8q21.11 microdeletion syndrome encompasses heterozygous overlapping microdeletions on chromosome 8q21.11 resulting in intellectual disability, facial dysmorphism comprising a round face, ptosis, short philtrum, Cupid's bow and prominent low-set ears, nasal speech and mild finger and toe anomalies.

Summary:
Epidemiology
The prevalence is unknown but 8q21.11 microdeletion syndrome is rare. To date, 13 cases, of which 5 from the same family, have been clinically and molecularly characterized without a notable gender discrepancy.
Clinical description
Very frequent facial anomalies in patients with 8q21.11 microdeletions include a round face with full cheeks, ptosis, short philtrum, small mouth with downturned corners and a Cupid's bow of the upper lip, low-set and prominent ears and nasal speech. Mild to moderate intellectual disability is present in all affected individuals. Mild finger and toe anomalies such as camptodactyly, syndactyly of the 3rd and 4th fingers, and broadening of the first rays are relatively common. Most also suffer from hypotonia. Other features comprise a high forehead, short palpebral fissures, wide nasal bridge, underdeveloped alae, micrognathia, short neck, hearing loss and ophthalmic manifestations including strabismus, sclerocornea and microphthalmia.
Etiology
The syndrome is caused by a heterozygous deletion at chromosome region 8q21.11, reported in the majority of patients. The constant microdeletion overlap region contains the ZFHX4 gene, a microRNA gene of unknown function, as well as a pseudogene and in 7 cases heterozygous deletions of PEX2 were noted. Microdeletions appear de novo or are inherited from affected parents in an autosomal dominant manner.
Diagnostic methods
Diagnosis is based on clinical manifestations leading to cytogenetic analysis. The 8q21.11 microdeletion can be detected using a range of molecular techniques including array based comparative genomic hybridization (array CGH) and fluorescence in situ hybridization (FISH).
Differential diagnosis
Differential diagnosis includes Schilbach-Rott syndrome, auriculo-condylar (question mark ear) syndrome, Frydman syndrome, Kabuki syndrome (see these terms). The syndrome also bares resemblance with distal 22q11.2 microdeletion syndrome and 10p13 microdeletion syndrome. The entity should not be confused with the 8q22.1 microdeletion (see this term) found in patients with Nablus mask-like facial syndrome.
Antenatal diagnosis
Antenatal diagnosis of 8q21.11 microdeletion is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis. Preimplantation genetic diagnosis should be available for at risk couples.
Genetic counseling
Cytogenetic testing and genetic counseling should be offered to parents of affected individuals, informing them of the 50% risk of recurrence. Although the 8q21.11 microdeletion occurs sporadically, most deletions appearing de novo, a small number of patients have been inherited from affected parents.
Management and treatment
Management involves assessment, developmental therapies and a regular follow-up by a primary care physician and if required by appropriate specialists. Affected children almost invariably need special education. Early diagnosis and access to therapies with attention to speech and language, motor development and cognition are recommended.
Prognosis
Prognosis depends on clinical features. Adult affected individuals, despite their learning difficulties specifically regarding abstract thinking and planning ahead, function normally in everyday life. Fertility and life expectancy does not seem to be reduced.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM


The 8q22.1 microdeletion syndrome or Nablus mask-like facial syndrome is a rare microdeletion syndrome associated with a distinct facial appearance.

Summary:
Epidemiology
It has been reported in four unrelated patients.
Clinical description
A mask-like facial appearance is the most characteristic feature with blepharophimosis, tight appearing glistening facial skin, flat and broad nose, dysplastic ears and unusual scalp hair pattern. Camptodactyly, joint contractures, unusual dentition and mild developmental delay can be observed. Cryptorchidism in boys and a happy disposition are constant.
Etiology
This microdeletion was identified by comparative genomic hybridisation (CGH) microarray.

                            Last update:
                            October 2010

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


A multiple congenital anomalies/dysmorphic - intellectual disability syndrome characterized by feeding problems, growth retardation, microcephaly, developmental delay, digital and vertebral anomalies, joint laxity/dislocation, cardiac and renal defects, and dysmorphic facial features (including plagiocephaly, prominent forehead, bitemporal narrowing, bilateral coloboma, epicanthal folds, malformations of the outer and middle ear, wide nasal bridge, anteverted nares, prominent and bulbous nose tip, long philtrum, thin lips, high and narrow palate, micrognathia with prognathism/retrognathism, full cheeks, and short, broad neck). Additional variable manifestations include obstructive apneas, recurrent pneumonia, and seizures.


9p13 microdeletion syndrome is a rare chromosomal anomaly syndrome, resulting from a partial interstitial deletion of the short arm of chromosome 9, characterized by mild to moderate developmental delay, hand tremors, myoclonic jerks, attention deficit-hyperactivity disorder and a social personality. Patients also present bruxism, short stature and minor facial dysmorphic features (e.g., bilateral epicantic folds, broad, flat nasal bridge, anteverted nares, low-set ears micro/retro-gnathia).


A rare, genetic, intellectual disability malformation syndrome characterized by global developmental delay, intellectual disability, delayed speech and language development, epilepsy, autistic behavior, and moderate facial dysmorphism (including elongated face, narrow forehead, arched eyebrows, horizontal palpebral fissures, hypertelorism, epicanthus, midface flattening, short nose, long and featureless philtrum, thin upper lip, macrostomia, and prominent chin). Additional variable manifestations include microcephaly, hypotonia, hypertrichosis, and strabismus.


9q31.1q31.3 microdeletion syndrome is a rare, genetic, syndromic intellectual disability characterized by mild intellectual disability, short stature with high body mass index, short neck with cervical gibbus and dysmorphic facial features. A metabolic syndrome, including type 2 diabetes, hypercholesterolemia and hypertension has also been reported.


A partial monosomy of the long arm of chromosome 9 characterized by intellectual disability, developmental delay with pronounced speech delay, short stature, and muscular hypotonia. Common craniofacial dysmorphic features consist of microcephaly, prominent forehead, round face, arched eyebrows, upslanting palpebral fissures, strabismus, short nose, and thin upper lip. Other clinical findings include epilepsy, ataxia, unspecific brain MRI findings, early-onset primary dystonia, nail dysplasia, and bone malformations, in particular patellar abnormalities, epistaxis, and cutaneous-mucous telangiectasias.


A rare amyloidosis that complicates chronic inflammatory disorders and is characterized by the aggregation and deposition of amyloid fibrils composed of serum amyloid A protein, an acute phase reactant. The kidney is involved in virtually all patients and dominates the clinical picture. Other frequently involved sites are the liver, the spleen, suprarenal gland, gut and less frequently the heart.

Summary:
Epidemiology
The exact prevalence is not known. AA amyloidosis occurs in less than 5% of patients with chronic inflammatory disorders. The disease is more frequent in certain countries like Finland, Japan, Turkey and the Middle East.
Clinical description
The predominant feature of AA amyloidosis at diagnosis is renal dysfunction, proteinuria and nephrotic syndrome. AA amyloidosis complicates chronic inflammatory disorders and is typically preceded by many years of active inflammatory disease. These may include chronic inflammatory arthritis, (rheumatoid arthritis, juvenile idiopathic arthritis), chronic infections (bronchiectasis, osteomyelitis, tuberculosis), auto-inflammatory diseases (familial mediterranean fever (FMF), TRAPS syndrome), Crohn's disease and less commonly Castleman's disease, Schnitzler syndrome, vasculitis or neoplasias (lymphoma, mesothelioma). In almost 25% of cases with AA, the cause of inflammation remains unclear (idiopathic AA amyloidosis) and it has been proposed that obesity may have a role in these cases. In the last decades, the progressive improvement of treatment for rheumatic diseases has reduced the number of cases driven by inflammatory arthritis and, in parallel, increased the number of patients with an underlying chronic infectious disease or idiopathic AA amyloidosis.
Etiology
Chronic inflammatory disorders are associated with elevated levels of the acute-phase reactant, serum amyloid A protein (SAA) protein. AA amyloid fibrils are derived from SAA through a process of cleavage, misfolding, and aggregation. Amyloid fibrils associate with other moieties, including glycosaminoglycans and serum amyloid P component (SAP), forming deposits that disrupt structure and function of tissues and organs.
Diagnostic methods
Diagnosis of AA amyloidosis requires the demonstration of amyloid deposits on tissue biopsy revealed by Congo red staining on light microscopy and apple green birefringence on polarized light microscopy and amyloid typing by light microscopy, immunoelectron microscopy or proteomic analysis. Amyloidosis is suspected when signs of renal dysfunction (renal failure and proteinuria) are noted in the background of a chronic inflammatory disease with persistent elevated SAA concentration.
Differential diagnosis
Differential diagnoses include AL amyloidosis, familial renal amyloidosis and other causes of renal dysfunction like membranous glomerulonephritis and renal vein thrombosis.
Management and treatment
Treatment of AA amyloidosis relies on treating the underlying inflammatory disease (antimicrobial therapy in chronic infections, colchicine in FMF, immunosuppressive agents in chronic arthritis). The aim of therapy is the reduction of SAA concentration (ideally <10 mg/L) in order to minimize the risk of disease progression and possibly to reverse organ dysfunction. Successful treatment of the underlying inflammatory disorders reduces SAA concentrations. In patients with end stage renal disease and controlled underlying disease, renal transplantation could be considered as a valuable treatment option.
Prognosis
Factors associated with a poor prognosis are older age, a reduced serum albumin concentration, end-stage renal failure at baseline, and the degree by which the SAA concentration is elevated during follow-up. Patients with underlying chronic infectious diseases have a worse outcome. Twenty-four hour proteinuria and estimated glomerular filtration rate (eGFR) can identify patients with higher risk of end-stage renal failure at diagnosis.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Pr Giovanni PALLADINI | EuroBloodNet*

                                * European Reference Network


A rare, hereditary amyloidosis with primary renal involvement characterized by renal interstitial and medullary deposition of amyloid, low plasma levels of ApoA-1 and slow disease progression. Main clinical signs and symptoms are hypertension, proteinuria, hematuria and edema due to chronic renal insufficiency leading to end stage renal disease. Hepatosplenomegaly, progressive cardiomyopathy and involvement of skin, testes and adrenals (hypergonadotropic hypogonadism) have also been reported.


