Very long chain acyl-CoA dehydrogenase deficiency

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid oxidation with a variable presentation including: cardiomyopathy, hypoketotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis.

Summary:
Epidemiology
Over 400 cases have been reported worldwide. Prevalence in Germany is of 1/50, 000.
Clinical description
VLCADD is a clinically heterogeneous disease, with 3 major phenotypes. Severe infantile VLCADD has an early onset, usually within the first 3-12 months of life and as early as the neonatal period, with high mortality and a high incidence of hypoketotic hypoglycaemia, liver disease, cardiac arrhythmias and cardiomyopathy. Pericardial effusion is also reported. Moderately severe infantile/childhood VLCADD has a later onset (early neonatal period to early childhood) and usually presents with hypoketotic hypoglycemia, lower mortality and rarely cardiomyopathy. Late-onset myopathic VLCADD presents in older children and young adults (usually >10 years of age) with isolated skeletal muscle involvement, exercise intolerance, myalgia, rhabdomyolysis and myoglobinuria usually triggered by exercise, fasting, cold/heat and/or stress but viral infection can also precipitate/exacerbate this presentation. In rare cases it can lead to renal failure and can be fatal. Some patients presenting with myopathic disease may have a previous history of hypoglycemia in infancy/childhood.
Etiology
VLCADD is caused by mutations in the ACADVL gene (17p13.1). Mutations of this gene lead to dysfunction of mitochondrial beta-oxidation of long-chain fatty acids.
Diagnostic methods
Abnormal plasma or blood acylcarnitine profile identifies virtually all patients with the severe/moderately severe phenotypes by demonstrating increased C14:1 and C14:1/C12:1 ratios together with elevations of C12, C16, C16:1, C18 and C18:1 species. Occasionally patients with mainly myopathic disease can give an essentially normal profile when metabolically stable. Crisis urine organic acid analysis generally shows a non-specific abnormal pattern of C6-C14 dicarboxylic and hydroxydicarboxylic acids. Newborn screening is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands, Portugal and Spain (milder ''late-onset'' patients may not be detected). VLCADD is confirmed by showing two pathogenic mutations in the ACADVL gene. Fatty acid oxidation flux assays in cultured fibroblasts or direct measurement of VLCAD activity in lymphocytes or fibroblasts can also clarify difficult diagnoses.
Differential diagnosis
Differential diagnosis includes other long chain fat oxidation defects. Myopathic carnitine palmitoyl transferase II deficiency (see this term) has a presentation identical to the myopathic presentation of VLCADD.
Antenatal diagnosis
Antenatal diagnosis is possible when mutation(s) have been identified within the family.
Genetic counseling
VLCADD is inherited autosomal recessively and genetic counseling is available.
Management and treatment
Dietary treatment along with strict avoidance of fasting is essential in infants/children and involves a low long-chain fat diet in combination with medium chain triglycerides. An emergency regimen should be available for each patient to use when they cannot tolerate their prescribed diet. Medical treatment should be sought immediately if there is evidence of decompensation. Those with a milder phenotype should limit exercise and cold/heat exposure and avoid fasting. Treatment with bezafibrate offers potential benefit in myopathic patients with residual enzyme activity, although this awaits full clinical evaluation.
Prognosis
VLCADD can be fatal but thanks to newborn screening programs, the outcome is improving for all phenotypes. Prognosis is much better for milder phenotypes provided that there is adherence to treatment protocols.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Simon OLPIN


Vestibular schwannoma is a rare tumor of the posterior fossa originating in the Schwann cells of the vestibular transitional zone of the vestibulocochlear nerve that can be benign, small, slow growing and asymptomatic or large, faster growing and aggressive and potentially fatal, presenting with symptoms of hearing and balance impairment, vertigo, ataxia, headache and fifth, sixth or seventh cranial nerve dysfunction and facial numbness.


A rare autoinflammatory syndrome characterized by adult onset of rheumatologic manifestations such as recurrent fever, skin and pulmonary inflammation, ear and nose chondritis, vasculitis, deep vein thrombosis, and arthralgia. Laboratory examination reveals progressive hematologic abnormalities including macrocytic anemia and thrombocytopenia, as well as elevated inflammatory markers. Bone marrow biopsy shows hypercellularity and signs of bone marrow dysplasia. The disease primarily occurs in males and is caused by somatic mutations on chromosome Xp11.


Vibratory urticaria is a rare, genetic urticaria characterized by the development of localized, short-lasting (resolving within 1 hour), pruritic, erythematous, edematous hives in response to repetitive frictional or vibratory stimulation of the skin, which in some cases is accompanied by facial flushing, headache or the sensation of a metallic taste. Concomitant local mast cell degranulation and increased histamine serum levels are additional typical findings.


Vici syndrome is a very rare and severe congenital multisystem disorder characterized by the principal features of agenesis of the corpus callosum, cataracts, oculocutaneous hypopigmentation, cardiomyopathy and combined immunodeficiency.

Summary:
Epidemiology
Prevalence is unknown. Only 20 cases have been reported to date.
Clinical description
Vici syndrome is usually diagnosed in the first years of life. The phenotype is variable but the principal diagnostic features are almost always present at onset or evolve over time. Swallowing and feeding difficulties may be noted early on and may lead to failure to thrive. Cataracts are the most frequent ocular abnormality observed but others include optic nerve hypoplasia (see this term), nystagmus and photophobia. Hypopigmentation of eyes and hair is relative to the familial or ethnic background. Cardiomyopathy may evolve over time, leading to progressive heart failure. Most patients suffer from recurrent infections during infancy, often affecting the respiratory, gastrointestinal and urinary tracts, but can also include mucocutaneous candidiasis, conjunctivitis and sepsis. An associated skeletal muscle myopathy with hypotonia and motor developmental delay is common. Some patients can display facial dysmorphism (cleft lip/palate and micrognathia), or rarely, other dysmorphic features (i.e. syndactyly). Sensorineural hearing loss has been reported in some and is probably underdiagnosed. Other structural CNS abnormalities, psychomotor retardation and seizures may also be present. Thymus, thyroid, liver and kidney involvement, as well as hematological abnormalities, have been rarely reported. Death is mainly due to cardiac complications or severe infections.
Etiology
Vici syndrome is due to mutations in the EPG5 gene (18q12.3) which encodes an important autophagy regulator, ectopic P-granules autophagy protein 5 (epg5). The autophagy pathway involves several tightly regulated steps, evolving from the initial formation of phagophores to autophagosomes, whose fusion with lysosomes results in the final structures of degradation, autolysosomes. Formation of autolysosomes is specifically disturbed by an epg5 deficiency.
Diagnostic methods
Diagnosis is based mainly on the presence of the characteristic clinical features. Brain MRI visualizes agenesis of the corpus callosum and an ocular examination (slit lamp exam) can identify any cataracts or ocular abnormalities. Electrocardiogram (ECG) and cardiac ultrasound are useful in assessing cardiac function. Immunological studies are also performed. Molecular genetic testing, identifying mutations in the EPG5 gene, confirms diagnosis.
Differential diagnosis
Differential diagnoses include Marinesco-Sjogren syndrome, Chédiak-Higashi syndrome, Griscelli syndrome, DiGeorge syndrome or ataxia-telegiectasia (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation.
Genetic counseling
Inheritance is autosomal recessive and genetic counseling is possible.
Management and treatment
Treatment of Vici syndrome is purely supportive. In patients with seizures, anticonvulsant therapy should be instituted. Tube feeding may be necessary in those with feeding difficulties. Intercurrent infections should receive prompt and aggressive antibiotic treatment. In those with severe immunodeficiency, intravenous immunoglobulin replacement and antimicrobial prophylaxis should be considered. Cardiac function should be monitored regularly and immediate medical treatment instituted in case of evolving cardiac failure. Cataracts can be surgically corrected and hearing aids can be provided as necessary. Thyroid, liver and kidney function should be regularly monitored.
Prognosis
The overall prognosis is poor but may improve if the condition is diagnosed early and if cardiac and immunological aspects of the disease are managed proactively.

                            Last update:
                            May 2014

                            - Expert reviewer(s):
                            Dr Heinz JUNGBLUTH


VIPoma is an extremely rare type of pancreatic neuroendocrine tumor (see this term) that secretes vasoactive intestinal polypeptide (VIP) leading to the manifestations of watery diarrhea, hypokalemia and achlorhydia or hypochhlorhydia (known as WDHA syndrome).

