunorubicin and others. The neoplastic cells often show rearrangements involving the mixed lineage leukemia gene at 11q23. This subgroup of t-MN is typically associated with overt leukemia, without preceding myelodysplastic syndrome, developing 2-3 years after exposure, presenting with non-specific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement.


Acute myeloid leukemia with 11q23 abnormalities

A rare tumor arising from hematopoietic and lymphoid tissues characterized by abnormal proliferation and differentiation of a clonal population of myeloid stem cells carrying unspecific 11q23 abnormalities. Clinical manifestations result from accumulation of malignant myeloid cells within the bone marrow, peripheral blood and other organs, and include leukocytosis, anemia, thrombocytopenia, fatigue, anorexia and weight loss.


Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)

A rare acute myeloid leukemia (AML) with recurrent genetic anomaly disorder characterized by an inv(16)(p13q22) or t(16;16)(p13;q22) cytogenic abnormality, which generates a CBFB-MYH11 fusion gene, presenting with typical morphologic features of AML as well as abnormal bone marrow eosinophils (seen in all stages of maturation with no significant signs of maturation arrest). Myeloid sarcoma and involvement of the central nervous system is relatively common. Cytology reveals myeloblasts, a significant monocytic component and variable numbers of immature eosinophils with atypical purple-violet granules in addition to eosinophilic granules. Presence of the fusion gene is sufficent for diagnosis irrespective of blast count.


Acute myeloid leukemia with CEBPA somatic mutations

A subtype of acute myeloid leukemia with recurrent genetic abnormalities, characterized by clonal proliferation of myeloid blasts harboring somatic mutations of the CEBPA gene in the bone marrow, blood and, rarely, other tissues. It can present with anemia, thrombocytopenia, and other nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly).


Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)

A subtype of acute myeloid leukemia with recurrent genetic abnormalities characterized by clonal proliferation of myeloid blasts in the bone marrow, blood and, rarely, other tissues. Bone marrow typically shows small, hypolobated megakaryocytes and multilineage dysplasia. Patients typically present with leukocytosis, anemia, variable platelet counts and a variety of nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding, bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly). High resistance to conventional chemotherapy is reported.


Acute myeloid leukemia with minimal differentiation

A rare subtype of acute myeloid leukemia characterized by clonal proliferation of poorly differentiated myeloid blasts in the bone marrow, blood or other tissues. It usually presents with anemia, thrombocytopenia and other nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly). Low remission rates are reported.


Acute myeloid leukemia with NPM1 somatic mutations

A subtype of acute myeloid leukemia with recurrent genetic abnormalities characterized by leukocytosis, thrombocytosis and nonspecific symptoms related to ineffective hematopoiesis (fatigue, bleeding and bruising, recurrent infections, bone pain), with frequent extramedullary involvement typically presenting as gingival hyperplasia and lymphadenopathy. The disease is characterized by clonal proliferation of myeloid blasts harboring mutations of the NPM1 gene in the bone marrow, blood and other tissues. It is associated with multilineage dysplasia, involving the myeloid, monocytic, erythroid, and megakaryocytic cell lineages.


Acute myeloid leukemia with t(6;9)(p23;q34)

A rare subtype of acute myeloid leukemia with recurrent genetic abnormalities characterized by clonal proliferation of poorly differentiated myeloid blasts in the bone marrow, blood, or other tissues in patients who present the t(6;9)(p23;q34) translocation. Frequently associated with multilineage bone marrow dysplasia, it usually presents with anemia, thrombocytopenia (often pancytopenia), and other nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly). Basophilia, as well as poor response to chemotherapy, has been reported.