A rare hereditary amyloidosis with primary renal involvement characterized by variable onset of renal insufficiency with edema, hypertension, proteinuria, and azotemia, eventually leading to end-stage renal disease. Amyloid cardiomyopathy and histopathological evidence of amyloid deposition in other organs, such as the spleen, liver, adrenal glands, and pancreas, among others, have also been described.


A rare nonhereditary systemic amyloidosis characterized by slowly progressive renal dysfunction, increased serum creatinine, mostly normal urine analysis with no significant proteinuria and associated heart disease. Cardiac involvement presents as hypertrophic obstructive cardiomyopathy, left ventricular outflow tract obstruction, coronary artery disease and conduction system abnormalities. Histology reveals medullar amyloid deposits, renal tubular atrophy, interstitial fibrosis, and glomerular sclerosis.


A rare developmental disorder characterized by facial, limbs and genital features, and a disproportionate acromelic short stature.

Summary:
Epidemiology
AAS prevalence is not known, but less than 100 cases have been reported in the literature since the first description in 1970. However, prevalence estimates are thought to be around 1/25,000. About 40 molecularly proven cases are published worldwide.
Clinical description
AAS predominantly concerns males. Facial features include widow's peak and hypertelorism, both observed in female carriers, and downslanting palpebral fissures, broad nasal bridge, anteversed nostrils, low set and protuberant ears, maxillary hypoplasia and transverse crease below the lower lip. AAS patients have short and broad hands and feet, interdigital webbing, clinodactyly, and hyperextension of proximal interphalangeal joints and flexion at distal interphalangeal joints causing swan neck deformity of fingers. Size is generally normal at birth, but growth is slow in infancy and childhood, leading to short stature until puberty, which is often delayed. A growth spurt in late teens, generally, results in a moderate short stature. Genital anomalies may include cryptorchidism, macroorchidism, shawl scrotum and, more rarely, hypospadias. Fertility is normal. Female carriers may have only a subtle phenotype with hypertelorism and widow's peak. Patients may present a neurodevelopmental phenotype with learning and behavioural disabilities that are often confined to early childhood. When present, mental impairment is rarely severe.
Etiology
Although clinically and genetically heterogeneous, the best characterized form of the disorder is caused by mutations in the FGD1 gene (faciogenital dysplasia 1 gene; Xp11.21). Other gene(s) might be involved since most familial cases still do not have identified genetic cause.
Diagnostic methods
Clinical diagnosis is based on physical examination and the recognition of the most distinctive clinical hallmarks. Molecular genetics, based on analysis of the FGD1 gene, may confirm diagnosis.
Differential diagnosis
When molecular diagnosis is not conclusive, all possible options for differential diagnosis should still be considered, including Noonan syndrome, SHORT syndrome, pseudohypoparathyroidism and Robinow syndrome (see these terms).
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is technically possible when the disease-causing mutation in the family is known (the majority of mutations are family specific). However, prenatal testing is unlikely to be requested frequently, because usually physical signs can be mild and the clinical heterogeneity makes difficult a prediction of the phenotype, even within the same family.
Genetic counseling
AAS is an X-linked disease, but autosomal dominant and autosomal recessive transmissions have also been reported. Genetic counseling thus requires in depth investigation of patient's family history.
Management and treatment
There is no curative treatment for AAS. Preliminary results of growth hormone administration in childhood do not seem to show a significant effect. Learning problems and attention deficit and hyperactivity disorder (ADHD), in case, may require a neuropsychiatric intervention.
Prognosis
The majority of patients present a good prognosis. Typically, they have a good evolution into adulthood with an age-related improvement of mental status.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Alfredo ORRICO


A very rare genetic disorder characterised by the following congenital malformations: hydrocephalus (due to Dandy-Walker anomaly), cleft palate, and severe joint contractures.

Summary:
Epidemiology
Less than 20 cases have been reported in the literature.
Clinical description
The fingers are thin with absent knuckles and reduced creases over the joints, and patients show an inability to make a full fist. Additional findings may include deformed ears, ptosis, an inability to open the mouth fully, heart defects, and clubfoot.
Etiology
The aetiology remains unknown. There are currently no human genes associated with this disease.
Diagnostic methods
The features of the hand are especially important for the diagnosis.
Differential diagnosis
Clinical overlap between Aase-Smith syndrome I and Gordon syndrome (see this term) has been suggested, due to the presence of distal arthrogryposis and cleft palate in both syndromes.
Genetic counseling
Autosomal dominant inheritance is suggested.
Management and treatment
In the absence of a specific treatment, supportive care and surgical correction should be offered.

                            Last update:
                            July 2007


A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 54-61 years and progressive Alzheimer's disease-like dementia. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.


A form of hereditary cerebral hemorrhage with amyloidosis characterized by severe cerebral amyloid angiopathy (CAA), predominantly hemorrhagic strokes and dementia.

Summary:
Epidemiology
The prevalence is unknown. It has been seen in three Dutch families, that are most likely related (before 17th century), to date. Approximately 200-300 patients are known to be affected.
Clinical description
HCHWA-D presents with hemorrhagic stroke between the ages of 39-76 years (average age 50 years). In one third of cases, the initial stroke is fatal, recurrent strokes are seen in those who survive and patients often suffer from serious disability. Cognitive decline can be a presenting symptom in some cases but often occurs after the initial or recurrent strokes. Dementia is seen in the majority of patients with HCHWA-D over the age of 40. Epilepsy is also seen in half of patients who have already experienced a previous stroke.
Etiology
HCHWA-D is due to a mutation in the APP gene on chromosome 21q21.2, encoding the beta-amyloid precursor protein. The mutation leads to extensive amyloid-beta deposition in the meningocortical arterioles, causing them to weaken and rupture.
Diagnostic methods
The diagnosis is clear when a patient presents with a lobar hemorrhage and is known to come from an affected family. Imaging studies show diffuse white matter damage as well as hemorrhages. Genetic testing reveals a mutation in the APP gene.
Differential diagnosis
Differential diagnoses include other conditions that could cause intracerebral hemorrhage such as coagulopathies, vasculitis (see these terms), CNS neoplasms, cerebral vascular malformations, ischemic stroke and antecedent trauma.
Antenatal diagnosis
Antenatal diagnosis is possible but is rarely performed.
Genetic counseling
As HCHWA-D is inherited autosomal dominantly, genetic counseling is possible when a family member is diagnosed with the disease. Pre-symptomatic genetic testing is possible.
Management and treatment
There is currently no acute or preventive treatment for HCHWA-D. Symptomatic treatment (with corticosteroids and antiepileptic drugs) can be given. On pragmatic grounds, antihypertensive treatment is recommended for those with mild to moderate hypertension.
Prognosis
The prognosis is poor. HCHWA-D is often fatal, either acutely at first presentation or, on average, 10 years after symptom onset and after multiple strokes.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Joost HAAN  - Pr G.M. [Gisela] TERWINDT


A form of hereditary cerebral hemorrhage with amyloidosis characterized by age of onset between 50-66 years of age, memory impairment, myoclonic jerks, expressive dysphagia, short-stepped gait, personality changes, and lobar intracerebral hemorrhages. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.


A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 50 years of age, dementia and lobar intracerebral hemorrhage. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.


A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 45 years of age, progressive Alzheimer's disease-like dementia, and lobar intracerebral hemorrhage in some patients. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.


A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset between 50-70 years of age, recurrent lobar intracerebral hemorrhages and cognitive decline. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.


A severe, familial hypobetalipoproteinemia characterized by permanently low levels (below the 5th percentile) of apolipoprotein B and LDL cholesterol, and by growth delay, malabsorption, hepatomegaly, and neurological and neuromuscular manifestations.

Summary:
Epidemiology
It is very rare, with an estimated prevalence of less than 1/1,000,000.
Clinical description
Abetalipoproteinemia manifests during the first year of life or in young childhood. It is often associated with growth delay, hepatomegaly with steatosis, diarrhea with steatorrhea, and fat malabsorption. Spastic ataxia, atypical retinitis pigmentosa, acanthocytosis, a low level of liposoluble vitamins, and major cytolysis and even cirrhosis can occur.
Etiology
Abetalipoproteinemia is a result of mutations of two alleles of the MTTP gene (MTP; 4q24). Other severe early familial hypobetalipoproteinemias are inherited in a codominant manner and are a result of mutations of two alleles of the APOB gene (2p24-p23).
Diagnostic methods
Diagnosis is based on lipid analysis, after 12 hours of fasting, carried out on the patient and their parents to measure serum levels of LDL (<0.10g/L), triglycerides (<0.20 g/L), and apolipoprotein B (<0.10g/L). Identification of steatorrhea and truncated apolipoprotein B after oral lipid intake, measurement of liposoluble vitamins (A, E, K), testing for acanthocytosis (on blood smears), complete neurological examination, hepatic ultrasound and eye examination can also be carried out. Identification of mutations of the MTTP or APOB genes confirms the diagnosis.
Differential diagnosis
Differential diagnoses include metabolic diseases with hepatic overload, with steatosis and/or hepatomegaly, atypical diseases of the central and peripheral nervous system, and secondary causes of hypocholesterolemia (iatrogenic or systemic).
Antenatal diagnosis
Prenatal diagnosis is possible when the causal mutations in both parents are known.
Genetic counseling
Abetalipoproteinemia is inherited in a recessive manner.
Management and treatment
Management should be undertaken in specialized centers.
Prognosis
The prognosis is severe, with a significantly reduced life expectancy.

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                            Dr Pascale BENLIAN


An extremely rare multiple congenital malformation syndrome characterized by the association of ablepharon, macrostomia, abnormal external ears, syndactyly of the hands and feet, skin findings (such as dry and coarse skin or redundant folds of skin), absent or sparse hair, genital malformations and developmental delay (in 2/3 of cases). Other reported manifestations include malar hypoplasia, absent or hypoplastic nipples, umbilical abnormalities and growth retardation. It is a mainly sporadic disorder, although a few familial cases having been reported, and it displays significant clinical overlap with Fraser syndrome.