Summary:
Epidemiology
The incidence of VIPoma in the general population is of less than 1/10,000,000 individuals per year. There is a slight female predominance.
Clinical description
The median age of diagnosis is the fifth decade of life but VIPoma can occur at any age. The most common presentation includes chronic watery diarrhea (described as >3L/day, odorless, blood and mucus free and unaffected by fasting), hypokalemia (manifesting with muscle weakness, abdominal muscle cramps, or respiratory depression), and various dietary deficiencies (iron and B12 deficiency) caused by achlorhydia/hypochlorhydia. Other less common manifestations include nausea, vomiting, weight loss, bloating, indigestion, skin rash and facial flushing, backache and lethargy. In 60-80% of cases, metastasis has occurred at the time of diagnosis as symptoms usually only occur once a tumor has reached a certain size. The most common site of metastasis is liver but lung, lymph node and kidney involvement have also been reported. If untreated, prolonged dehydration can lead to renal failure and cardiac arrest. In rare cases, VIPomas are non-functional.
Etiology
Most cases are sporadic but VIPomas can also occur in association with multiple endocrine neoplasia type 1 (MEN1; see this term). VIPomas are, in 90% of cases, located in the pancreas (mainly in the body and tail) and are usually solitary with a diameter ranging from 1-7cm. The remainder (10%) originate from non-pancreatic tissue such as the colon, liver and neural crest-derived tissues (mainly pediatric cases). These tumors secrete VIP, which stimulates cyclic adenosine monophosphate (cAMP) production in the intestine, causing increased water and electrolyte secretion into the lumen. VIP also has an inhibitory effect on gastric mucosa parietal cells leading to decreased gastric acid production.
Diagnostic methods
Diagnosis is based on clinical, laboratory and imaging findings. Typical blood laboratory findings include elevated VIP levels (>200pg/mL is diagnostic), hypokalemia, hypochlorhydia or achlorhydia, hyperglycemia, hypercalcemia and non-anion gap metabolic acidosis. Computed tomography (CT) and octreotide scans, magnetic resonance imaging (MRI) and endoscopic ultrasound can be used to localize neoplasms, confirming diagnosis. Immunohistochemically, VIPomas stain positively for VIP, synaptophysin, chromagranin A, somatostatin, neuron specific enolase and cytokeratin.
Differential diagnosis
Differential diagnoses include all other causes of chronic diarrhea such as malabsorption syndrome, Crohn disease, ulcerative colitis, microscopic colitis (see these terms), and gastrointestinal infections.
Management and treatment
Initial treatment focuses on replacing the massive loss of fluids, restoring electrolyte levels and reversing acidosis. Some patients may require intravenous fluid and potassium replacement in a hospital setting. Octreotide (a somatostatin analogue) is successful in controlling diarrhea and reducing VIP hormone levels. Loperamide may also be used. Surgical resection is the standard treatment in those with primary or metastatic VIPoma. Unresectable metastatic disease has been treated with chemotherapy (docorubicin/streptozocin regimen) in some cases.
Prognosis
Prognosis is highly variable and is dependent on many factors. In those with benign, surgically resectable tumors, the reported 5-year survival rate is almost 95%.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Run YU


A rare group of infectious disease characterized by malaise, fever, exhaustion, vascular permeability, decreased plasma volume, coagulation abnormalities and varying degrees of hemorrhage. Severity of hemorrage is affected by a variety of contributing factors (depending on the pathogen and the host, whether it is primary infection or reinfection) and severly ill patients often show signs of bleeding under skin, in internal organs and in orifices. They may develop circulatory collapse, multisystem organ failure, shock, nervous system malfunction, coma, delirium, and seizures. A variety of rashes and ocular manifestations can also be associated with the diseases. They are caused by several different families of RNA viruses, including members of arenaviruses, bunyaviruses, filoviruses and flaviviruses that are capable of causing high morbidity and mortality.


A rare acquired skeletal muscle disease characterized by sudden onset of muscle weakness, tenderness, and pain during or following recovery from a viral illness. The most commonly reported underlying viral infections are influenza B and A, the latter being the significantly less frequent cause. Most cases occur in children. Symptoms are often limited to the calf muscles, but other muscle groups may be involved as well. The condition is typically self-limiting, resolving within several days, although rhabdomyolysis with renal failure and compartment syndrome have been reported.


Virus-associated trichodysplasia spinulosa is a rare infectious skin disease characterized by the development of follicular papules with keratin spicules in various parts of the body, predominantly in the face (e.g. nose, eyebrows, auricles), that is due to polyomavirus infection in immunocompromized patients.


A rare, life-threatening, non-inflammatory vasculopathy characterized by diffuse precipitation of calcium in viscera (mainly in the heart or lungs, but also in the stomach or kidneys) leading to fibrosis and thrombosis, which eventually causes tissue necrosis. Depending on the affected organ, patients may present with dyspnea, cough and respiratory failure or acute heart block and subsequent sudden cardiac death. The disease predominantly affects patients with end-stage kidney disease (ESKD) on dialysis.


Visceral neuropathy-brain anomalies-facial dysmorphism-developmental delay syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, neuropathic visceral dysmotility (resulting in neurogenic megacystis and sometimes chronic intestinal pseudo-obstruction syndrome), intracerebral calcifications, and dysmorphic facial features (including broad forehead, downslanted palpebral fissures, strabismus, protruding and low-set ears, and retrognathia). Microcephaly and renal abnormalities have also been reported.


Visual snow syndrome is a rare neurologic disease characterized by persistent continuous bilateral visual experience of flickering snow-like dots throughout the visual field in association with other visual (including palinopsia, enhanced entopic phenomena, nyctalopia, photophobia and photopsia) and non-visual (migraine with or without aura, tinnitus and occasionally tremor) symptoms.


Vitamin B12-responsive methylmalonic acidemia

An inborn error of vitamin B12 (cobalamin) metabolism characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia and intellectual deficit, which responds to vitamin B12. There are three types: cblA, cblB and cblD-variant 2 (cblDv2).

Summary:
Epidemiology
To date, over 120 patients with cblA, 66 patients with cblB and 6 patients with cblDv2 have been reported. Prevalence of 1/48,000-1/61,000 have been reported for methylmalonic acidemia (MA) of all causes in North America, and 1/26,000 in China, but only a subset of this is vitamin B12-responsive MA.
Clinical description
Patients usually present in infancy or early childhood with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, hepatomegaly and coma. They may also show signs of anemia (not megaloblastic), have potentially life-threatening ketoacidosis and/or hyperammonemia, and developmental delay and intellectual deficit, with metabolic stroke affecting the brain stem. MA frequently leads to end-stage renal failure by adolescence or adulthood. Patients with cblB are usually more severely affected than patients with cblA.
Etiology
Vitamin B12-responsive MA is caused by defects in the synthesis of adenosylcobalamin (AdoCbl). There are three distinct complementation classes, cblA, B and Dv2. cblA is caused by mutations in the MMAA gene (4q31.1-2); cblB by the MMAB gene (12q24.1); and cblDv2 by the  MMADHC gene (2q23.2). The previously reported cblH disorder has been shown to be cblDv2.
Diagnostic methods
Diagnosis is based on increased methylmalonic acid in blood and urine. Neonatal screening for propionylcarnitine and/or increased propionylcarnitine-to-acetylcarnitine ratio in dried blood spots by tandem mass spectrometry (MS/MS) has become common, but specific identification of methylmalonic acid remains crucial.
Differential diagnosis
Differential diagnoses include MA with homocystinuria (see this term), caused by defects in cblC, D and F, which can be differentiated by the presence of megaloblastic anemia, or vitamin B12-unresponsive MA without homocystinuria (see this term), which also can present early in life (<1 to 4 weeks) with similar symptoms. Complementation analysis can be used to identify the group involved, or sequencing of the causative genes to identify the affected gene.
Antenatal diagnosis
Antenatal diagnosis is possible by measurement of methylmalonate in amniotic fluid and maternal urine at mid-trimester and by studies of functional mutase activity and cobalamin metabolism in cultured amniotic fluid cells. Molecular diagnosis is possible if the gene affected and the mutation(s) in the family are known.
Genetic counseling
Transmission is autosomal recessive (1 in 4 recurrence risk/pregnancy).
Management and treatment
Treatment involves a protein-restricted diet, which should be instituted as soon as life-threatening manifestations such as ketoacidosis or hyperammonemia have been resolved, and intramuscular injections of vitamin B12, with or without carnitine (mainly effective in cblA). A good response to cobalamin supplementation has been reported in most cblA patients and in nearly half cblB patients. Oral antibiotics may also be useful to reduce propionic acid from gut flora.
Prognosis
The prognosis varies with the complement involved, with cblA patients having the most favorable prognosis (most patients well at ages up to 30 years) and cblB patients less favorable. cblDv2 appears similar to cblA, although the number of patients is small. One complication in long-term surviving patients is chronic renal failure.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Vitamin B12-unresponsive methylmalonic acidemia type mut- is an inborn error of metabolism characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia and intellectual deficit, which does not respond to administration of vitamin B12.

Summary:
Epidemiology
Prevalence of this form of the disorder is not known. More than 450 cases have been reported to date.
Clinical description
The disease typically presents very early in life (<1 to 4 weeks), although later onset cases have been observed, with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, developmental delay, intellectual deficit, hepatomegaly and coma. Patients may show signs of anemia. They may also have potentially life-threatening ketoacidosis and/or hyperammonemia, renal and neurological complications, metabolic stroke and cardiomyopathy. mut- is generally less severe than vitamin B12-unresponsive methylmalonic acidemia type mut0 (see this term) and may in some cases respond to vitamin B12 therapy. Long term complications include metabolic stroke and development of end stage renal failure. These complications are more frequent in mut0 than in mut-.
Etiology
The disease is caused by partial deficiency in the activity of the mitochondrial vitamin B12-dependent enzyme methylmalonyl-CoA mutase which is a result of mutations in the MUT gene (6p21).
Genetic counseling
It is transmitted as an autosomal recessive trait.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Vitamin B12-unresponsive methylmalonic acidemia type mut0 is an inborn error of metabolism characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia and intellectual deficit, which does not respond to administration of vitamin B12.

Summary:
Epidemiology
Prevalence of this disorder is not known.
Clinical description
The disease typically presents very early in life (<1 to 4 weeks), although rare later onset cases have been observed, with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, developmental delay, intellectual deficit, hepatomegaly and coma. Patients may show signs of anemia. They may also have potentially life-threatening ketoacidosis and/or hyperammonemia, renal and neurological complications, metabolic stroke and cardiomyopathy.
Etiology
The disease is caused by complete deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase which is a result of mutations in the MUT gene (6p21).
Genetic counseling
It is transmitted as an autosomal recessive trait.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Vitamin B12-unresponsive methylmalonic acidemia is an inborn error of vitamin B12 (cobalamin) metabolism characterized by recurrent ketoacidotic crises or transient vomiting, dehydration, hypotonia and intellectual deficit, which does not respond to administration of vitamin B12. There are two types of vitamin B12-unresponsive methylmalonic acidemia: mut0 and mut- (see these terms).