Acute myeloid leukemia with t(8;16)(p11;p13) translocation

A distinct form of Acute myeloid leukemia (AML) in which this chromosomal anomaly is found de novo or in therapy-related AML cases, and is characterized by frequent extramedullary involvement (mainly hepatomegaly, splenomegaly, lymphadenopathies, cutaneous infiltration, but also gum, bone, central nervous system, testicles involvement), severe coagulation disorder (disseminated intravascular coagulopathy or primary fibrinolysis) and poor prognosis. Morphologically, a blast population with a myelomonocytic stage of differentiation is observed.


Acute myeloid leukemia with t(8;21)(q22;q22) translocation

A rare acute myeloid leukemia with recurrent genetic anomaly disorder characterized by a t(8;21)(q22;q22) balanced translocation cytogenetic abnormality, forming a RUNX1-RUNX1T1 fusion gene, presenting with morphological characteristics which include myeloblasts with indented nuclei, basophilic cytoplasm with a prominent paranuclear hof that may contain a few azurophilic granules, prominent and possibly large promyelocytes, myelocytes and metamyelocytes, easily identifiable Auer rods and, more variably, bone marrow eosinophilia. Myeloid sarcoma is frequently present at diagnosis. Detection of the t(8;21)(q22;22) translocation is sufficient for diagnosis irrespective of blast count.


Acute myeloid leukemia with t(9;11)(p22;q23)

A tumor of hematopoietic and lymphoid tissues characterized by the most common AML-causing MLL translocation, resulting in the MLL-MLLT3-fusion protein. It can occur either as a primary neoplasm or secondary to previous chemo-/radiation therapy. Clinical manifestations result from accumulation of malignant myeloid cells within the bone marrow, peripheral blood and other organs and include leukocytosis, anemia, thrombocytopenia, fever, bone pain, fatigue, pallor, easy bruising and frequent bleeding.


Acute myeloid leukemia with t(9;22)(q34.1;q11.2)

A rare acute myeloid leukemia (AML) with recurrent genetic anomaly characterized by the presence of bone marrow and peripheral blood myeloblasts with features ranging from those of minimal differentiation to granulocytic maturation, demonstrating t(9;22)(q34.1;q11.2) or molecular genetic evidence of BCR-ABL1 fusion. Evidence of chronic myeloid leukemia (CML) is absent. Patients most commonly present with leukocytosis with blast predominance and variable anemia and thrombocytopenia. Splenomegaly is less frequent and peripheral blood basophilia lower than in patients with myeloid blast transformation of CML. The disease occurs primarily in adults, and response to traditional AML therapy or tyrosine kinase inhibitor therapy alone is typically poor.


A group of neoplasms arising from precursor cells committed to the myeloid cell-line differentiation. All of them are characterized by clonal expansion of myeloid blasts. They manifest by fever, pallor, anemia, hemorrhages and recurrent infections.