A rare, congenital, non-syndromic heart malformation characterized by more or less than one coronary ostium at the left and at the right aortic sinus of Valsalva. It may be asymptomatic or it leads to myocardial ischemia and technical difficulties during coronary angiography.


Abnormal origin of right or left pulmonary artery from the aorta

A rare, congenital, heart malformation characterized by anomalous origin of one branch of the pulmonary arteries directly from the aorta and a normal origin of the other pulmonary artery from the main pulmonary artery coming from the right ventricular outflow tract. Patients present respiratory distress, congestive heart failure and failure to thrive within the first days/months of life.

Summary:
Epidemiology
The incidence is estimated at 0.1% of all congenital cardiac anomalies.
Clinical description
Abnormal origin of right or left pulmonary artery from aorta usually occurs in infants or in the newborns where it manifests by respiratory distress, recurrent respiratory infection, moderate to severe pulmonary hypertension, congestive heart failure, and failure to thrive within the first months of life. Infants are usually cyanotic and may present chest pain and dyspnea on exertion. Two forms may be distinguished: anomalous origin of the left pulmonary artery from the aorta (AOLPA; about 25% of cases) and anomalous origin of the right pulmonary artery from the aorta (AORPA; about 75% of cases). Abnormal origin of right or left pulmonary artery from aorta frequently occurs as an isolated form with or without patent arterial duct. However, AOLPA may be associated with Tetralogy of Fallot, Right aortic arch, aortopulmonary window and anomalous subclavian arteries. On the contrary, patent ductus arteriosus and aortic coarctation or interruption (type A) may be associated with AORPA. Atrial and ventricular septal defects may be also present.
Etiology
The pathogenesis still remains unknown, although an association has been reported with 22q11.2 deletion syndrome in children with AOLPA, usually associated with Right aortic arch, Tetralogy of Fallot and Absent pulmonary valve. Indeed, deletions 22q11.2 may impair the second heart field causing anomalies of development of the pharyngeal pouch derivate, aortic arches and conotruncal part of the heart.
Diagnostic methods
Initial diagnosis is made with 2D-echocardiography which allows the definition of morphology and the detection of systemic or supra-systemic pressures in the right ventricle. Diagnosis is confirmed by catheterization, angiocardiography, MRI and CT angiography.
Differential diagnosis
Occasionally, one pulmonary artery (more frequently the left one) can origin via a patent ductus arteriosus coming from the aorta, however this morphological anomaly should be differentiated from Abnormal origin of right or left pulmonary artery from aorta.
Genetic counseling
Abnormal origin of right or left pulmonary artery from aorta is usually non-syndromic and sporadic. However, association with the 22q11.2 deletion syndrome is described in patients with AOLPA. Familial recurrence has also been reported.
Management and treatment
Early diagnosis and surgical treatment are mandatory in order to prevent cardiac failure and pulmonary hypertension. Treatment involves different techniques to implant the anomalous pulmonary artery branch to the main pulmonary artery. This includes direct implantation, end-to-end anastomosis with a synthetic graft, homograft patch, and an "aortic-ring" flap. In cases with AOLPA, the direct implantation technique is the strategy of choice, while for AORPA, different technique employing autologous tissues for increasing the length of the pulmonary artery branch may be used. Postoperative restenosis across the anastomotic site is frequently observed. Postoperative echocardiographic study is thus recommended to detect presence of stenosis.
Prognosis
Patients treated early in life have good short and long-term outcome. If left untreated, the disease may lead to congestive cardiac failure and pulmonary hypertension, with 30% of infants dying within 3 months. Palliative treatment such as pulmonary artery banding, ligation of the associated ductus arteriosus and aortopulmonary shunt, increases mortality substantially.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr Bruno MARINO


A rare, neurodegenerative disease characterized by progressive cognitive impairment, spastic tetraparesis, and cerebellar ataxia resulting from amyloid deposits in the brain. Spasticity with increased deep tendon reflexes and tone are early symptoms, muscular rigidity evolves later. Progressive mental deterioration usually starts with apathy and impaired memory with progression to complete disorientation.


An orofacial clefting syndrome that is characterized by a cleft palate, ocular coloboma, hypospadias, mixed conductive-sensorineural hearing loss, short stature, and radio-ulnar synostosis.

Summary:
Epidemiology
To date, 4 cases from a single family have been described in the literature.
Clinical description
Abruzzo-Erickson syndrome is a congenital disorder characterized by a cleft palate, ocular coloboma, hypospadias, mixed conductive-sensorineural hearing loss, short stature, and radio-ulnar synostosis. Additional features include ear malformation, a wide gap between the second and third metacarpals, ulnar deviation, facial asymmetry, dental abnormalities and congenital heart malformation (such as interauricular communication). These manifestations overlap with those of CHARGE syndrome, however, in contrast to CHARGE syndrome; patients with Abruzzo-Erickson syndrome do not show intellectual disability nor choanal atresia or genital hypoplasia.
Etiology
The complete etiology of Abruzzo-Erickson syndrome is still unknown but the recent identification of a novel mutation in the gene TBX22 (Xq21.1) (a gene known to cause X-linked cleft palate and ankyloglossia (CPX) co-segregating in the family strongly indicates that it is a mutation partially responsible for the phenotypic variation.
Diagnostic methods
Diagnosis is based upon clinical observations. Genetic and molecular testing allow to complete the diagnosis.
Differential diagnosis
Differential diagnosis include CHARGE syndrome.
Antenatal diagnosis
Antenatal diagnosis is theoretically possible by DNA analysis of fetal cells in maternal blood.
Genetic counseling
Abruzzo-Erickson syndrome is inherited in an X-linked recessive manner, with a carrier female having a 50 % risk of transmitting the mutation to her offspring.
Management and treatment
Correction of some abnormalities require extensive multidisciplinary craniofacial surgery.
Prognosis
Life expectancy seems normal based on long-term observations of three affected individuals in the family.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Dr Michael ABRUZZO  - Dr Robert ERICKSON


Absence deformity of leg-cataract syndrome

A very rare congenital limb malformation syndrome characterized by absence deformity of one leg, progressive scoliosis, short stature, and congenital cataract associated with dysplasia of the optic nerve. No intellectual deficit has been reported. There have been no further descriptions in the literature since 1968.


Absence of fingerprints-congenital milia syndrome

A rare syndrome characterized by neonatal blisters and milia (small white papules, especially on the face) and congenital absence of dermatoglyphics on the hands and feet. It has been reported in two kindreds (one of which contained 13 affected individuals spanning three generations) and in an unrelated individual. Some affected patients also showed bilateral partial flexion contractures of the fingers and toes, and webbing of the toes. The syndrome is inherited as an autosomal dominant trait.


A rare congenital anomaly of the great veins characterized by absence of the left brachiocephalic vein (or innominate vein), resulting in an anomalous venous vasculature. Patients are usually asymptomatic and the anomaly is typically discovered intraoperatively. An association with persistence of left superior vena cava, permanent levoatrial cardinal vein or anomaly of the inferior vena cava has been reported in some cases.


A rare vascular anomaly characterized by congenital absence of the right or left pulmonary artery, usually ending within 2 cm of its expected origin from the pulmonary trunk. Patients often also have other cardiovascular abnormalities and respective symptoms and are then typically diagnosed in infancy or childhood, while isolated cases generally present with a mild clinical course and may go undiagnosed until adulthood. Presenting clinical features in isolated cases include hemoptysis, exertional dyspnea, and recurrent respiratory infections. The condition is typically accompanied by marked changes of lung tissue and may, if unrecognized, result in massive hemoptysis and pulmonary hypertension.


A rare, non-syndromic, uterovaginal malformation characterized by underdevelopment of the uterus, ranging from complete absence to the presence of bilateral rudimentary horns with or without a cavity. Patients usually present with primary amenorrhea, abdominal/pelvic pain and/or infertility.


Absent radius-anogenital anomalies syndrome

A rare, genetic limb reduction defects syndrome characterized by bilateral radial aplasia/hypoplasia manifesting with absent/short forearms in association with anogenital abnormalities (e.g. hypospadias or imperforate anus). Additional features reported include hydrocephalus and absent preaxial digits. There have been no further descriptions in the literature since 1993.


Absent thumb-short stature-immunodeficiency syndrome

An exceedingly rare, autosomal recessive immune disease characterized by thumb aplasia, short stature with skeletal abnormalities, and combined immunodeficiency described in three sibships from two possibly related families. The skeletal abnormalities included unfused olecranon and the immunodeficiency manifested with severe chickenpox and chronic candidiasis. No new cases have been reported since 1978.


Absent tibia-polydactyly-arachnoid cyst syndrome

Tibia absent - polydactyly - arachnoid cyst syndrome is a very rare constellation of multiple anomalies, including absence or hypoplasia of the tibia.

Summary:
Epidemiology
It has been described in 3 sibs (two males and one female).
Clinical description
The syndrome is characterized by absence or hypoplasia of the tibia, pre and postaxial polydactyly of the hands and/or feet, syndactyly of the toes, shortening and bowing of other long bones, and retrocerebellar arachnoid cyst.
Genetic counseling
Parental consanguinity reported in the family suggests an autosomal recessive pattern of inheritance.

                            Last update:
                            December 2010


A rare congenital malformation characterized by the absence of calvarial bones, dura mater and associated muscles while skull base, facial bones and brain structures are normal. Central nervous system is usually unaffected, however some neuropathological abnormalities such as holoprosencephaly, hydrocephalus, micropolygyria and gyration anomalies can be present. Prenatal diagnosis by ultrasonography is usually confirmed by magnetic resonance imaging as it can be confused with anencephaly or encephalocele.


Acanthosis nigricans-insulin resistance-muscle cramps-acral enlargement syndrome

This syndrome is characterised by the association of acanthosis nigricans, insulin resistance, severe muscle cramps and acral hypertrophy.