Summary:
Epidemiology
Prevalence of 1/48,000-1/61,000 has been reported for methylmalonic aciduria of all causes in North America, and 1/26,000 in China, but only a subset of this is vitamin B12-unresponsive methylmalonic acidemia.
Clinical description
Patients with vitamin B12-unresponsive methylmalonic acidemia without homocystinuria typically present very early in life (<1 to 4 weeks) with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscular hypotonia, hepatomegaly and coma. Later-onset manifestations may include developmental delay and intellectual deficit. Patients may also show signs of anemia which is not megaloblastic. They may also have potentially life-threatening ketoacidosis and/or hyperammonemia, renal and neurological complications, metabolic stroke and cardiomyopathy. Later-onset and milder phenotypes have also been observed, particularly in mut- patients. Long term consequences are neurological damage due to metabolic stroke and end-stage renal failure. These complications are more frequent in mut0 than in mut-.
Etiology
Vitamin B12-unresponsive methylmalonic acidemia without homocystinuria is caused by complete (mut0) or partial (mut-) deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase. This deficiency is caused by mutations in the MUT gene (6p21).
Diagnostic methods
Diagnosis is based on the finding of increased methylmalonic acid in blood and urine. There is increased propionylcarnitine and/or increased propionylcarnitine-to-acetylcarnitine ratio in dried blood spots by tandem mass spectrometry (MS/MS). Diagnosis can be confirmed by somatic cell studies or molecular genetic testing.
Differential diagnosis
Differential diagnoses include methylmalonic acidemia with homocystinuria (see this term), caused by defects in cblC, cblD and cblF, which can be differentiated by the presence of megaloblastic anemia, or vitamin B12-responsive methylmalonic acidemia without homocystinuria (see this term), which usually presents slightly later in life (1 month to 1 year). Complementation analysis can be used to identify the cbl or mut complement involved.
Antenatal diagnosis
Antenatal diagnosis is possible by measurement of methylmalonate in amniotic fluid and maternal urine at mid-trimester and by studies of functional mutase activity and cobalamin metabolism in cultured amniotic fluid cells. Molecular genetic prenatal diagnosis is also possible when the mutations segregating in the family are known.
Genetic counseling
The disorder is transmitted in an autosomal recessive manner.
Management and treatment
Treatment involves a protein-restricted diet, which should be instituted as soon as life-threatening problems such as ketoacidosis or hyperammonemia have been resolved. Oral antibiotics may also be useful. Liver transplantation has been attempted in a limited number of patients but this does not usually offer complete protection against renal and neurological complications.
Prognosis
Despite dietary treatment, patients remain vulnerable to life-threatening metabolic decompensation. Other long-term complications include progressive renal failure, metabolic stroke and other neurological symptoms, as well as cardiomyopathy. Life-expectancy is decreased in mut0 patients compared to mut- patients.

                            Last update:
                            March 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Vitamin K antagonist embryofetopathy is characterized by a group of symptoms that may be observed in a fetus or newborn when the mother has taken oral vitamin K antagonists, such as warfarin during pregnancy. Vitamin K antagonists are anticoagulant drugs that provide efficient thromboprophylaxis and that can cross the placenta. 5-12 % of infants exposed to warfarin between 6-9 weeks gestation present nasal hypoplasia and skeletal abnormalities, including short limbs and digits (brachydactyly), and stippled epiphyses. Warfarin fetopathy with central nervous system abnormalities (hydrocephalus, intellectual disability, spasticity, and hypotonia) or ocular abnormalities (microphthalmia, cataract, optic atrophy), fetal loss, and stillbirth, occurs in infants exposed at later gestations. Additional features that have been reported after in utero warfarin exposure include facial dysmorphism (cleft lip and/or palate, malformed ears), choanal atresia or stenosis, aorta coarctation, situs inversus totalis, bilobed lungs, and ventral midline dysplasia.


Vocal cord and pharyngeal distal myopathy (VCPDM) is a rare autosomal dominant distal myopathy characterized by adult onset of muscle weakness in the feet and hands (slowly progressing to involve proximal limb muscles) combined with vocal or swallowing dysfunction and frequent respiratory muscle involvement in later stages. Normal to mildly elevated creatine kinase (CK) serum levels and rimmed-vacuolated dystrophic muscle fiber changes are associated laboratory and pathologic findings.

Summary:
Epidemiology
Worldwide prevalence is unknown but more than 70 patients (of North American, European, and Japanese origin) have been reported to date.
Clinical description
Onset of muscle weakness is between 30-63 years (mean in the forties) and may initially be asymmetric. It most frequently begins with involvement of ankle and toe extensors with foot drop or may manifest in the hands. Weakness in the ankles renders the gait very unstable resulting in a waddling and steppage gait. In the hands, the extensors of the fingers and the abductor pollicis brevis (with atrophy) are affected to varying degrees. Progression of muscle weakness and wasting to proximal upper and lower limb muscles is common. Bulbar involvement with dysphonia and dysphagia may be initially absent but appear as disease progresses. Initially, voice is usually nasal or hoarse and dysphagia mild (with difficulty swallowing solid food), but progressive vocal cord weakness eventually leads to aspiration. Some patients display respiratory impairment with a low vital capacity that may progress to respiratory failure. Ocular muscle involvement is not observed.
Etiology
VCPDM is caused by a c.254C>G mutation in the MATR3 gene (5q31.3) which results in substitution of a conserved amino acid (S85C) in the nuclear protein Matrin-3. It harbors nuclear import and export motifs in addition to several DNA and RNA binding sites. Currently, the mechanism by which S85C alteration in Matrin-3 leads to myopathy remains largely unknown.
Diagnostic methods
The diagnosis of VCPDM is clinical and involves vocal cord examination by laryngoscopy (which reveals bowing of the vocal cords and constantly flowing secretions, resulting from incomplete closure of the glottis and pharyngeal muscle weakness). Needle EMG shows myopathic changes. Muscle biopsies reveal chronic non-inflammatory myopathy with variations in fiber size, fiber splitting and subsarcolemmal rimmed vacuoles, with pathologic changes being scant in the quadriceps and severe in the gastrocnemius. CK serum levels range from normal to an 8 fold increase. Molecular genetic screening revealing mutation in the MATR3 gene confirms diagnosis.
Differential diagnosis
Differential diagnosis includes Welander distal myopathy, oculopharyngeal muscular dystrophy, and oculopharyngodistal myopathy.
Genetic counseling
VCPDM is inherited in an autosomal dominant manner. Genetic counseling can inform affected individuals about the 50% risk of disease transmission to their offspring.
Management and treatment
Currently, there is no cure for VCPDM. Ankle-foot orthotic braces and/or canes are used to aid in ambulation. For patients suffering from vocal cord weakness, injection of agents that add bulk and act as stiffeners (teflon, gel foam, fat), or bilateral silastic-implant medialization of the vocal folds, may aid in reducing aspiration. Ventilation or oxygen therapy may be needed if patient presents severe respiratory muscle involvement.
Prognosis
Prognosis of patients suffering from vocal cord and pharyngeal weakness is highly influenced by the quality of long-term respiratory care, if it is needed. Moreover, as distal upper limb muscles weaken, hand may partially curl closed, leading to a general loss of grip and dexterity. Ambulation is usually preserved.

                            Last update:
                            September 2018

                            - Expert reviewer(s):
                            Dr Johanna PALMIO  - Pr Bjarne UDD


Vogt-Koyanagi-Harada disease is a bilateral, chronic, diffuse granulomatous panuveitis typically characterized by serous retinal detachment and frequently associated with neurological (meningitis), auditory, and dermatological alterations.

Summary:
Epidemiology
Annual incidence is estimated at 1/400,000. The condition predominantly affects young women and individuals with darker pigmentation (those of Asian, Hispanic, or Native American origin). Children may be affected, but the mean age of onset is about 30 years of age (ranging from 10 to 52 years).
Clinical description
The most common clinical manifestations are headaches (67% of cases), ocular involvement with panuveitis, skin vitiligo, alopecia, and inner ear disturbances. The disease can be divided into four clinical stages. The prodromic stage is characterized by nonspecific symptoms such as fever, headaches, nausea and vertigo, and then by neurologic symptoms such as muscle weakness, hemiparesis, hemiplegia, dysarthria and orbital pain. In the ophthalmologic stage, occurring a few days after the prodromic stage, patients complain of blurred vision, ocular pain, and photophobia or central scotoma (bilateral in 80% of cases). Bilateral, serous, non-rhegmatogenous retinal detachment often occurs. Hearing disturbances (75%) and dizziness may also be present. The convalescent stage, occurring within three months of disease onset, is characterized by the apparition of cutaneous signs such as poliosis involving the eyebrows and eyelashes (and sometimes the scalp and body hair), hair loss, and vitiligo (usually perilimbal). Recurrent uveitis and ophthalmologic complications appear in the final stage, the chronic recurrent stage.
Etiology
Pathogenesis has been linked to immunological disorders targeting the melanocytes, and which involve T-cell-mediated cytotoxicity and apoptosis. However, the etiology is still not completely understood. An association between disease susceptibility and positive blood tests for the HLA-DRB1*0405 haplotype has been reported.
Diagnostic methods
Diagnosis is clinical. Cerebrospinal fluid analysis revealing pleocytosis can confirm the diagnosis.
Management and treatment
Management should involve a multidisciplinary team with dermatologists, ophthalmologists, and neurologists. High doses of corticosteroids usually provide efficient treatment, but immunosuppressors may also be used.
Prognosis
With early and aggressive treatment, the prognosis is usually favorable, but acute hearing and vision alterations may occur.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Dr Olivier CALVETTI  - Dr Caroline LAURENT-CORIAT  - Pr Michel PAQUES


A familial cancer predisposition syndrome associated with a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma/paraganglioma.