Summary:
Epidemiology
Annual incidence rate of AML is estimated to be 1/33,000-1/25,000 in Europe.
Clinical description
Although, AML can occur at any age, it is typically a disease affecting elder people, usually more than 65 years. The main clinical picture consists of a short time period with pallor, fatigue, fever, infections and hemorrhages. Presence of all these features is not compulsory. Central nervous system infiltration is uncommon and mainly related with monocytic variants. Extramedullary accumulation of myeloid blasts in different tissues, mainly skin, can be observed and is known as myeloid sarcoma (see this term). Testes are usually not affected.
Etiology
Pathogenesis of AML is still unclear but a two-hit model has been suggested as the probable mechanism for leukemogenesis. That means that AML could be the consequence of at least 2 different types of gene mutations. Class I mutations resulting in proliferative advantage while the class II mutations alter the normal hematopoietic differentiation. Examples of class I mutations are those of FLT3-ITD or KIT mutations. Class II mutations include CEBPA mutations. Controversy is also still in the type of cell from which AML arises. While data supporting progenitor cells committed to specific myeloid cell type has been reported, other studies argue in favor for a more immature stem.
Diagnostic methods
Diagnosis relies on laboratory findings showing anemia, thrombocytopenia and leucopenia or leukocytosis which result from disturbed hematopoietic function due to bone marrow and peripheral blood infiltration by immature blast cells. Diagnosis of AML also relies on bone marrow aspirate or biopsy after the disease has been suspected. Bone marrow should have at least 20% of myeloid blasts to be considered as AML. After morphological examination, immunophenotyping of leukemic cells, cytogenetic and molecular analysis should be performed.
Differential diagnosis
Differential diagnosis includes megaloblastic anaemia, myelodysplastic syndromes, acute lymphoblastic leukemia, acute biphenotypic leukemia, chronic myeloid leukemia (myeloid blast phase), and metastases of tumors such rhabdomyosarcoma and neuroblastoma (see these terms).
Management and treatment
For young patients, treatment consists of an induction cycle with cytarabine plus idarubicin or daunorubicin in a typical 3 + 7 schedule with the first objective to reach complete response (CR). About 75% of the patients achieve CR, but virtually all of them will relapse if additional treatment (consolidation therapy) is not given. Based on stratification, patients can be treated with chemotherapy consolidation or allogenic hematopoietic stem cell transplantation (HSCT). Refractory or relapsed AML is treated with a second induction course adding new drugs (such gemtuzumab ozogamicin) to the standard treatment. Some drugs such as azacitidine or decitabine are available for the treatment of elderly AML patients under specific circumstances.
Prognosis
Prognosis varies widely according to cytogenetics, molecular findings, response to induction treatment and age, between others. Overall, long-term survivors account for 40% of young patients. For children less than 15 years, overall survival rates are 60-70%. Prognosis of elder patients is rather poor.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Federico MOSCARDÓ


A rare acute myeloid leukemia disorder characterized by increased blast cells (myeloblasts, monoblast, and/or promonoblasts), representing more than 20% of the total bone marrow (BM) or peripheral blood differential counts, with 20-80% of BM cells being of monocytic lineage. Clinical presentation is the result of bone marrow involvement and extramedullary infiltration by the leukemic cells and includes asthenia, pallor, fever, dizziness, respiratory symptoms, easy bruising, bleeding disorders, and neurological deficits. Gingival hyperplasia, organomegaly, especially hepatosplenomegaly, and lymphadenopathy may also be associated.


Acute necrotizing encephalopathy of childhood

A rare neurologic disease characterized by a rapid onset of seizures, an altered state of consciousness, neurologic decline, and variable degrees of hepatic dysfunction following a respiratory or gastrointesitnal infection (e.g. mycoplasma, influenza virus) in a previously healthy child. Brain MRI of patients reveals bilateral, multiple, symmetrical lesions predominantly observed in thalami and brainstem, but also in periventricular white matter and cerebellum in some cases.


A severe form of citrullinemia type 1 characterized biologically by hyperammonemia and clinically by progressive lethargy, poor feeding and vomiting, seizures and possible loss of consciousness, within one to a few days of birth, with variable signs of increased intracranial pressure. The condition can lead to significant neurologic deficits.


A rare intoxication with opioids, a large group of alkaloid analgesics, mainly characterized by miosis (pinpoint pupil), respiratory depression (bradypnea/apnea) and central nervous system depression (sedation or coma). Other manifestations include hypotension, reduced bowel motility, hypothermia and hypoglycemia. Naloxone, a competitive inhibitor of the mu-opioid receptor, is a potent antagonist and is used as the antidote for opioid intoxication.


A rare variant of Guillain-Barré syndrome characterized by acute post-ganglionic sympathetic and parasympathetic failure presenting several weeks after acute infection with gastrointestinal symptoms (abdominal pain, vomiting, constipation, diarrhea, gastroparesis, ileus), orthostatic hypotension, erectile dysfunction, urinary frequency, urgency or retention, vasomotor instability with acrocyanosis and reduced salivation, lacrimation and sweating.