Summary:
Epidemiology
At least five cases have been described in the literature so far.
Clinical description
Enlargement of the kidneys was also reported in some cases.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            April 2008


A rare inborn error of metabolism characterized by a deficiency in erythrocyte catalase, an enzyme responsible for the breakdown of hydrogen peroxide. The disorder is usually asymptomatic but may be associated with oral ulcerations and gangrene, or diabetes mellitus and atherosclerosis in certain populations.


A rare congenital non-syndromic heart malformation characterized by an accessory mitral valve leaflet or various accessory mitral valve structures. It may be asymptomatic or present at various ages with symptoms of left ventricular outflow tract obstruction, low cardiac output due to subaortic obstruction or congestive heart failure. In some cases, it may be a source of cardioembolism. The malformation may be isolated or associated with other congenital heart malformations.


A rare asymptomatic embryopathy characterized by the presence of pancreatic tissue in other sites of the body such as the splenic pedicle, gonadic pedicles, intestinal mesentery, duodenum wall, upper jejunum, or, more rarely, the gastric wall, ileum, gallbladder or spleen.

Summary:
Epidemiology
Prevalence is unknown and only a few cases have been reported in the literature so far.
Etiology
The anomaly is caused by migration of pancreatic cells during embryogenesis.

                            Last update:
                            April 2009

                            - Expert reviewer(s):
                            Pr Frédéric BARGY


A rare, congenital, atrioventricular valve malformation characterized by fixed or mobile accessory tissue on the tricuspid valve, usually associated with other complex congenital heart anomalies (atrial septal defect, ventricular septal defect, transposition of great arteries, tetralogy Fallot). It may present clinically with systolic murmur, dyspnea, cyanosis, depending also on accompanying congenital heart anomaly.


A rare adult-onset disorder of neurodegeneration with brain iron accumulation (NBIA) characterized by anemia, retinal degeneration, diabetes and various neurological symptoms.

Summary:
Epidemiology
To date 56 cases have been reported and prevalence has been estimated at about 1/1,000,000-1/1,200,000.
Clinical description
Aceruloplasminemia presents in adulthood with neurological symptoms including ataxia, involuntary movements (blepharospasm, grimacing, facial and neck dystonia, tremors, and chorea), parkinsonism, depression, and cognitive dysfunction accompanied by retinal degeneration, diabetes mellitus, and iron-refractory anemia.
Etiology
Aceruloplasminemia is caused by a complete absence of ceruloplasmin ferroxidase activity caused by homozygous mutation of the ceruloplasmin (CP) gene (3q23-q24).
Diagnostic methods
Diagnosis is based on the absence of serum ceruloplasmin and some combination of low serum copper concentration, low serum iron concentration, high serum ferritin concentration as well as hepatic iron overload. The diagnosis is strongly supported by characteristic MRI findings of abnormal low intensities reflecting iron accumulation on the brain (striatum, thalamus, dentate nucleus) and liver on both T1- and T2- weighted images. Genetic testing can confirm the diagnosis.
Differential diagnosis
Differential diagnoses include other forms of later-onset, slowly progressing NBIA including atypical pantothenate kinase-associated neurodegeneration (PKAN) and neuroferritinopathy, hereditary hemochromatosis, Wilson disease, Huntington disease, dentatorubral pallidoluysian atrophy (DRPLA), juvenile Parkinson disease, hereditary spinocerebellar ataxias (see these terms) and drug effects or toxicity.
Antenatal diagnosis
Prenatal testing for pregnancies at increased risk may be available through laboratories offering custom prenatal testing if the disease-causing mutations have been identified in an affected family member.
Genetic counseling
Aceruloplasminemia is inherited in an autosomal recessive manner.
Management and treatment
Treatment is based on intravenous and oral iron chelators (deferiprone or deferasirox), which have been associated with improvement in diabetes and neurological symptoms. Combined IV desferrioxamine and fresh-frozen human plasma (FFP) is effective in decreasing iron content in the liver. Antioxidants such as vitamin E and oral administration of zinc may prevent tissue damage.
Prognosis
Prognosis may include heart failure due to cardiac iron overload. To date five patients with aceruloplasminemia are known to have died from heart failure probably due to cardiac iron overload in their sixties. In the absence of heart failure and with good treatment of diabetes, the prognosis is good.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Hiroaki MIYAJIMA


A form of potassium-aggravated myotonia (PAM) which shows dramatic improvement with the use of acetazolamide (ACZ).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Symptoms generally manifest during childhood (before 10 years old), with myotonia of the facial, limbs and/or intercostal muscles that is triggered by potassium ingestion, fasting and mildly by cold exposure and exercise. Muscle stiffness is generally painful. Additional clinical signs include generalized muscle hypertrophy, percussion myotonia of proximal upper extremity muscles, thenar eminence and tongue and myotonia in the eyelids. Paralysis or weakness is never observed.
Etiology
ACZ-responsive myotonia is a sodium muscle channelopathy due to missense mutations of the SCN4A gene, encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4.
Genetic counseling
Transmission is autosomal dominant.
Management and treatment
Myotonia is dramatically improved with ACZ but when ACZ does not control myotonia or when side-effects occur such as kidney stone formation, mexiletine can be used as replacement therapy.

                            Last update:
                            October 2010

                            - Expert reviewer(s):
                            Dr Savine VICART


An extremely rare genetic syndrome characterized by the association of microcephaly, intellectual deficit and achalasia (with symptoms of coughing, dysphagia, vomiting, failure to thrive and aspiration appearing in infancy/early-childhood). Antenatal exposure to Mefloquine was reported in one simplex case.


A rare, lethal type of achondrogenesis characterized by dwarfism with extremely short limbs, narrow chest, short ribs that are easily fractured, soft skull bones and distinctive histological features of the cartilage.


A rare, lethal type of achondrogenesis characterized by severe micromelia with very short fingers and toes, a flat face, a short neck, thickened soft tissue around the neck, hypoplasia of the thorax, protuberant abdomen, a hydropic fetal appearance and distinctive histological features of the cartilage.


A rare, lethal type of achondrogenesis, and part of the spectrum of type 2 collagen-related bone disorders, characterized by severe micromelia, short neck with large head, small thorax, protuberant abdomen, underdeveloped lungs, distinctive facial features such as a prominent forehead, a small chin, a cleft palate (in some) and distinctive histological features of the cartilage.


A rare group of lethal skeletal dysplasias characterized by an endochondral ossification deficiency that leads to dwarfism with extreme micromelia, a small thorax, a prominent abdomen, anasarca and polyhydramnios. There are three types of achondrogenesis that exist and that differ clinically, radiologically, histologically and genetically: achondrogensis type 1a, type 1b and type 2.


A primary bone dysplasia with micromelia characterized by rhizomelia, exaggerated lumbar lordosis, brachydactyly, and macrocephaly with frontal bossing and midface hypoplasia.

Summary:
Epidemiology
Achondroplasia estimated incidence is at about 1/25,000 live births worldwide.
Clinical description
Characteristic clinical features (short limbs with rhizomelia, long and narrow trunk and macrocephaly with frontal bossing and midfacial hypoplasia with depressed nasal bridge) are often times visible at birth. Hands are broad, short and trident shaped. Hypotonia is common, leading to hypermobile joints particularly in the lower extremities. A smaller foreamen magnum or abnormal shape can lead to serious sequelae in infancy like spinal cord compression or vertebral artery compression leading to central apnea. Thoracolumbar kyphosis is very common in infancy, with 90% resolving over time. Midface hypoplasia in combination with adenoid and tonsil hypertrophy can lead to obstructive sleep apnea. Chronic otitis media can lead to conductive hearing loss. Achievement of gross motor skills is slower than typical due to short limbs, short neck, and large head, in addition to hypotonia. Dental crowding is common. Genu varum often occurs in childhood. Lower lumbar spinal stenosis with accompanying neurological deficits, has an increased frequency in adulthood, as does cardiovascular disease. Obesity is a common issue. Adults reach a height of 131±5.6 cm (men) and 124±5.9 cm (women). Affected women must deliver by caesarian section due to small pelvis size.
Etiology
Achondroplasia is due to a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, encoding a transmembrane receptor that is important in regulating linear bone growth, among other functions. Almost all mutations affect a specific glycine that is substituted to an arginine (G380R), leading to a gain of function mutation.
Diagnostic methods
There are no clinical diagnostic criteria for achondroplasia. Diagnosis is based on radiological and clinical findings. A skeletal survey will demonstrate generalized metaphyseal irregularities. Molecular genetic testing can confirm a diagnosis by the presence of a FGFR3 mutation in almost all individuals.
Differential diagnosis
Differential diagnoses include hypochondroplasia, thanatophoric dwarfism (types I and II), and SADDAN.
Antenatal diagnosis
Prenatal diagnosis can occur incidentally during routine prenatal ultrasound examination in the 3rd trimester when shortened long bones are noted. In these cases or when a parent is known to have achondroplasia, fetal DNA can be tested for the FGFR3 mutation to confirm diagnosis. Pre-implantation genetic diagnosis is possible in specialized laboratories.
Genetic counseling
Inheritance is autosomal dominant so genetic counseling is warranted. In 80% of cases, it is due to a de novo mutation in children with parents of average stature. If one parent has achondroplasia there is a 50% risk at each pregnancy of passing it on to offspring. If both parents have achondroplasia, there is another 25% risk that the offspring will have homozygous achondroplasia which is incompatible with life.
Management and treatment
Management is multidisciplinary and anticipatory care is essential. Neonates should have imaging of the brain and cervical spine to access the foreamen magnum and check for hydrocephalus as well as polysomnography to check for central sleep apnea. Abnormalities in either study should warrant a prompt referral to neurosurgical colleagues for evaluation and possible surgical treatment. Regardless of imaging, activities which lead to a risk of injury to the craniocervical junction should be avoided. Treatment of ear infections and serous otitis media, along with assessment of any hearing problems is needed. Speech therapy can be offered if concerns arise. Treatment of obstructed sleep apnea may include adenotonsillectomy, weight loss, and/or continuous positive airway pressure. Weight gain should be monitored in childhood to avoid later complications. Social and psychological support should be offered. Progressive and symptomatic leg bowing can be treated surgically. Adult patients may require a lumbar laminectomy to treat spinal stenosis. Some may choose controversial limb lengthening procedures.
Prognosis
There is only a slight decrease in life expectancy compared to the general population, potentially due to cardiovascular disease.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Elaine PEREIRA


A rare autosomal recessive retinal disorder characterized by color blindness, nystagmus, photophobia, and severely reduced visual acuity due to the absence or impairment of cone function.