Summary:
Epidemiology
Prevalence is estimated at 1/53,000 and annual birth incidence at 1/36,000. Men and women are equally affected. Mean age at diagnosis is 26 years (range: infancy - 7th decade).
Clinical description
Retinal hemangioblastomas are the most common presenting feature (multiple and bilateral in about 50% of cases). They are usually asymptomatic, but they can cause retinal detachment, macular edema, glaucoma, and vision loss. Central nervous system (CNS) hemangioblastomas are the presenting feature in about 40% and occur overall in 60-80% of patients. They are most often located in the cerebellum, but also in the brainstem and spinal cord. They are benign but cause symptoms by compressing adjacent nervous tissue. In the cerebellum they are most often associated with increased intracranial pressure causing headaches, vomiting, and limb or truncal ataxia (difficulty in controlling fine movements of the arms and legs and unsteadiness in walking). Multiple renal cysts are very common and there is an increased lifetime risk of RCC (up to 70%). Some patients have pheochromocytomas that can be asymptomatic, but may cause hypertension. Epididymal cysts and cystadenomas (60% of male patients) may occur, as well as multiple pancreatic cysts (most patients). Non-secretory pancreatic islet cell tumours occur in a minority (10-15%). Endolymphatic sac tumors (ELST) are also been found (up to 10%) and may cause hearing loss. Head and neck paragangliomas are rare (0.5%). The mean age at diagnosis of tumors (e.g. haemangioblastoma, RCC) in VHL disease is considerably younger than in non-inherited sporadic cases. The clinical manifestations of VHL disease van vary between family members.
Etiology
VHL disease is caused by pathogenic variants (mutations) in the VHL gene (3p25.3), a classic tumor suppressor. Most cases are diagnosed via a germline mutation. In addition to VHL disease, pathogenic variants in the VHL gene can also cause, albeit more rarely, predisposition to isolated phaeochromocytoma/paraganglioma and familial erythrocytosis (polycythemia).
Diagnostic methods
Diagnosis can be made in the presence of a single typical tumor (e.g. retinal or CNS hemangioblastomas or RCC) and a positive family history of VHL. If there is no family history (about 20% of cases occur de novo), multiple tumors (e.g. two hemangioblastomas or a hemangioblastoma and an RCC) are required for diagnosis. A complete blood count, measurement of urinary or plasma catecholamine metabolites and urinalysis may be indicative of polycythemia, pheochromocytoma/paraganglioma, and RCC bit regular ophthalmology review and MRI scans are the mainstay of surveillance. Imaging studies can be used to detect CNS tumors, pheochromocytoma/paraganglioma, endolymphatic sac tumors, renal tumors, and renal and pancreatic cysts.
Differential diagnosis
Differential diagnoses include multiple endocrine neoplasia, neurofibromatosis type 1, polycystic kidney disease, tuberous sclerosis, Birt-Hogg-Dube syndrome, and hereditary pheochromocytoma-paraganglioma syndromes associated with succinate dehydrogenase subunit mutations (SDHB, SDHC and SDHD).
Antenatal diagnosis
Prenatal diagnosis is possible when a pathogenic variant has been detected in an affected family member.
Genetic counseling
Inheritance is autosomal dominant with age-dependent penetrance. Most cases are familial and at risk relatives should be identified and offered surveillance and, when available, cascade testing (relatives who test negative can be discharged from follow-up). Surveillance is commenced in early childhood and genetic testing of children can be offered to avoid unnecessary surveillance.
Management and treatment
Surveillance to enable early detection of VHL-related tumors is the mainstay of management. Surveillance (ophthalmologic, MRI brain and abdominal scans, laboratory testing) is lifelong and reduces morbidity and mortality. Tumors detected by surveillance may not require immediate intervention and there are agreed consensus protocols to keep some tumors under surveillance until certain size thresholds are reached (e.g. 3 cm diameter for RCC). When treatment of VHL tumors is indicated surgery has been the most frequently used intervention for abdominal and CNS lesions but recently medical therapy with HIF-2 antagonist (e.g. belzutifan) has become an option in some countries.
Prognosis
Regular surveillance and early detection and management of tumors has reduced the morbidity and mortality of VHL disease and recently average life expectancy has been estimated to be ~64 years.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Pr Eamonn MAHER | ERN GENTURIS*

                                * European Reference Network


Von Voss-Cherstvoy syndrome is a very rare disorder with phocomelia of upper limbs, encephalocele, variable brain anomalies, urogenital abnormalities, and thrombocytopenia.

Summary:
Epidemiology
Less than 15 cases have been reported.
Clinical description
The spectrum of upper limb defects varies from radial agenesis and phocomelia to amelia. A meningoencephalocele is constant. The intellectual development may be normal.
Etiology
Pathogenesis and cause of this syndrome are unknown.
Genetic counseling
Parental consanguinity reported in a family suggests an autosomal recessive pattern of inheritance.

                            Last update:
                            May 2010


A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a partial, quantitative plasmatic deficiency of an otherwise structurally and functionally normal von Willebrand factor (VWF).

Summary:
Epidemiology
The type 1 disease is considered to be the most common form of VWD, accounting for between 50-75% of cases but its prevalence is probably overestimated.
Clinical description
Age of onset of bleeding anomalies varies, with earlier onset and more severe symptoms being associated with more severe VWF deficiency. The bleeding anomalies are generally characterized by mucocutaneous hemorrhage (menorrhagia, epistaxis, or prolonged bleeding after trauma or a surgical intervention). Hematomas and hemarthrosis are very rare.
Etiology
VWD is caused by mutations in the VWF gene (12p13.3). The anomalies responsible for type 1 VWD generally lead to intracellular retention or rapid clearance of VWF from the circulation. However, families have been described in which no mutations in the VWF gene have been detected indicating that other genetic factors are also implicated. To date, the main additional factor associated with the disease is the ABO blood group, with levels of VWF in blood group O being 25-35% lower than in non-O blood groups.
Diagnostic methods
The presence of bleeding manifestations in the patient and in at least one family member is obligatory for diagnosis. Laboratory diagnosis relies on detection of parallel decreases in functional and VWF antigen levels to values below 40% of normal, in the absence of notable anomalies in the distribution or structure of the VWF multimers. Moderate deficiency of factor VIII (FVIII) may also be present.
Differential diagnosis
Given the variation in VWF levels (particularly among individuals with blood group O) and the occurrence of abnormal bleeding events in the general population, it may be difficult to differentiate between unaffected individuals and those with type 1 VWD. Evaluation of patients using the bleeding score and studies of family history are therefore essential for diagnosis. Differentiation between acquired von Willebrand syndrome (AVWS), which occurs in association with another underlying pathology, and inherited VWD is more problematic, especially if the type 1 VWD is secondary to an increased clearance. Measurements of VWF levels (antigen and functions) generally allow VWD to be distinguished from hemophilia A.
Genetic counseling
Type 1 VWD is transmitted in an autosomal dominant manner. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks (some patients may be carriers for the most severe form type 3), and to allow screening for detection of other affected family members.
Management and treatment
Medication (such as tranexamic acid for ENT (ear, nose and throat) bleeding anomalies and estrogen-progesterone treatment for menorrhagia) provides an effective treatment and may be prescribed alone or as an adjuvant therapy. Desmopressin (which triggers a transitory release of endogenous VWF stored in the epithelial cells) may be administered in cases when a specific curative or preventative treatment is required. The response to desmopressin is usually good for patients with type 1 disease. Substitution therapy with purified human VWF constitutes an alternative treatment in case of major bleeding problems, for patients in which desmopressin is contraindicated, those with a poor response to desmopressin, or those in which tachyphylaxis occurs.
Prognosis
Type 1 VWD is generally not life-threatening and does not lead to functional VWF impairment.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND  - Pr Sophie SUSEN


A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a qualitative deficiency and functional anomalies of the Willebrand factor (VWF). Depending on the type of functional abnormalities, this form is classified as type 2A, 2B, 2M or 2N.

Summary:
Epidemiology
The subtypes of type 2 VWD account for between 20-45% of cases of VWD; the prevalence wordwide is estimated at 1/107,000.
Clinical description
Age of onset of the bleeding anomalies varies, with earlier onset being associated with more severe VWF deficiency. Four type 2 VWD subtypes have been described: types 2A, 2B and 2M are characterized by mucocutaneous manifestations (menorrhagia, epistaxis, gastrointestinal hemorrhage etc.); type 2N is mainly characterized by post traumatic soft tissue bleedings. There is an increased risk of abnormal bleeding following an invasive procedure associated with all type 2 subtypes.
Etiology
The VWF gene (12p13.3) anomalies that lead to type 2 VWD involve the well-defined functional domains of the VWF protein. Three of these subtypes are associated with anomalies in the interaction of VWF with platelets and/or the subendothelium, and are caused by decreased affinity for platelets in combination with VWF multimerization anomalies (type 2A), increased VWF affinity for platelets (type 2B), or decreased VWF affinity for platelets or collagen and normal VWF multimerization (type 2M). The fourth subtype (type 2N) is associated with decreased VWF affinity for factor VIII (FVIII); the interactions between the platelets and the vessel walls are often normal and the FVIII deficiency is usually only moderate.
Diagnostic methods
For subtypes 2A, 2B and 2M, diagnosis is suspected following detection of a notably more profound decrease in functional VWF levels than in VWF antigen levels. This discrepancy between the functional VWF levels and VWF antigen levels also allows the type 2 disease to be distinguished from VWD type 1. However, more specific laboratory tests (analysis of the structure and distribution of the multimers) are required to diagnose the exact type 2 subtype. A thrombocytopenia can be observed in type 2B. Diagnosis of type 2N is suspected when the decrease in FVIII levels is much greater than that of VWF, and confirmed by a factor VIII binding assay.
Differential diagnosis
Subtypes 2A, 2B and 2M can be differentiated from acquired von Willebrand syndrome (AVWS), clinically by the onset of bleeding manifestations at a young age, a family history of the disease and the absence of an underlying pathology, and through molecular analysis revealing a mutation in the VWF gene. The factor VIII binding assay, together with molecular analysis of the VWF gene, allows type 2N VWD to be distinguished from mild hemophilia A.
Genetic counseling
Most subtypes of type 2 VWD are transmitted in an autosomal dominant manner except for type 2N and some rare forms of type 2A which are autosomal recessive. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks, and to allow screening for detection of other affected family members. In case of recessive transmission where both parents are carriers of the disease-causing mutation, the at-risk couple should be informed that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Medication (such as tranexamic acid for ENT (ear, nose and throat) bleeding anomalies and estrogen-progesterone therapy for menorrhagia) provides an effective treatment and may be prescribed alone or as an adjuvant therapy. The response to desmopressin varies depending on the type 2 subtype, as the endogenous VWF released from the endothelial cells in response to this treatment displays the same functional anomalies as plasmatic VWF. Desmopressin is contraindicated in patients with subtype 2B. Preventative or curative treatment for abnormal bleeding events often involves substitution therapy with purified human VWF. Platelet concentrates may have to be transfused in some patients with type 2B.
Prognosis
For patients managed within specialized hemostasis hospital centers, the prognosis is favorable, even for those with the most severe forms of the disease.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND  - Pr Sophie SUSEN


A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with a decrease in the affinity of the Willebrand factor (VWF) for platelets and the subendothelium caused by a deficiency of high molecular weight VWF multimers. The disease manifests as mucocutaneous bleeding (menorrhagia, epistaxis, gastrointestinal hemorrhage, etc.).