A rare unclassified acute myeloid leukemia characterized by an acute panmyeloid proliferation with blasts constituting more than 20% of cells in the bone marrow or peripheral blood, accompanied by fibrosis of the bone marrow. Patients typically present with acute onset of severe constitutional symptoms, bone pain, and pancytopenia. Splenomegaly is minimal or absent. The disease is rapidly progressive with poor therapy response.


A rare vascular condition characterized by the sudden blockage of an artery supplying blood to the limbs by a blood clot, causing acute limb ischemia. The clinical presentation is variable and depends on the time course of vessel occlusion, the presence of an underlying vascular disease, and the recruitment of collateral circulation. Symptoms can develop over a period of hours to days and typically include limb pain, pallor, absent pulse, poikilothermia, paresthesia, and limb paralysis. The condition can quickly progress to infarction and loss of the limb.


Acute poisoning by drugs with membrane-stabilizing effect

A rare clinical situation characterized by acute, potentially life-threatening toxic effects of drugs acting on voltage-gated sodium or calcium channels, such as tricyclic antidepressants, anticonvulsants, local anesthetics and antiarrhythmics, some beta-blockers, and chloroquine. Clinical manifestations include abnormal ECG findings (intraventricular conduction block with widening of the QRS complex, T wave flattening, prolongation of the QT interval) and variable signs and symptoms depending on the drug, typically involving the cardiovascular and central nervous system, among others.


A rare, acquired, demyelinating neuropathy disease characterized by acute, symmetric, monophasic sensory neuropathy without motor involvement, typically manifesting with numbness in the distal lower limbs which progressively extends to all the limb, tingling sensation in the distal lower limbs, generalized areflexia, and unsteady gait, as well as clumsiness of the upper limbs, pseudoathetosis and loss of vibration sense.


A rare radiation-induced disorder resulting from whole body exposure to large doses of penetrating radiation (>0.7 Gray) within a very short period of time (usually minutes) and characterized by bone marrow syndrome with pancytopenia (mild symptoms of which may occur already at 0.3 Gray), gastrointestinal syndrome resulting in mostly fatal infection, dehydration, and electrolyte imbalance (occurring at doses >10 Gray), and cardiovascular/central nervous system syndrome with watery diarrhea, convulsions, coma, and death within three days of exposure (occurring at doses >50 Gray). The syndrome develops in four clinical stages (prodromal/latent/manifest illness/recovery or death) of variable duration.


A rare variant of Guillain-Barré syndrome characterized by acute onset monophasic sensory neuropathy with diminished or absent tendon reflexes, loss of proprioception, positive Romberg sign and nerve conduction features of demyelination. It presents several weeks after acute infection with paresthesias, ataxia and neuropathic pain.


A rare inflammatory demyelinating disorder of the spinal cord that can be either idiopathic (IATM) or secondary to a known cause (SATM).