Summary:
Epidemiology
The prevalence is estimated to be 1/30,000-1/50,000 worldwide.
Clinical description
ACHM is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, and reduced or complete loss of color discrimination. Most individuals have complete ACHM, with total lack of function in all three types of cones. Rarely, individuals have incomplete ACHM, with similar, but generally less severe symptoms.
Etiology
Five genes (GNAT2 (1p13), PDE6C (10q24), PDE6H (12p13), CNGA3 (2q11.2), and CNGB3 (8q21.3)) have been associated with ACHM, all encoding key components of the cone phototransduction cascade (G-protein GNAT2 > phosphodiesterase PDE6C/PDE6H > cyclic nucleotide gated channel CNGA3/CNGB3). Mutations in CNGB3 are the most prevalent, followed by CNGA3, while the others are rare causes of ACHM.
Diagnostic methods
The diagnosis of ACHM is based on clinical ophthalmological examination, psychophysical testing (i.e. color vision) and electrophysiological testing (electroretinography - ERG) where a loss of photopic but normal scotopic responses is observed. Optical coherence tomography shows progressive disruption and/or loss of the inner/outer segment junction of the photoreceptors and an attenuation of the retinal pigment epithelium (RPE) within the macular region. The diagnosis is verified by molecular genetic analysis of the causative genes.
Differential diagnosis
Differential diagnosis includes blue cone monochromatism (BCM), Leber congenital amaurosis, other cone dystrophies (see these terms), and cerebral achromatopsia
Antenatal diagnosis
Prenatal diagnosis may be offered by specialized laboratories to at-risk couples.
Genetic counseling
ACHM is transmitted in an autosomal recessive manner. Carrier testing for family members at risk of mutations is possible once the disease-causing mutations have been identified in the family. Furthermore, genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.
Management and treatment
There is no specific therapy available. Management is symptomatic and includes regular ophthalmological follow-up examination. Patients should be informed about the possibility of using filtering glasses or contact lenses (red tinted or brown) to reduce photophobia and to improve contrast sensitivity. Low-vision aids include high-powered magnifiers for reading.
Prognosis
ACHM is usually a stationary disease, yet macular degeneration can occur.

                            Last update:
                            August 2013

                            - Expert reviewer(s):
                            Dr Susanne KOHL


A very rare, malignant, epithelial tumor of the pancreas characterized, macroscopically, by a usually large, well-circumscribed, fully or partially encapsulated, solid mass, often with hemorrhage, necrosis and cystic changes, in any portion of the pancreas and, histologically, by neoplastic cells with variable degrees of differentiation and morphology, ranging from acinar structures similar to normal pancreatic acini to large sheets of poorly differentiated neoplastic cells. Presenting symptoms are typically non-specific and include abdominal pain, weight loss, vomiting, nausea, and/or, less commonly, jaundice. Immunohistochemical evidence of acinar-specific products is observed. Association with Lynch syndrome, familial adenomatous polyposis, and pancreatic panniculitis has been reported.


A rare teratogenic disorder due to acitretin or etretinate exposure during the first trimester of pregnancy, carrying a risk of fetal malformations of approximately 20%, including central nervous system, craniofacial, ear, thymic, cardiac and limb anomalies.

Summary:
Epidemiology
To date, 3 infants/fetuses with anomalies indicative or possibly indicative for the embryopathy whose mothers were treated with acitretin during the first trimester of pregnancy have been reported in the literature. In addition, 23 infants/fetuses with anomalies indicative or possibly indicative for the embryopathy whose mothers were treated with etretinate during the first trimester or before pregnancy have been reported in the literature.
Clinical description
Acitretin/Etretinate embryopathy is characterized by multiple congenital anomalies involving the central nervous system (with neurodevelopmental delay), retinal or optic-nerve, craniofacial (microcephaly, facial dysmorphism displaying epicanthal folds, low nasal bridge, anteverted nostrils, high and cleft palate, micrognathia) and ear abnormalities (microtia/anotia, cup-shaped ears, bilateral sensorineural deafness). Thymic and cardiac defects (atrioventricular canal defect, conotruncal heart malformation, aortic-arch defect) are also observed. Severe anomalies of upper and lower limbs have also been described.
Etiology
Acitretin/etretinate embryopathy is due to acitretin or etretinate exposure during the first trimester of pregnancy. Acitretin is an aromatic retinoid analog of vitamin A used for the treatment of severe forms of psoriasis and disorders of keratinization. Acitretin/etretinate have a teratogenic potential since it affects cellular differentiation and proliferation.

                            Last update:
                            August 2014

                            - Expert reviewer(s):
                            Pr Christof SCHAEFER


Acquired aneurysmal subarachnoid hemorrhage

A rare, life threatening rare neurologic disease characterized by a sudden rupture of an intracranial aneurysm into the subarachnoid space. It usually presents with a sudden, severe, excruciating headache accompanied by nausea, vomiting and syncope. Other features may include focal neurological signs, third and sixth nerve palsies, seizures and cardiac failure. Early complications include rebleeding, hydrocephalus, and seizures.


A type of acquired angioedema (AAE) characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Like other forms of AAE it has a later onset than HAE (see this term) and occurs generally in adults over the age of 50 where there is no family history of the disease.
Etiology
The disease occurs due to an acquired C1-INH deficiency. It is often associated with lymphoproliferative or autoimmune diseases which produce immune factors that destroy C1-INH leading to low levels of C1-INH, C1q complement and C4 complement.
Management and treatment
The treatments used for HAE can be effective for AAE but the most effective strategy is the treatment of the associated disease.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr Laurence BOUILLET


Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Like other forms of AAE, it has a later onset than HAE (see this term) and occurs generally in adults over the age of 50 and there is no family history of the disease.
Etiology
The disease occurs due to an acquired C1-INH deficiency caused by malfunctioning B cells that secrete autoantibodies to the C1-INH molecule that neutralize C1-INH activity. AAE type 2 is often associated with dysglobulinemia of unknown origin.
Management and treatment
The treatments used for HAE can be effective for AAE but the most effective strategy is to decrease C1-INH antibody level with corticosteroids or rituximab.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr Laurence BOUILLET


Acquired angioedema with C1Inh deficiency

A rare non-histaminic angioedema characterized by potentially life-threatening episodes of edema of subcutaneous and/or mucosal tissues without urticaria, caused by excessive consumption of C1 esterase inhibitor (C1-INH) in the context of lymphoproliferative or autoimmune diseases. Patients typically present in the fourth decade of life or later and without a family history of angioedema. Clinical manifestation includes nonpitting edema of the skin predominantly involving the face, but also the limbs or genitals, as well as abdominal pain due to involvement of the gastrointestinal mucosa, and severe edema of the upper airway and oral mucosa. Laboratory examination shows low C1-INH activity and low C3, C4, and C1q levels. Autoantibodies to C1-INH are frequently detectable.


A rare disease characterized by the occurrence of transitory and recurrent subcutaneous and/or submucosal edemas resulting in swelling and/or abdominal pain due to an acquired C1 inhibitor (C1-INH) deficiency.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Onset most commonly occurs after 50 years of age. Patients present with white, circumscribed nonpruritic edemas that remain for a period of 48 to 72 hours and recur with variable frequency. The edemas may involve the digestive tract resulting in a clinical picture similar to that seen in intestinal occlusion syndrome, sometimes associated with ascites and hypovolemic shock. Laryngeal edema can be life-threatening with a risk of death of 25% in the absence of appropriate treatment. Dental procedures are a triggering factor for laryngeal edema. Edemas of the face are a risk factor for laryngeal involvement.
Etiology
The edemas are triggered by increased permeability of the blood vessels in response to elevated levels of bradykinin as a result of the C1-INH deficiency. Type 1 AAE (see this term) is frequently associated with lymphoproliferative syndromes and accelerated consumption of C1-INH, and with autoimmune diseases that may manifest several years after the initial episodes of angioedema. Type 2 AAE (see this term) is associated with the presence of autoantibodies to the C1-INH that neutralize C1-INH activity and are often associated with dysglobulinemia of unknown origin. AAE can also be induced by renin-angiotensin-aldosterone system blockers (RAAS-blocker-induced angioedema; see this term).
Diagnostic methods
Diagnosis relies on clinical findings, measurement of C4 concentrations and on quantitative and functional analysis of C1-INH. C1q levels are low in patients with AAE but are normal in patients with hereditary angioedema (see this term).
Differential diagnosis
The differential diagnosis should include intestinal occlusion syndrome, hereditary angioedema and histamine-induced angioedema (of allergenic or nonallergenic origin) generally associated with urticaria.
Management and treatment
Treatment of the associated disease should generally allow episodes to be controlled and lead to normalization of C1-INH levels. In the absence of an associated disease, the treatments used to manage the hereditary forms of angioedema may be of benefit.
Prognosis
The prognosis depends on the risk of developing hematological manifestations. Rituximab can be an alternative treatment in cases of AAE associated with C1-INH antibodies.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr Laurence BOUILLET


Acquired arginine vasopressin deficiency

A subtype of central diabetes insipidus (CDI) characterized by polyuria and polydipsia, due to an idiopathic or secondary decrease in vasopressin (AVP) production.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
It occurs equally in both sexes and in all age groups but most often has an onset around the ages of 10-20. Symptoms include polyuria, polydipsia, usually associated with weight loss, and nocturia.
Etiology
Acquired CDI is secondary to a condition damaging the central nervous system or it is idiopathic (unknown etiology). Causes that lead to damage of the hypothalamus-neurohypophyseal brain region include head trauma (resulting from an accident or surgery), congenital abnormalities (pituitary stalk interruption syndrome (PSIS, see this term), infections (meningitis, encephalitis), autoimmune disorders (primary hypophisitis, see this term) and inflammatory (sarcoidosis and Wegener's granulomatosis, see these terms) or neoplastic (germinoma, meningioma, Langerhans cell histiocytosis, craniopharyngioma (see these terms), Rathke cleft cysts and metastasis). Up to 50% of CDI cases are idiopathic and the cause is unknown but autoimmunity is suspected to be involved in a number of them.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Dr Stefano GHIRARDELLO


A group of human prion diseases characterized by progressive, invariably fatal neurodegeneration resulting from accidental transmission of prions. The group comprises iatrogenic Creutzfeldt-Jakob disease (CJD), which results from transmission of CJD prions in the course of medical procedures or treatments, and variant CJD (transmission via consumption of products from prion-diseased cows or via blood transfusion from an affected individual).