A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with increased affinity of the Willebrand factor (VWF) for platelets leading to rapid clearance of both the platelets (increasing the risk of thrombocytopenia) and VWF from the plasma. The disease manifests as mucocutaneous bleeding (menorrhagia, epistaxis, gastrointestinal hemorrhage, etc.).


A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with decreased affinity of the Willebrand factor (VWF) for platelets or collagen in the absence of any deficiency of high molecular weight VWF multimers. The disease manifests as mucocutaneous bleeding (menorrhagia, epistaxis, gastrointestinal hemorrhage, etc.).


A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with a marked decrease in the affinity of the Willebrand factor (VWF) for factor VIII (FVIII). Abnormal bleeding manifestations are less frequent in this VWD subtype than in other forms of the disease. The disease manifests mainly as soft tissue bleeding (haematoma, post-operative bleeding, etc.).


A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a total or near-total absence of Willebrand factor (VWF) in the plasma and cellular compartments, also leading to a profound deficiency of plasmatic factor VIII (FVIII). It is the most severe form of VWD.

Summary:
Epidemiology
The type 3 disease is the rarest form of VWD, accounting for less than 5% of all cases. The average prevalence in Europe and the USA is approximately 1/500,000; however, the prevalence worldwide, including within Europe, can vary depending on the country of origin and the level of consanguinity, and can be as frequent as 1/200,000.
Clinical description
Onset usually occurs during the neonatal period or in infancy, but later onset has been reported. The bleeding anomalies are mainly characterized by mucocutaneous hemorrhage (epistaxis, menorrhagia, postpartum hemorrhage, gastrointestinal bleeding etc.) and prolonged bleeding after surgical interventions. As in hemophilia patients, hematomas and hemarthrosis may occur in individuals with type 3 VWD due to the severe FVIII deficiency. Cerebral hemorrhage has also been reported.
Etiology
The disease is caused by homozygous or compound heterozygous mutations (mainly missense or large mutations) in the VWF gene (12p13.3) that lead to synthesis of a truncated protein or allele silencing.
Diagnostic methods
Diagnosis is straightforward and is based on the absence of detectable VWF measured by all available methods (including functional and immunologic assays and agarose gel electrophoresis), accompanied by a secondary FVIII deficiency with a decrease to between 1 and 10% of normal levels.
Differential diagnosis
Measurements of VWF levels generally allow VWD type 3 to be distinguished from moderate hemophilia A. Type 3 VWD is also generally easy to distinguish from other hereditary forms of VWD.
Antenatal diagnosis
In at risk pregnancies, when the pathogenic variants have been previously identified in a family member, the identification of underlying VWF mutations may be used for prenatal diagnosis.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be recommended for at risk couples (where both parents are unaffected carriers) informing them that the risk of having an affected child is 25% for each pregnancy.
Management and treatment
Patients with type 3 VWD do not respond to desmopressin and therefore substitution therapy with purified human VWF associated, at least for the first injection, with FVIII is the principle preventative or curative treatment. Long-term prophylactic treatment with regular injections of purified human VWF may be required for patients with recurrent bleeding events. Some patients (5-10 % of cases) develop alloantibodies against VWF rendering the substitution treatment ineffective; the formation of immune complexes is sometimes associated with an anaphylactic response. In these cases, alternative treatments, such as continuous infusion of recombinant factor VIII or recombinant activated factor VII, should be considered. There are some preliminary reports of use of emicizumab in allo-immunized type 3 patients.
Prognosis
Type 3 VWD is the most severe form of VWD and, in the absence of appropriate management in specialized hemostasis hospital centers, the manifestations can be life-threatening and lead to functional impairment.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND  - Pr Sophie SUSEN


A rare, inherited bleeding disorder characterized by defective platelet adhesion and secondary coagulation defect that manifests as abnormal bleeding of variable severity occurring either spontaneously or in association with an invasive procedure. Three main subtypes are defined based on the type of von Willebrand factor defect: partial (type 1) or total (type 3) deficiency, and qualitative/functional anomalies (type 2).

Summary:
Epidemiology
The prevalence of Von Willebrand disease (VWD) in the general population is estimated at between 0.6 and 1.3% (including all forms) depending on the study, but the prevalence of symptomatic VWD that requires specific treatment is approximately 1/10 000. Type 3 VWD is much more rare (1/1 000 000).
Clinical description
Age of onset varies, with earlier onset being associated with more severe VWF deficiency. The disease manifests as abnormal bleeding of variable severity occurring either spontaneously or in association with an invasive procedure. The bleeding anomalies are generally characterized by mucocutaneous hemorrhage (epistaxis, menorrhagia, bleeding from minor wounds, etc.) but hematomas and hemarthrosis may occur in more severe forms.
Etiology
VWD is caused by mutations in the VWF gene (12p13.3) encoding the multimeric VWF protein. The VWF protein has an intraplatelet, endothelial and plasmatic localization and plays essential roles both in the interaction of platelets with the injured vessel wall and in the transport and stabilization of factor VIII (FVIII).
Diagnostic methods
Diagnosis relies on laboratory tests involving functional and immunological assays of VWF and FVIII levels. Determination of the type of VWD requires other specific tests such as studies of the distribution of VWF multimers.
Differential diagnosis
Measurements of VWF levels (antigen and functions) generally allow VWD to be distinguished from hemophilia A. However, these tests do not allow differentiation of type 2N VWD, which requires more specific assays. Differentiation between acquired von Willebrand syndrome (AVWS), which occurs in association with another underlying pathology, and inherited VWD is more problematic. The fact that individuals in the general population belonging to blood group O may also have moderately lower levels of VWF should also be taken into consideration in the differential diagnosis.
Antenatal diagnosis
In at risk pregnancies, the identification of underlying VWF mutations may be used for prenatal diagnosis of type 3 VWD.
Genetic counseling
VWD is most often transmitted in an autosomal dominant manner, however, the mode of inheritance is autosomal recessive for type 3 VWD and for some of the type 2 subtypes. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks, and to allow screening for detection of other affected family members. For couples at risk of having a child with type 3 disease, genetic counseling may be best discussed in a specialized multidisciplinary center.
Management and treatment
Management depends on the type of VWD. Desmopressin is generally an effective preventative or curative treatment for abnormal bleeding in type 1 VWD. In patients with type 2 disease, the response to desmopressin is variable and substitution therapy with purified human VWF is often required. Desmopressin does not constitute an effective treatment for patients with type 3 disease, and thus these individuals require substitution therapy with purified human VWF associated, at least for the first injection, with FVIII.
Prognosis
For patients managed within specialized hemostasis hospital centers, the prognosis is favorable, even for those with the most severe forms of the disease.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND  - Pr Sophie SUSEN


VPS11-related autosomal recessive hypomyelinating leukodystrophy

A rare genetic leukodystrophy identified in families of Ashkenazi Jewish descent, characterized by infancy onset of severe global developmental delay with very limited or absent speech and sometimes complete absence of motor development, hypotonia, spasticity, and acquired microcephaly. Seizures, hearing loss, visual impairment, and autonomic dysfunction have also been described. Brain imaging shows delayed myelination and other white matter abnormalities.


A rare vulvar carcinoma characterized by a malignant epithelial neoplasm of glandular origin and/or with glandular characteristics arising in the vulva, including adenocarcinoma of mammary gland type, sweat gland type, and intestinal type, as well as adenocarcinomas of the Bartholin glands and Paget disease of the vulva. Depending on the type of tumor and disease stage, patients may present with a solitary vulvar mass, bleeding, or (in the case of Paget disease) a pruritic, erythematous, eczematous lesion.


A rare vulvar carcinoma characterized by a slowly growing ulcer or nodule which is histologically composed of demarcated nests of palisaded basal cells originating at the epidermal-dermal junction. Occasionally, the tumor may be extensively pigmented. Patients most commonly present with pruritus. The lesion is usually treated by local excision, although groin metastases have been reported.


A group of rare tumors of the vulva comprising HPV-associated and HPV-independent squamous cell carcinomas as the most frequent malignant vulvar tumors, basal cell carcinomas, adenocarcinomas, and Bartholin gland carcinomas. Depending on the type of tumor and disease stage, patients may present with a painless vulvar mass or ulcer, or with pruritus, a burning sensation, pain, or bleeding.