Summary:
Epidemiology
Annual incidence of IATM is estimated between 1/1,000,000 and 1/250,000. Incidence of SATM is variable and depends of the underlying disease.
Clinical description
Age of onset and clinical course vary depending on the form. The clinical manifestations common to both forms include motor involvement (limb weakness, stiffness and muscle spasms with impaired respiratory function in cases with involvement of the upper spinal cord), sensory manifestations (back pain, paresthesia, numbness and neuropathic pain) and autonomic findings (sexual dysfunction, urinary urge/retention, bowel urge/retention and autonomic dysreflexia). Other signs depend on the associated diseases in SATM, with involvement of cranial and peripheral nerves. IATM has a monophasic course whereas SATM may be relapsing.
Etiology
IATM is believed to be an immune-mediated disease, due to a late immune response against a recent infection that inadvertently targets the spinal cord. SATM is due to an inflammatory disease: multiple sclerosis (MS), neuromyelitis optica (NMO), systemic lupus erythematosus (SLE) and Sjögren's syndrome (see these terms), and may also be due to an infectious disease (bacterial, parasitic or viral).
Diagnostic methods
Diagnosis requires MRI of the spinal cord to confirm the presence of Acute transverse myelitis and cause, if any. Laboratory tests are also essential for identifying the cause of SATM: analysis of the cerebrospinal fluid may reveal the presence of oligoclonal bands (commonly seen in MS) or bacterial/viral/parasitic infections; serology may reveal the presence of autoantibodies to aquaporin-4 (NMO), anti-double-stranded DNA antibodies (SLE) or anti-Ro/SS-A antibodies (Sjögren's syndrome).
Differential diagnosis
The differential diagnosis includes acute transverse myelopathy associated with fistulae, trauma, acute compressive lesions (such as metastases and epidural abscess) and infarction of the spinal cord.
Management and treatment
Treatment approaches depend on the presence of an associated disease. Acute treatment may include corticosteroids and plasma exchange in steroid-resistant patients. The benefit of intravenous immunoglobulins and cyclophosphamide remains to be established. Long-term care includes symptomatic management, rehabilitative therapy, and, in case of SATM, long-term maintenance treatment to prevent relapses or disease progression.
Prognosis
The prognosis is variable, unpredictable and depends on the response to treatment. SATM is often relapsing and prognosis depends on prevention of further episodes.

                            Last update:
                            June 2010

                            - Expert reviewer(s):
                            Dr Anu JACOB  - Dr Alison L JONES


Acute tricyclic antidepressant poisoning

A rare, potentially lethal intoxication characterized by life-threatening arrhythmias (sinus tachycardias, premature ventricular contractions, ventricular arrhythmias), anticholinergic toxidrome (mydriasis, dry mucous membrane, tachycardia, hypertension), central nervous system toxicity (lethargy, coma, myoclonic jerks), refractory hypotension and sudden death.


A rare acute leukemia of ambiguous lineage characterized by clonal proliferation of primitive hematopoietic cells, primarily in the bone marrow and blood, lacking lineage-specific markers and detectable genotypic alterations. The patients present with leukocytosis, anemia, variable platelet count and a variety of nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (lymphadenopathy, splenomegaly, hepatomegaly).


A rare acquired retinal disorder characterised by sequential focal degeneration of photoreceptors, retinal pigment epithelium and choroid, with the majority of patients experiencing sudden onset photopsia and acute scotomas. Although patients typically retain decent visual acuity, blind spot enlargement and retinal pigment epithelial disturbances tend to develop over time. Individuals also often complain of distortion of central vision, photophobia and difficulty with night vision, with more advanced cases reporting loss of peripheral vision.


A rare disorder characterized by neurological dysfunction, hepatic failure and cardiomyopathy due to a deficiency of complex I of the respiratory chain.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Patients present predominantly with neurological, hepatic and /or cardiomyopathic disease with isolated NADH-CoQ reductase deficiency (see this term). Manifestations include failure to thrive, hypertrophic cardiomyopathy, exercise intolerance, liver disease and mild to severe neurological dysfunction.
Etiology
ACAD9 deficiency is caused by a mutation in the  ACAD9 gene (3q21.3) that encodes the protein ACAD9. This protein has only relatively recently been described but is quite widely expressed in tissues and has activity as an acyl-CoA dehydrogenase with overlapping substrate specificity with very long-chain acyl-CoA dehydrogenase (VLCAD). It also acts an assembly factor for complex I of the respiratory chain and therefore has a vital role in the production of a functioning mitochondrial respiratory chain.
Genetic counseling
The mode of inheritance is autosomal recessive and genetic counseling is possible.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Simon OLPIN


A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 20-30 years, major systemic amyloidosis and recurrent lobar intracerebral hemorrhages. Unlike other forms of hereditary cerebral hemorrhage with amyloidosis, this subtype is due to a mutation in the CST3 gene (20p11.2), encoding the precursor protein cystatin C.