Acquired cystic disease-associated renal cell carcinoma

A rare subtype of renal cell carcinoma, ocurring in the context of end-stage kidney disease and acquired cystic kidney disease, characterized by a usually well circumscribed, solid, multifocal, bilateral tumor with inter- or intracellular microlumen formation (leading to cribiform architecture). Tumors are often diagnosed incidentally in early stages, although complications caused by renal cysts (dull flank or abdominal pain, fever) or renal parenchymal bleeding may mask the underlying neoplastic process. Most have an indolent behavior.


A rare lipodystrophic syndrome characterized by loss of adipose tissue, and is a syndrome of insulin resistance that leads to increased cardiovascular risk. Acquired generalized lipodystrophy is related to a selective loss of subcutaneous adipose tissue occurring exclusively at the extremities (face, legs, arms, palms and sometimes soles).

Summary:
Epidemiology
More than 100 cases have been described and the female to male ratio is 3:1.
Clinical description
The clinical phenotype is similar to that of Berardinelli-Seip syndrome (see this term), but lipoatrophy appears secondarily during childhood, adolescence or adulthood, and as a result the syndrome is thought to be acquired. In some cases, loss of adipose tissue is localized, especially if it is preceded by a panniculitis. The syndrome is associated with a voracious appetite and an acceleration of growth in adolescents. One third of cases are accompanied by acanthosis nigricans and a polycystic ovary syndrome (see these terms). Hepatomegaly with steatosis and a risk of cirrhogenous progression is common. Biologically, hyperinsulinemia and insulin-resistant diabetes are observed, often associated with severe hypertriglyceridemia with low plasma levels of leptin and adiponectin. Proteinuria associated with focal segmental glomerulosclerosis or with membranoproliferative glomerulonephritis have been reported recently, as well as dysregulation of growth hormone. Three types of the disease have been described: 1) a form with panniculitis (inflammatory nodules followed by lipoatrophy), 2) an autoimmune form that is readily associated with other syndromes such as chronic active hepatitis, Hashimoto struma and hemolytic anemia, but also with dermatomyositis and Sjogren's syndrome (see these terms), 3) idiopathic.
Etiology
The cause of the disease remains unknown. There may be infectious triggering factors (there was a recent case of the panniculitis type that appeared after tuberculosis) or an autoimmune mechanism. A recent publication showed activation of the classical complement pathway (low C4). This is in contrast to acquired partial lipodystrophy (see this term) which affects the upper half of the body and is characterized by an activation of the alternative complement pathway (low C3). Progression towards partial lipoatrophy, focal or generalized, has been reported in patients with dermatomyositis, amongst whom this could be a late relapse, and it is more common that the antibody anti-p155 is present. The hypothesis of an underlying genetic factor has not been rejected.
Diagnostic methods
Diagnosis is clinical and should be confirmed by an assessment of body fat, in particular by biphotonic absorptiometry and magnetic resonance imaging.
Differential diagnosis
Differential diagnoses include other forms of extreme insulin resistance (Rabson-Mendenhall syndrome, leprechaunism, Berardinelli type lipodystrophy and insulin resistance syndromes types A and B; see these terms) and other lipodystrophies.
Management and treatment
The treatment of the metabolic manifestations is a priori no different to the treatment of other forms of insulin resistance: physical exercise, insulin sensitizers such as metformin or pioglitazone, insulin (or preferably insulin analogues), antihypertensives, and monitoring and treatment of hypertriglyceridemia. The efficacy of recombinant human leptin has been demonstrated on the metabolic level but this therapy is not available in all countries. In serious autoimmune forms of the disease, immunosuppressive therapy may be indicated.
Prognosis
The prognosis is not well known but is probably related to cardiovascular risk (linked to the insulin-resistance syndrome) and to the underlying cause of the disease.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Pr Marie-Christine VANTYGHEM


Acquired hemophagocytic lymphohistiocytosis associated with malignant disease

A rare, secondary hemophagocytic lymphohistiocytosis characterized by occurring as either initial presentation of a malignant disease or at any stage during chemotherapy. The common associated malignancies are lukemias, B-cell, T-cell or NK-cell lymphomas, and Hodgkin lymphoma. Typical clinical manifestation includes fever, hepatosplenomegaly and cytopenias, combined with specific laboratory findings.


A rare cutaneous paraneoplastic disease characterized by the presence of excessive lanugo-type hair on the glabrous skin of face, neck, trunk and limbs that can be associated with additional clinical features such as burning glossitis, papillary hypertrophy of the tongue, diarrhea, dysgeusia, and/or weight loss. It is associated with lymphoma or cancer of the gastrointestinal system, urinary tract, lung, breast, uterus or ovary.


A rare epidermal disease characterized by rough, dry skin with prominent, plate-like scaling. It is non-hereditary and usually arises during adulthood in the context of a variety of diseases or conditions, like various types of cancer, autoimmune diseases, endocrine disorders, nutritional deficiencies, but also as a side effect of certain medications. Severity depends on the underlying disease or condition.


Acquired idiopathic sideroblastic anemia

A rare myelodysplastic syndrome (MDS) characterized by ineffective hemopoiesis affecting one or more blood cell lineages (myeloid, erythroid or megakaryocytic) leading to peripheral blood cytopenias and an increased risk of developing leukaemia.

Summary:
Epidemiology
In Europe, the incidence of new cases of RARS is estimated at around 1 per 100,000 people per year but precise values are not available. Incidence increases with age by a factor of around 10 in those aged 70 and over.
Clinical description
It occurs mainly in elderly people or people of late middle age at a rate that varies somewhat around the world.
Etiology
The cause is not known. It appears to be a clonal disorder arising from a haemopoetic stem cell abnormality but is not associated with any particular cytogenetic change except for a few reports of chromosomal rearrangements involving Xq13.
Diagnostic methods
Diagnosis requires examination of both blood and bone marrow, investigation into possible secondary acquired causes and careful attention to any family and clinical history that would suggest an inherited type of sideroblastic anaemia (see these terms).
Differential diagnosis
RARS can be separated from other categories of MDS by the presence in the bone marrow of more than 15% of ringed sideroblasts in the erythroid cells, an absence of dysplasia in the other cell lineages and a low percentage of myeloid blasts (<5%).
Management and treatment
Treatment is mainly supportive and directed towards alleviating the symptoms of anaemia and avoidance or treatment of iron overload that results from any blood transfusion. Regular full blood count monitoring is important.
Prognosis
The risk of transformation to leukaemia is low (between 5 to 10% at 10 years in those with a normal karyotype and no dependence on blood transfusion) compared with other groups of MDS (for example 50% at 8 months in the group with thehighest risk), and the prognosis is good. Life expectancy in those over 70 years of age with RARS may be no different to that of the general population. The development of bi-lineage or multi-lineage dysplasia, the emergence of cells which are karyotypically abnormal, or an increased dependency on blood transfusions herald a worse prognosis and may indicate more vigorous intervention.

                            Last update:
                            May 2008

                            - Expert reviewer(s):
                            Dr Ala AL-SABAH  - Dr Alison MAY


A rare hair disorder characterized by the appearance of lustreless, curly, frizzy, and coarse hair generally during adolescence predominantly in the frontal, temporal, and vertex regions of the scalp. Eyelashes, as well as growth and pigmentation of the hair, may also be affected.


A rare hematologic disease characterized by increased levels of methemoglobin in the blood due to exposure to oxidizing agents like nitrates or nitrites, a variety of medications (most commonly local anesthetics), or aniline dyes, among others. Clinical manifestations include cyanosis, dizziness, headache, dyspnea, confusion, and coma. The severity of symptoms ranges from mild to life-threatening, depending on the percentage of methemoglobin.


Acquired monoclonal Ig light chain-associated Fanconi syndrome

A rare monoclonalgammopathy characterized by renal proximal tubule dysfunction secondary to monoclonal kappa light chain deposits in proximal tubular cells. Clinical presentation is with variable chronic kidney disease, low molecular weight proteinuria, aminoaciduria, hyperphosphaturia, uricosuria, bicarbonaturia, and non-diabetic glycosuria. Renal phosphate and urate wasting may cause hypophosphatemia and hypouricaemia.