A rare vulvovaginal tumor characterized by intraepithelial neoplastic proliferation of the vulvar epithelium, histologically presenting proliferation of atypical basal cells with basal layer involvement, enlarged nuclei, hyperchromasia, pleomorphic cells and increased numbers of mitotic figures. Patients are frequently asymptomatic, although vulvar pruritus/pain/burning, dysuria and/or dyspareunia may be associated. Concurrent anogenital involvement is frequent. Two subtypes, usual type VIN (uVIN) and differentiated type VIN (dVIN) exist, with uVIN typically being associated with HPV infection and presenting multifocal, elevated lesions around the introitus and/or labia majora, and dVIN being related to chronic inflammation and lesions consisting of poorly demarcated pink or white plaques that are often associated with lichen sclerosus or lichen planus. Diffusely positive p16 immunohistochemistry and high Ki-67 proliferation index in uVIN futher differentiates this subtype from dVIN, this latter being consistently negative for p16 while presenting p53 positivity.


A rare vulvar carcinoma characterized by an ulcer, nodule, macule, or pedunculated mass which is histologically composed of infiltrating islands of malignant squamous cells. Histological subtypes include keratinizing, non-keratinizing, basaloid, warty, and verrucous carcinomas. Some tumors are associated with human papilloma virus, smoking, high grade squamous intraepithelial lesion, chronic vulvar inflammatory disorders, or differentiated vulvar intraepithelial neoplasia. Patients may present with discharge, bleeding, or pain. Most important prognostic features are tumor depth and lymph node status.


A rare, non-malformative vulvovaginal disease characterized by a combination of erosive or desquamative lichen planus (LP) of vulval, vaginal and gingival mucosae, with a high propensity for scarring and stricture formation. Additional sites of involvement are frequently observed (in particular, tongue, buccal mucosae, skin and perianal LP). Patients may be asymptomatic or, more commonly, present with pain, burning, discomfort and bleeding, dyspareunia, and seropurulent vaginal discharge.


Vulvovaginal rhabdomyosarcoma is a rare vulvovaginal tumour, a highly malignant soft tissue sarcoma composed of cells with round to oval or spindle-shaped nuclei and eosinophilic cytoplasm that may show differentiation towards striated muscle cells. It usually affects children and presents with a vulvar or vaginal mass that may be polypoid or grape-like (embryonal subtype) and associated with bleeding and ulceration.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by moderate to severe intellectual disability, neurologic signs and symptoms (such as seizures, spasticity, strabismus), characteristic dysmorphic facial features (including broad forehead, hypertelorism, downslanting palpebral fissures, broad and flat nasal bridge, midline notch of upper lip, lack of upper central incisors, incomplete oral cleft, and prominent mandible), and acne scars. Hearing impairment, pseudo-bulbar palsy, growth retardation, and skeletal anomalies (camptodactyly, clinodactyly, bilateral cubitus valgus, pes cavus/planus) have also been described.


A subtype of Waardenburg syndrome (WS) characterized by congenital deafness, minor defects in structures arising from neural crest resulting in pigmentation anomalies of eyes, hair, and skin, in combination with dystopia canthorum.

Summary:
Epidemiology
The prevalence of WS1 is unknown; the worldwide prevalence of WS is estimated at around 1/40,000. WS1 is one of the most common types of WS.
Clinical description
Clinical manifestations vary within and between families and frequently include congenital sensorineural deafness, which is often a non-progressive profound bilateral hearing loss, dystopia canthorum, heterochromic or hypoplastic blue irides, white forelock, typically in the midline or early graying of the scalp hair before age 30 years. All these manifestations along with a suggestive family history are major criteria. Minor criteria include congenital leukoderma, synophrys/medial eyebrow flare, broad/high nasal root with prominent columella, hypoplastic alae nasi. Spina bifida can also occur in rare cases.
Etiology
WS is genetically heterogeneous. WS1 is caused by a heterozygous mutation in the paired box-containing PAX3 gene on chromosome 2q36.1. This syndrome is secondary due to the absence of melanocytes in the skin, hair, eyes and the striavascularis ductus cochlearis and a consequence of abnormal migration of cells derived from the neural crest.
Diagnostic methods
Over 90% of cases who meet diagnostic criteria for WS1 have identifiable mutations in PAX3. WS1 is defined by the association of at least 2 major, or 1 major and at least 2 minor clinical criteria, as delineated by the Waardenburg Consortium criteria, including dystopia canthorum. The distance between the inner canthi, pupils, and outer canthi calculates a W index for the diagnosis of lateral displacement of the inner canthi. A W index of more than 1.95 shows dystopia. Dystopia canthorum may be difficult to characterize in babies but is the most penetrant sign.
Differential diagnosis
Differential diagnosis includes Waardenburg syndrome type 2, 3 and 4, piebaldism, Tietz syndrome, oculocutaneous albinism, Vogt-Koyanagi-Harada disease(see these terms) and other forms of congenital non-progressive sensorineural hearing loss.
Genetic counseling
In the majority of cases, WS1 is transmitted as an autosomal dominant disorder with a large variable inter- and intrafamilial expressivity. Some affected patients present with a de novo mutation.
Management and treatment
Hearing aids to counter hearing loss and effective therapy to improve language, communication, and cognitive skill are recommended. Associated manifestations are treated as appropriate (e.g. cosmetics to manage the pigmentation defects).
Prognosis
With hearing aids, prognosis is good for most WS1 affected individuals.

                            Last update:
                            October 2015

                            - Expert reviewer(s):
                            Dr Véronique PINGAULT


An autosomal dominant subtype of Waardenburg syndrome (WS) characterized by varying degrees of deafness and pigmentation anomalies of eyes, hair and skin, but without dystopia canthorum.

Summary:
Epidemiology
The prevalence of WS2 is unknown; the worldwide prevalence of WS is estimated at around 1/40,000. WS2 is one of the most common types of Waardenburg syndrome.
Clinical description
Clinical manifestations for WS2 resemble those of Waardenburg syndrome type 1 (WS1; see this term). Sensorineural hearing loss (77%) and heterochromia iridum (47%) are the two most important clinical features for WS. In addition, individuals with WS2 lack dystopia canthorum and are usually more frequently affected by hearing loss and heterochromia iridum. In some cases (mutation in SOX10 gene), patients may present associated signs of Kallmann syndrome (anosmia, hypogonadism; see this term) and/or neurological defects (neurological Waardenburg syndrome).
Etiology
WS2 is genetically very heterogeneous and still much of the etiology of WS2 remains elusive. Mutations have been found in MITF (3p14-p13; subtype designated as WS2A), SNAI2 (8q11.21; WS2D), and SOX10 (22q13.1; WS2E) genes. Furthermore WS2 loci have been mapped to chromosome 1p21-p13.3 (subtype designated as WS2B) and to chromosome 8p23 (designated as WS2C). Digenic inheritance of MITF mutation in combination a TYR mutation (and/or the TYRR402Qhypomorphic allele) has been reported in two families with WS2 and ocular albinism.
Diagnostic methods
Diagnosis is determined by the presence of major and minor characteristic clinical features according to the Waardenburg Consortium criteria, as well as by genetic testing.
Differential diagnosis
Differential diagnosis includes Waardenburg syndrome type 1 and 4, piebaldism, Tietz syndrome, oculocutaneous albinism (see these terms) and other forms of congenital non-progressive sensorineural hearing loss.
Genetic counseling
In the majority of cases, WS2 is transmitted as an autosomal dominant disorder with a large variable inter- and intrafamilial expressivity. Some affected patients present with a de novo mutation.
Management and treatment
Hearing aids to counter hearing loss and effective therapy to improve language, communication, and cognitive skill are recommended. Pigmentation defects do not require medical care but cosmetic products are available. Rarely, in case of extended depigmentation, care is taken to protect the skinand eyesfrom the sun.
Prognosis
With hearing aids, prognosis is good for most affected individuals with WS2.

                            Last update:
                            October 2015

                            - Expert reviewer(s):
                            Dr Véronique PINGAULT


A very rare subtype of Waardenburg syndrome (WS) that is characterized by limb anomalies in association with congenital hearing loss, minor defects in structures arising from neural crest, resulting in pigmentation anomalies of eyes, hair, and skin.

Summary:
Epidemiology
Incidence is unknown, but WS3 is the rarest form of all Waardenburg syndrome types.
Clinical description
WS3 is characterized by the association of limb anomalies (predominantly involving upper limbs, with hypoplasia of the musculoskeletal system, flexion contractures, fusion of the carpal bones, syndactylia) with features of Waardenburg syndrome (see this term), which include congenital sensorineural hearing loss, hypopigmentation abnormalities of irides, hair and skin and minor facial dysmorphism in combination with dystopia canthorum.
Etiology
WS3 is caused by heterozygous or homozygous mutations in the PAX3 (2q36.1) gene.
Diagnostic methods
Diagnosis is made through criteria of the association of WS1 manifestations with limb anomalies. PAX3 gene analysis confirms diagnosis resulting in an abnormality of melanocytes of skin, ears and hair.
Antenatal diagnosis
Antenatal diagnosis is possible for affected parents.
Genetic counseling
The defects are more severe in homozygous than heterozygous forms. Genetic counseling is recommended.
Management and treatment
Hearing aids to counter hearing loss, effective therapy to improve language, communication, and cognitive skill and limbs physiotherapy are recommended. Associated manifestations are treated as appropriate (e.g. skin and eyes protection from the sun).
Prognosis
Due to the very few number of cases described so far, information on prognosis and quality of life is limited. Disease progression is variable, with symptoms being more severe in homozygous than in heterozygous forms.

                            Last update:
                            October 2015

                            - Expert reviewer(s):
                            Dr Véronique PINGAULT


Waardenburg syndrome (WS) is a disorder characterized by varying degrees of deafness and minor defects in structures arising from neural crest, including pigmentation anomalies of eyes, hair, and skin. WS is classified into four clinical and genetic phenotypes.