Summary:
Epidemiology
To date, less than 100 cases have been reported in the medical literature.
Clinical description
Presentation is often in patients over 50 years of age with a degree of chronic kidney disease (CKD). There will be low molecular weight proteinuria, generalised aminoaciduria, uricosuria, phosphaturia, bicarbonaturia (which may cause a mild metabolic acidosis) and normoglycemic glycosuria. Low molecular weight proteinuria is the most sensitive test, and non-diabetic glycosuria is the most specific. There may be hypophosphatemia and hypouricemia and/or a mild metabolic acidosis. Urinary phosphate wasting may be severe enough to cause bone demineralization and rickets in children or osteomalacia in adults. Bone pain or pathological fractures are a possible presentation of this condition. The disease often occurs in the setting of monoclonal gammopathy of undetermined significance and less commonly in multiple myeloma or Waldenstrom macroglobulinemia.
Etiology
Typically, the monoclonal light chains are of the variable kappa-1 (VK1) subgroup which resist proteolysis in the proximal tubular cells, and results in self-aggregation and crystal formation in the endolysosomal compartment.
Diagnostic methods
Diagnosis is made by demonstrating the renal Fanconi syndrome with the presence of low molecular weight proteinuria (and phosphaturia or glycosuria, if present) along with a monoclonal gammopathy. The diagnosis may be confirmed by a kidney biopsy (which may be indicated when establishing the diagnosis of myeloma). Findings on light microscopy include atrophy, dedifferentiation and intracytoplasmic inclusions in the proximal tubule epithelium. Proximal tubule cells are typically positive for kappa LCs (and less frequently lambda LCs) on immunofluorescence. Ultrastructural studies reveal crystals (rhomboid), located in proximal tubular cells lysosomes or free in the cytoplasm. Additional investigations required include bone marrow aspiration or biopsy to identify the clone, and evaluation of serum and urine immunoglobulin free light chains.
Differential diagnosis
Differential diagnosis should include other types of monoclonal gammopathy of renal significance (AL amyloidosis, monoclonal immunoglobulin deposition disease, and myeloma cast nephropathy), in addition to other causes of FS (including autoimmune disorders, drugs, or heavy metal poisoning).
Management and treatment
If there is severe urinary phosphate wasting, or osteomalacia (low bone mineral density) then phosphate supplements should be given. Bone demineralization starts before the serum phosphate falls. All patients with an associated overt lymphoid disorder should receive appropriate chemotherapy. Otherwise, treatment should be adapted to the degree of renal failure. CKD 1-3 stages: chemotherapy should be considered to slow progression to ESRD. Cyclophosphamide, bortezomib or thalidomide-based treatment are the best options. High dose melphalan (HDM) supported by autologous peripheral blood cell transplantation (ASCT) may be performed in selected nonresponding patients, although the benefit of this strategy remains to be proven. CKD 4-5 stages: patients who are eligible for renal allograft, chemotherapy (including HDM/ASCT) should be considered prior to transplantation. In patients not eligible for renal transplantation, introduction of chemotherapy has no benefit.
Prognosis
Progression of CKD is slow.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Stephen WALSH | ERKNet*

                                * European Reference Network


A rare acquired lipodystrophy characterized by bilateral, symmetrical lipoatrophy of the upper body (face, neck, arms, thorax and sometimes upper abdomen) with sparing of the lower extremities and cephalothoracic progression. The disease may be associated with low serum levels of C3 and presence of C3-nephritic factor.

Summary:
Epidemiology
The prevalence in Europe is less than 1/100 000. There is a female predominance with a female-to-male ratio of 4:1.
Clinical description
Onset typically occurs during childhood or adolescence but may occur as late as the fourth or fifth decade of life. Lipoatrophy is slowly progressive, starts on the face and then extends downwards to the neck, shoulders, upper limbs and/or thorax. The hips, thighs, distal legs and gluteal regions are initially normal, however, lipohypertrophy may present post-puberty, especially in females. Mesangiocapillary glomerulonephritis is reported in one third of patients and is associated with low complement-component 3 (C3) serum levels and the presence of C3-nephritic factor. Whilst there is an increased risk of insulin resistance and metabolic complications (including menstrual irregularities, hirsutism, diabetes mellitus, dyslipidemia, hypertension and hepatic steatosis), these are less frequently observed compared to other types of lipodystrophies. Occasionally, functional anomalies including sensorineural deafness, epilepsy, intellectual deficit, myopathy and retinal changes may be associated.
Etiology
Whilst the etiology is unknown, susceptibility has been linked to heterozygous mutations in the LMNB2 (19p12.3) gene, encoding the lamin B2 nuclear envelope protein. Nevertheless, this mutation is very inconstant. Moreover, the frequently early occurrence of the disease suggests yet unknown genetic causes, perhaps involved in the innate immunity.
Diagnostic methods
Diagnosis is essentially based on the characteristic subcutaneous fat loss pattern. Physical examination (including skin fold thickness measurements) and MRI studies are important to assess fat loss distribution. Measurement of serum complements and autoantibodies (low C3 and presence of C3-nephritic factor), absence of family history of lipodystrophy, an onset during childhood/adolescence, and biopsy may support diagnosis. Clinical judgement should be used for screening for co-morbidities.
Differential diagnosis
Differential diagnosis includes anorexia nervosa, cachexia, starvation, diencephalic syndrome, multiple symmetric lipomatosis and other rare progeroid syndromes and disorders affecting growth and development. In addition, other forms of acquired lipodystrophy observed may be associated with a broad spectrum of autoimmune diseases, including systemic lupus erythematosus, juvenile dermatomyositis, celiac disease, or pernicious anemia and vasculitis.
Management and treatment
Surgical management of the lipodystrophy is feasible, and is mainly aimed at aesthetic improvement. Treatment of the metabolic manifestations, if present, should follow the same guidelines as those used for other forms of insulin resistance: physical exercise, insulin-sensitizing medication (metformin or, if available, glitazones), agonists of GLP1 receptor, and finally insulin (or preferably insulin analogues)) and management of the hypertension and hypertriglyceridemia. Nephrological follow-up should also be recommended. Metreleptin, indication authorized in Europe, may be considered for hypoleptinemic patients with severe metabolic derangements, where other treatments have failed to achieve adequate metabolic control.
Prognosis
The prognosis is largely unknown but greatly depends on the extent of the nephropathy, which may progress to renal insufficiency.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Marie-Christine VANTYGHEM


A rare hemorrhagic disorder characterized by decreased factor II plasma levels in association with severe liver disease, vitamin K deficiency, or vitamin K antagonist treatment, or in the context of other conditions such as systemic lupus erythematosus, primary antiphospholipid syndrome, or infections. Patients present with increased bleeding tendency leading to easy bruising, frequent nosebleeds, hemorrhaging after surgery or trauma, and heavy menstrual bleeding, among others. Joint bleeding is uncommon.


A rare acquired dermis elastic tissue disorder characterized by clinical and histopathologic evidence of pseudoxanthoma elasticum in the absence of a family history or specific mutation. Patients present with predominantly cutaneous manifestations consisting of yellowish papules which coalesce into large plaques and are most commonly localized on the neck, axillae, groin, and flexural surfaces. Skin biopsy shows accumulation of clumped, calcified elastic fibers in the mid-dermis. Reported underlying factors include previous liver transplantation, exposure to penicillamine, or concomitant beta-thalassemia.


A life-threatening, rapidly progressive thrombotic disorder affecting mainly neonates and children that is characterized by purpuric skin lesions and disseminated intravascular coagulation. It may progress rapidly to multi-organ failure caused by thrombotic occlusion of small and medium-sized blood vessels. There are two forms of the disorder that are classified according to triggering mechanisms: acute infectious (the most common form), and idiopathic purpura fulminans.


A rare bleeding disorder marked by the same biological anomalies as those seen in hereditary von Willebrand disease (VWD) but which occurs in association with another underlying pathology, generally in elderly patients without any personal or family history of bleeding anomalies.

Summary:
Epidemiology
Prevalence is unknown, but Acquired von Willebrand syndrome (AVWS) is a rare disease that is underdiagnosed, with just over 300 cases reported in the literature so far.
Clinical description
The bleeding manifestations are similar to those occurring in hereditary VWD (prolonged bleeding after trauma, epistaxis, ecchymoses and gastrointestinal bleeding associated with angiodysplasia).
Etiology
Three principle pathogenic mechanisms have been described: 1) the presence of autoantibodies (inhibiting or noninhibiting) that form immune complexes with the von Willebrand factor (VWF) leading to rapid clearance of VWF from the circulation (the mechanism most commonly implicated in AVWS associated with monoclonal gammapathies and autoimmune diseases); 2) absorption of VWF onto malignant cell clones (the mechanism implicated in AVWS associated with neoplasia); 3) increased proteolysis of high molecular weight VWF multimers under abnormal hemorheologic conditions caused by cardiovascular malformations (such as aortic valve stenosis).
Diagnostic methods
The most accurate diagnostic tests rely on detection of abnormally low levels of VWF activity (ristocetin cofactor or collagen binding assays) in comparison to VWF antigen levels, and on demonstration of a selective deficiency of high molecular weight VWF multimers. Measurement of VWF propeptide levels may also be useful as they reflect the abnormally rapid clearance of VWF from the circulation. However, none of these tests allow AVWS to be distinguished from hereditary VWD. Detection of anti-VWF antibodies is pathognomonic of the acquired mechanism of VWF deficiency; however, these antibodies are only detected in 14% of suspected cases of AVWS. The finding of a monoclonal protein detected by serum protein electrophoresis is an argument for AVWS. Thus, it is the presentation of an acute bleeding disorder, in association with an underlying pathology (such as lympho- or myeloproliferative disorders, solid tumors, immunological or cardiovascular disorders) which generally leads to the diagnosis of acquired VWF deficiency.
Management and treatment
Management relies on identification and then treatment of the underlying pathology usually involving corticosteroids or immunosuppressors, chemotherapy, plasmapheresis or valve replacement. In cases when these treatments are not rapidly efficient, symptomatic treatment aiming to correct the VWF deficiency is used to prevent or to cure abnormal bleeding. The choice of treatment depends on the suspected physiopathology and clinical status: intravenous immunoglobulins (in case of IgG monoclonal gammopathy of undetermined significance), desmopressin or VWF concentrates (although pharmacokinetic studies may be required before any major surgical intervention as the half-life of endogenous or exogenous VWF may be significantly reduced), recombinant factor VIII concentrates (completely depleted of VWF) or, as a last-resort treatment option, recombinant activated factor VII.
Prognosis
The prognosis depends on the underlying pathology associated with the disease.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND  - Pr Agnès VEYRADIER


A rare peeling skin syndrome characterized by superficial peeling of the skin predominantly affecting the dorsa of the hands and feet.

Summary:
Epidemiology
Acral PSS is rare, the prevalence is unknown. Few cases have been described in the literature.
Clinical description
The disease manifests shortly after birth or in early childhood with superficial painless peeling on the palmar, plantar and dorsal surfaces of the hands and feet, that leaves residual erythema. Superficial blisters may be seen. Palmoplantar skin may also be hyperkeratotic. Seasonal variations are generally observed. Heat, humidity, occlusion, exposure to water and friction or minor trauma can induce exfoliation. The lesions are usually not painful and heal without scarring but a burning sensation may be experienced before or after peeling.
Etiology
Some cases result from mutations in the TGM5 gene or CSTA gene, encoding, respectively, transglutaminase-5 (one of the three transglutaminase isoforms involved in the cross-linking of the cornified cell envelope) or cystatin A (a protease inhibitor crosslinked to the cornified envelope).
Diagnostic methods
Clinical presentation is highly suggestive of the disease. Histological examination of skin lesion biopsies reveals tissue separation at the stratum granulosum-stratum corneum junction. Molecular analysis, if performed, may reveal a mutation in TGM5 or CSTA.
Differential diagnosis
Differential diagnosis includes epidermolysis bullosa simplex, keratolytic winter erythema, exfoliative ichthyosis, keratolysis exfoliativa, fungal infection (dermatophytes), psoriasis and dyshidrosis.
Antenatal diagnosis
The disease is not severe enough to justify prenatal screening.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
There is no effective treatment. Emollients are often used to reduce skin peeling. Patients must avoid immersion in water and are recommended to use absorbing powders or aluminum antiperspirants.
Prognosis
Life expectancy is normal. No significant impairment in quality of life is reported.

                            Last update:
                            January 2023

                            - Expert reviewer(s):
                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER | ERN-Skin*

                                * European Reference Network


A rare chronic form of localized lichen myxedematosus characterized by the development of multiple symmetrical skin-colored mucinous papules exclusively on the extensor surface of the hands and distal forearms.


A variant of self-healing collodion baby (SHCB) characterized by the presence at birth of a collodion membrane only at the extremities.

Summary:
Epidemiology
Only 2 cases were described in the literature.
Clinical description
In both cases, the babies healed soon after birth.
Etiology
In one case, molecular analysis was performed that revealed mutations in the TGM1 gene encoding transglutaminase 1, an enzyme involved in the cornification of the stratum corneum.

                            Last update:
                            January 2012

                            - Expert reviewer(s):
                            Pr Juliette MAZEREEUW-HAUTIER


A rare multiple congenital anomalies syndrome characterized by limb deficiencies and renal anomalies that include split hand-split foot malformation, renal agenesis, polycystic kidneys, uterine anomalies and severe mandibular hypoplasia. An autosomal recessive mode of inheritance has been suggested.


A rare syndrome of multiple congenital anomalies characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesico-ureteral reflux, bladder diverticula), and ophthalmological abnormalities (mainly colobomas, but also microphthalmia, ptosis, and Duane anomaly). The phenotype overlaps with other SALL4-related disorders including Okihiro syndrome and Holt-Oram syndrome.


A rare polymalformative syndrome characterized by agenesis of corpus callosum (CC), distal anomalies of limbs, minor craniofacial anomalies and intellectual disability.

Summary:
Epidemiology
The prevalence is not known but fewer than 50 cases have been published since the first description in 1979.
Clinical description
In acrocallosal syndrome (ACS), craniofacial anomalies include macrocephaly with prominent forehead and occiput, hypertelorism, large anterior fontanel, short nose with broad nasal bridge and anteverted nostrils, and short mandible. Cases of anencephaly were observed as well as an extra bone within the anterior fontanel, a calvarian defect or a Dandy-Walker malformation. CC hypoplasia or agenesis is the main distinctive feature of ACS. It may be associated with arachnoidal cysts in about one third of cases and with various other brain abnormalities (medulla oblongata, temporal lobe or pons hypoplasia, micropolygyria and hypoplasia or agenesis of cerebellar vermis with a molar tooth sign). Distal anomalies of limbs include preaxial or postaxial polydactyly or polysyndactyly of toes and/or hands. The large majority of ACS patients have intellectual disability that is severe in 80% of cases, and substantial global developmental delay. Additional malformations have been described occasionally: short philtrum/upper lip, high-arched palate, cleft lip/palate, heart defects, hypospadias and inguinal and umbilical hernias.
Etiology
Mutations in kinesin KIF7 (15q26.1) and, rarely, in the transcriptional activator GLI3 (7p14.1) are responsible for ACS. Both genes are involved in the ciliary sonic hedgehog pathway and their mutations most likely influences the early development of midline structures during embryogenesis.
Diagnostic methods
Given the high variability of phenotypes, any two of the following criteria evokes the ACS diagnosis: (1) total or partial absence of the CC, (2) minor craniofacial anomalies, (3) moderate to severe global developmental delay with hypotonia and (4) polydactyly. Molecular genetic testing can be used to confirm the diagnosis and to guide genetic counseling.
Differential diagnosis
Differential diagnosis includes Greig cephalopolysyndactyly syndrome, syndrome orofaciodigital type I, Smith-Lemli-Opitz syndrome, Rubinstein-Taybi syndrome, Gorlin syndrome, Aicardi syndrome, as well as Meckel-Gruber syndrome and hydrolethalus in the extreme forms.
Antenatal diagnosis
Antenatal diagnosis is based on ultrasonography examination from the 20th week of gestation and magnetic resonance imaging (MRI) of the fetus.
Genetic counseling
ACS is an autosomal recessive disease. For parents of an affected individuals, there is therefore a 25% recurrence risk for a subsequent pregnancy. If the gene mutation in the kinesin/transcriptional activator genes has been identified in an affected sibling, molecular genetic diagnosis can be offered after chorionic villus sampling.
Management and treatment
Surgical intervention may be considered for the polydactyly. Management is otherwise supportive with periodical evaluation by a child neurologist/neuropsychiatrist in order to monitor the evolution of the intellectual development or onset of seizures, as well as enabling and supporting therapies (including non-verbal communication) and special education programs.
Prognosis
Prognosis depends on the severity of malformations and hypotonia, and on the occurrence of seizures.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Tania ATTIE-BITACH | ITHACA*

                                * European Reference Network


A rare skeletal dysplasi, characterized clinically by short stature of variable degrees with short limbs, brachydactyly and narrow thorax.

Summary:
Epidemiology
It has been described in 5 individuals in 2 families.
Clinical description
Affected patients have normal intelligence. Radiographically, cone-shaped epiphyses are observed in the hands, the proximal part of the femur, and, to a variable degree, at the shoulders, knees, and ankles.
Etiology
Homozygous mutations in the Indian hedgehog homolog gene (IHH; 2q33-q35), outside the region where brachydactyly type A-1 mutations are clustered, have been identified in affected patients.
Genetic counseling
The condition is transmitted as an autosomal recessive trait.

                            Last update:
                            February 2011


A rare genetic disorder characterized by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and intellectual deficit.

Summary:
Epidemiology
The incidence of ACFS has not been determined due to the low number of reported cases (9 to date). A similar occurrence among genders is expected.
Clinical description
The spectrum of defects occurring in ACFS is wide, and both interindividual variability and clinical differences among sibs have been reported. Bilateral or unilateral cleft hand is a constant feature. Cleft foot and cutaneous finger and toe syndactyly have been reported in some cases. Congenital heart defects of varying types have been detected in two thirds of patients. Facial anomalies are not specific for the syndrome, and clinical expression appears to be variable. Male patients manifest different genital anomalies, ranging from micropenis to cryptorchidism and hypospadias. Growth retardation is a common prenatal and postnatal finding. The frequency of intellectual deficit in ACFS is at present unknown due to the early death of most patients. Neurological anomalies such as hypotonia, hypertonia, and seizures have been reported in the first days and months of life.
Etiology
The genetic mechanism underlying ACFS is still unknown. Isolated or syndromic SHFM has been linked to different loci or genes. Mutations in the p63 gene, responsible for ectrodactyly - ectodermal dysplasia - cleft lip palate (EEC) syndrome (see this term) and related disorders with SHFM, have been excluded in a patient with ACFS.
Diagnostic methods
Diagnosis is based solely on clinical characteristics. The major diagnostic criteria include SHFM and CHD. Cleft lip/palate and genital anomalies are less common features. Although facial anomalies are not specific to this disorder, low-set dysmorphic ears appear to be a constant feature.
Differential diagnosis
Differential diagnosis includes other ectrodactyly syndromes and clefting conditions associated with genital anomalies. However, EEC syndrome, Rapp-Hodgkin syndrome (see these terms) and ectrodactyly-cleft lip/palate-hand/foot deformities-intellectual deficit can be ruled out based on lack of ectodermal involvement. Malpuech syndrome (see this term) can also be excluded based on distinct facial features and absent limb defects. CHD, cleft palate, and genital anomalies are features of genito-palato-cardiac syndrome, but none of the reported cases had ectrodactyly.
Antenatal diagnosis
The major features of ACFS can be detected prenatally by ultrasonography. A second trimester scan, including echocardiography and upper/lower limb evaluation, is recommended for monitoring pregnancies when parents have had a child with the disorder.
Genetic counseling
ACFS follows an autosomal recessive pattern of inheritance. The risk of transmitting the disease for the parents of an affected child seems to be up to 1 in 4.
Management and treatment
Patients are at high risk of death in the first months of age. Cardiac and respiratory problems should be treated by specialists. A nutrition specialist should be consulted for feeding problems. Surviving patients will benefit from physical therapy, which should start in the first months of life in babies manifesting hypotonia/hypertonia and motor delays. In surviving patients, neuropsychological assessment should be performed every year to check for developmental and cognitive delay.
Prognosis
Life expectancy is very low. Most reported patients survived only a few hours or months. Cardiopulmonary complications were the main cause of death.

                            Last update:
                            December 2010

                            - Expert reviewer(s):
                            Pr Bruno DALLAPICCOLA  - Dr Maria Cristina DIGILIO


An extremely rare lethal autosomal recessive disorder characterized by massive birth weight, swollen globular body, generalized edema, short limbs, postaxial polydactyly, thick skin, facial dysmorphism (slanted palpebral fissures, hypertelorism, epicanthic folds, dysplastic ears), excessive connective tissue, renal dysplasia, and in some patients, organomegaly, craniosynostosis with acrocephaly, omphalocele, cleft palate, and cryptorchidism. Fewer than 10 cases have been reported to date.