Summary:
Epidemiology
The worldwide incidence is estimated at around 1/40,000. Waardenburg syndrome type 1 (WS1) and type 2 (WS2) are the most common types of Waardenburg syndrome. Waardenburg syndrome type3 (WS3) and type 4 (WS4; see these terms) are rarer, with only a few cases of WS3 described worldwide so far. WS accounts for about 3% of all institutionalized cases of congenital hearing loss.
Clinical description
Clinical manifestations vary within and between families. Frequent clinical manifestations include congenital sensorineural deafness, heterochromic or hypoplastic blue irides, white forelock or early graying of the scalp hair before the age of 30 years. All these manifestations, along with a suggestive family history are major criteria, as is dystopia canthorum in WS1 and WS3. Minor criteria include congenital leukoderma, synophrys/medial eyebrow flare, broad/high nasal root with prominent columella and hypoplastic alae nasi. WS is defined by the association of at least 2 major, or 1 major and at least 2 minor clinical criteria (early graying of the hair is considered either a major or minor criteria depending of the WS type). WS1 combines these criteria with dystopia canthorum. The absence of dystopia canthorum clinically differentiates WS2 from WS1, whereas WS3 is similar to WS1, but additionally includes upper limb abnormalities. WS4 is characterized as WS2 with added characteristics of Hirschsprung disease.
Etiology
WS is genetically heterogeneous. To date, mutations in 6 different genes have been identified: PAX3 (2q36.1), MITF (3p14-p13), SNAI2 (8q11.21), SOX10 (22q13.1), EDNRB (13q22.3), and EDN3 (20q13.32). Mutations in PAX3 gene are associated with WS1 and WS3, while MITF gene is mutated in cases of WS2. Digenic inheritance of MITF mutation in combination with a TYR mutation (and/or the TYRR402Q hypomorphic allele) has been reported in two families with WS2 and ocular albinism (see this term). Homozygous SNAI2 deletions have been described in two WS2 patients. SOX10 mutations are found in WS4 and WS2 affected patients. Mutations in EDNRB and EDN3 genes have also been reported in WS4.

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                            Dr Véronique PINGAULT


Waardenburg-Shah syndrome (WSS), also known as Waardenburg syndrome type 4 (WS4) is characterized by the association of Waardenburg syndrome (sensorineural hearing loss and pigmentary abnormalities) and Hirschsprung disease (aganglionic megacolon).

Summary:
Epidemiology
Prevalence is unknown. So far, less than 100 cases have been reported in the literature worldwide.
Clinical description
Patients usually present in the neonatal period with pigmentary anomalies (including white forelock, eyebrows and eyelashes, heterochromia of the irides, possibly retinal pigment abnormalities and/or hypopigmented patches on the skin), neurosensory deafness (frequently bilateral, but can be unilateral) and intestinal obstruction presenting as bilious vomiting, inability to pass meconium and abdominal distension since birth. Depending on the gene involved, morphological abnormalities of the temporal bone (especially utricle and semi-circular canals), anosmia (with or without agenesis of the olfactory bulbs) and hypogonadotropic hypogonadism can be associated. ABCD syndrome is a rare variant expression of WSS, characterized by albinism, black lock, cell migration disorder of the gut neurocytes and deafness.
Etiology
WSS is caused by abnormal migration or differentiation of neural crest cells during embryonic development. This syndrome is genetically heterogeneous, composed of three etiological subtypes: WS4-A, WS4-B and WS4-C, caused by mutations in the EDNRB (13q22.3, coding for the endothelin-B receptor), EDN3 (20q13.32, coding for an endothelin receptor ligand) and SOX10 (22q13.1, coding for the SOX10 transcription factor) genes, respectively. These genes are involved in melanocyte development and nerve cells development in the intestine. Heterozygous mutations in EDNRB and EDN3 are often asymptomatic although patients may also present with less severe phenotypes (isolated Hirschsprung disease, isolated deafness, less extended hypopigmentation, or Waardenburg syndrome type 2). Specific mutations in SOX10 (particularly those predicted to truncate the protein at the level of the terminal coding exons) result in a more severe WSS variant with neurologic findings (neurologic Waardenburg-Shah syndrome, also called PCWH).
Diagnostic methods
Diagnosis is determined by the presence of major and minor characteristic clinical features according to the Waardenburg Consortium criteria, as well as history and physical examination for Hirschsprung disease utilizing plain abdominal X-ray, barium enema, anorectal manometry and rectal biopsy. Genetic molecular analysis confirms the diagnosis.
Differential diagnosis
The differential diagnosis includes other forms of Waardenburg syndrome, piebaldism and ermine phenotype, as well as other causes of hearing loss or Hirschsprung disease.
Antenatal diagnosis
Molecular prenatal diagnosis may be proposed to families in which the disease-causing mutation has been identified.
Genetic counseling
Genetic counseling should be adapted according to the mode of inheritance associated with the detected mutation. SOX10 mutations are inherited in an autosomal dominant manner. EDNRB and EDN3 mutations are inherited in an autosomal recessive manner in most families but are semi-dominant in some (with the index case usually carrying bi-allelic mutations, while heterozygous affected relatives present with isolated or milder signs of the disease).
Management and treatment
Management is only symptomatic. Surgical treatment is required for Hirschsprung disease. Hearing aids are recommended to ameliorate hearing impairment, as well as to improve language, communication and cognitive skills. Associated manifestations are treated as appropriate (e.g., cosmetics to manage the pigmentation defects, sunblock and sunglasses to protect skin and eyes from the sun).
Prognosis
The prognosis is often good, however, significant morbidity and mortality may be associated due to complications resulting from Hirschsprung disease (related to the size of the aganglionic intestinal segment).

                            Last update:
                            March 2018

                            - Expert reviewer(s):
                            Dr Véronique PINGAULT


WAC-related facial dysmorphism-developmental delay-behavioral abnormalities syndrome

A rare, genetic, syndromic intellectual disability characterised by several dysmorphic features, hypotonia, developmental delay, intellectual disability, behavioral problems, visual and hearing abnormalities, constipation, and feeding difficulties. Common dysmorphic features include coarse facies, broad forehead, synophrys, bushy eyebrows, deep-set eyes, downslanting palpebral fissures, epicanthus, depressed nasal bridge, bulbous nasal tip, posteriorly rotated ears, full cheeks, thin upper lip, inverted nipples, and hirsutism. Behavioral problems tend to be dominated by ADHD, but anxiety, aggressive outbursts and autistic features may also present.


Wagner disease is a rare hereditary vitreoretinopathy characterized by an anomaleous vitreous associated with myopia, cataract, chorioretinal atrophy, and peripheral tractional or rhegmatogenous retinal detachment.

Summary:
Epidemiology
About 100 patients with Wagner syndrome from only a few pedigrees have been described in the literature.
Clinical description
Affected patients typically exhibit low or moderate myopia, with only a few suffering from severe myopia. The disease has a juvenile onset with progressive nyctalopia and visual field constriction. Presenile cataract is a frequent cause of reduced central visual acuity. The hallmark of the disease is an optically empty central vitreous cavity and the presence of typical peripheral vitreous changes with fibrillary condensations, avascular strands and veils. The peripheral retina is progressively affected by pigmentary changes and chorioretinal atrophy. An abnormal pattern of dragged central retinal vessels (sometimes referred to as inverted papilla) and eventually pseudoexotropia due to an ectopic fovea are a common finding, usually not attributable to peripheral retinal traction. Retinal detachment is a relatively common complication in Wagner disease, the reported incidence rate varying from 7% to 50%. In a few patients, rhegmatogenous retinal detachment is due to flap tears or atrophic holes and occurs typically at a young age. More frequently, peripheral tractional retinal detachment is observed, occuring typically in middle-aged patients. In some cases, anterior chamber angle dysgenesis is observed.
Etiology
Wagner disease is a connective tissue disorder affecting the collagen and is associated with mutations in the CSPG2 or VCAN gene (5q13-q14). CSPG2 encodes chondroitin sulfate proteoglycan-2, also known as versican. Versican constitutes 5-15% of the total protein content of the vitreous gel. It is a large proteoglycan that forms large complexes by binding to hyaluronic acid and other vitreous structural molecules. Erosive vitreoretinopathy (ERVR), originally described as a distinct clinical entity, is an allelic disease, and the same intronic mutation in GSPG2 has been found in a family with ERVR and four families with Wagner disease.
Diagnostic methods
Diagnosis is based on the clinical picture. Molecular testing of CSPG2 mutations confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes Stickler syndrome, Goldmann-Favre disease, Familial Exudative Vitreoretinopahy, and Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) (see these terms).
Genetic counseling
Wagner disease is inherited as an autosomal dominant trait with near complete penetrance but variable expressivity.
Management and treatment
Regular ophthalmologic examinations should be performed. Retinal breaks without retinal detachment are treated by prophylactic laser- or cryocoagulation. For rhegmatogenous retinal detachment in a young patient, scleral buckling surgery or, less often, vitrectomy is performed. Tractional retinal detachment in the middle-aged or elderly patient requires often a combined procedure. Presenile cataract is treated by phacoemulsification and implantation of an artificial intraocular lens.
Prognosis
Overall prognosis seems to be moderate. In the original pedigree described by Wagner, about 50% of the affected members retained a useful vision of more than 20/40 after the age of 60.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Dr Christoph AMSTUTZ


A rare genetic disorder characterized by the association of complete or partial congenital aniridia (and associated eyes abnormalities), genitourinary anomalies (ranging from sexual ambiguity to ectopic testis), variable degrees of intellectual disability and an increased risk of developing Wilms tumors. A minority of patients develop kidney failure. Other variable findings may include obesity and duplicated halluces.

Summary:
Epidemiology
The prevalence of WAGR syndrome is approximately 1/500,000-1,000,000 people. There is no male or female predominance.
Clinical description
The disease has a broad range of clinical manifestations; most affected patients present with ≥ 2 clinical features. Onset is at birth, but it may be diagnosed at a later age, as clinical features can be hard to detect or do not show in many patients. Congenital aniridia of variable severity is almost systematically present at birth, and is often associated with other eye abnormalities such as cataract, glaucoma, limbal insufficiency, optic nerve hypoplasia, and corneal opacification/vascularization, leading to visual impairment. Some patients are at risk of developing end-stage renal disease, especially when presenting with Wilms tumor (45-60% of patients). Bilateral synchronous kidney tumors are the most common (4-7% of all Wilms tumors) and generally present at a younger age than unilateral tumors (< 5 years old). Patients may also present with genitourinary anomalies or neurological abnormalities, and variable intellectual disability or behavioral abnormalities. A large number of affected patients develops obesity. However, WAGR syndrome with childhood-onset obesity is called WAGRO syndrome.
Etiology
WAGR syndrome is a contiguous gene deletion syndrome involving an interstitial de novo 11p13 microdeletion of variable size (from 1 million to 26.5 million base pairs), which explains the variability of clinical signs. The affected genes include PAX6 and WT1. BDNF deletion can be included and is associated to the WAGRO phenotype.
Diagnostic methods
Diagnosis is based on clinical signs and may be delayed as some manifestation develop late or are easier to detect in the adult. Congenital aniridia in infants should prompt genetic testing to detect the specific deletions associated with the patient's phenotype and invalidate or confirm WAGR syndrome.
Differential diagnosis
The main differential diagnoses are isolated aniridia, anterior segment developmental abnormalities of the eye (e.g. Axenfeld-Rieger syndrome, coloboma of iris), aniridia-cerebellar ataxia-intellectual disability syndrome (also called Gillespie syndrome), Frasier syndrome, and Denys-Drash syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible in very rare familial cases when mutations/deletions have been identified.
Genetic counseling
Most cases are sporadic. In rare cases, the syndrome can be inherited in an autosomal dominant manner. In such cases, affected individuals should be offered genetic counseling informing them of the 50% risk of having an affected child at each pregnancy.
Management and treatment
Management and treatment are complex and require a multidisciplinary approach. Supportive measures should be provided for visual impairment and light sensitivity. Medical or surgical intervention may be required for eye abnormalities such as cataract, glaucoma or corneal complications. Surgery, chemotherapy and radiotherapy can be recommended for the treatment of tumors. Patients require lifelong oncological and ophthalmologic monitoring. Transplantation may be required for renal disease. The management of obesity has no specificity. Patients and their family often need psychological support, and patients may be enrolled in special education program.
Prognosis
WAGR syndrome is associated with significant morbidity (vision loss and intellectual disability). The development of Wilms tumors is the main factor of early mortality. With early detection and appropriate treatment, the prognosis is improved.

                            Last update:
                            September 2023

                            - Expert reviewer(s):
                            Pr Dominique BREMOND-GIGNAC | ERN-EYE*

                                * European Reference Network


Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoproliferative disorder characterized by the accumulation of monoclonal cells in the bone marrow and peripheral lymphoid tissues, and associated with the production of serum immunoglobulin M (IgM) monoclonal protein.

Summary:
Epidemiology
WM has an overall incidence of 1/260,000 persons/year in the USA and a prevalence estimate of about 1/102,220 in Europe. It accounts for approximately 2% of all hematological malignancies.
Clinical description
The median age at diagnosis is 72 years and it is twice as frequent in men. The main clinical features are hepatosplenomegaly, lymphadenopathy, constitutional symptoms, oronasal bleeding, hyperviscosity syndrome and cytopenia. Fatigue related to normochromic normocytic anemia is the most common presenting symptom. Visceral infiltration is rare but may target the stomach, small bowel, lungs, exocrine glands or skin, accounting for such symptoms as diarrhea, steatorrhea and purpura of the skin. Retinal hemorrhage or serious neurologic complications (mental confusion, stroke) may occur in cases with hyperviscosity syndrome. Peripheral neuropathy is present in up to 38% of WM patients. Nephrotic syndrome has been associated with WM in a few cases. Major complications include bone marrow failure, autoimmune cytopenia, large B-cell lymphoma, immune complex vasculitis and infections.
Etiology
Exact etiology is unknown. Immune-related factors are thought to be involved and WM clearly has a familial component as first degree relatives of WM patients have an increased risk of developing the disease. No susceptibility genes have yet been identified but susceptibility loci have been mapped to chromosome 6p21.3 and 4q and half of WM patients have 6q deletions on tumor cells. A highly recurrent MYD88 (3p22) somatic mutation (L265P) has recently been identified in 90% of WM patients.
Diagnostic methods
Diagnosis is confirmed by the presence of an IgM monoclonal protein in the serum and a bone marrow biopsy (showing ≥10% clonal lymphoplasmacytic cells). WM's pathologic designation is lymphoplasmacytic lymphoma according to the WHO Classification of Tumors. Cells test negative for CD3 and CD103 markers but express pan B cell markers CD19 and CD20. The median hemoglobin value seen at diagnosis is 10g/dL. Serum protein electrophoresis and immunofixation as well as computed tomography (CT) of abdomen and pelvis contribute to diagnosis. Splenomegaly and/ or lymphadenopathies are observed in 30% of the patients.
Differential diagnosis
Differential diagnoses include multiple myeloma, B-cell chronic lymphocytic leukemia, other forms of non-Hodgkin lymphoma (see these terms), and monoclonal gammapathies of undetermined significance. Infections like hepatitis, AIDS, and various rheumatological disorders also raise IgM levels. The presence of a MYD88 L265P mutation distinguishes WM from other closely-related B-cell chronic lymphoproliferative disorders such as marginal zone lymphoma without IgM spike.
Management and treatment
There is no cure for WM. Patients in an asymptomatic stage are simply monitored. Treatments given to symptomatic patients depend on many factors (e.g. age, disease progression) and can include alkylating agents, purine nucleoside analogs, rituximab (RT) and bortezomib. Initial treatment is usually an RT-based therapy like RT plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or dexamethasone, RT and cyclophosphamide (DRC). Bortezomib-based therapies are used when rapid disease control is needed or for patients who are candidates for autologous stem cell transplantation (ASCT). For those with profound cytopenias, DRC or RT is preferable. Salvage treatments can involve the use of the initial agents or agents of a different class, alone or combined. A PNA-based regimen or ASCT may be suitable for some as a salvage treatment option. Ibrutinib, a B-cell receptor pathway inhibitor, has recently been approved for symptomatic WM patients as a first-line treatment, particularly for those who are not candidates for chemo-immunotherapy, and in relapsing patients.
Prognosis
Median survival time is 5-6 years after starting treatment but WM can be stable or progress slowly for many years before needing treatment.

                            Last update:
                            March 2016

                            - Expert reviewer(s):
                            Pr Véronique LEBLOND


A rare form of congenital muscular dystrophy (CMD) associated with severe brain and eye abnormalities. It is the most severe form of CMD.

Summary:
Epidemiology
The incidence is estimated at 1-2/100,000 live births. Walker-Warburg Syndrome (WWS) has a worldwide distribution.
Clinical description
Patients present with global developmental delay, intellectual disability, generalized severe hypotonia, muscle weakness, seizures, and various eye defects which include microphthalmia, microcornea, lens defects, cataract, shallow anterior chamber, atrophy of the optic nerve, coloboma, glaucoma or buphthalmos. Brain MRI shows type II cobblestone lissencephaly in all cases, and may also show hydrocephalus, encephalocele, severe brainstem, and cerebellar hypoplasia with possible Dandy-Walker malformation. The corpus callosum is absent in some patients. White matter abnormalities can also be observed. Other urogenital or facial dysmorphic features can be found in rare patients.
Etiology
This disease caused by abnormal O-glycosylation of alpha-dystroglycan leading to brain abnormalities and congenital muscular dystrophy. At least 14 genes have been implicated in the etiology of WWS, and others are yet unknown. The most common mutations are found in Protein O-Mannosyltransferase 1 and 2 (POMT1 and POMT) genes, FKTN, and FKRP genes. LARGE and POMGNT1 genes from the alpha-dystroglycan glycosylation pathway were also linked to this disease. A mutation in the COL4A1 gene not directly related to posttranslational modification of dystroglycan has also been identified in some WWS patients without associated muscle involvement.
Diagnostic methods
Diagnosis is based on ultrasonography and fetal MRI for ocular and brain abnormalities. Laboratory investigations usually show elevated creatine kinase and myopathic/dystrophic muscle pathology with altered alpha-dystroglycan expression.
Differential diagnosis
Differential diagnoses include other types of congenital muscular dystrophies and myopathies with type II lissencephaly. Trisomy 13, 18 and many congenital syndromes with malformations of the brain also have similar clinical manifestations. Some in utero infections can also be associated with hydrocephaly, intrauterine growth restriction, and cataract.
Antenatal diagnosis
Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound after 22-25 weeks of gestational age (WGA) and fetal MRI at 30 WGA may be helpful for diagnosis in families where the molecular defect is unknown.
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
No specific treatment is available. Management is only supportive and preventive. Surgery is required in some patients for the treatment of hydrocephalus or encephalocele.
Prognosis
WWS is the most severe form of congenital muscular dystrophy. It is generally lethal in the first few months of life with most children dying before the age of three years.

                            Last update:
                            January 2023

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

                                * European Reference Network


WARS2-related combined oxidative phosphorylation defect

A rare mitochondrial oxidative phosphorylation disorder characterized by a spectrum of three main clinical phenotypes comprising a severe neonatal phenotype with early fatal lactic acidosis, a more protracted course with early-onset developmental delay, motor weakness, extrapyramidal signs, and with or without epilepsy, and a phenotype with normal early development and Parkinson-like symptoms starting around the age of one year. Additional, variably reported, signs and symptoms include cardiomyopathy, optic anomalies, hepatosplenomegaly, and abnormal brain MRI findings, among others. Deficiencies in mitochondrial oxidative phosphorylation enzymes are inconsistent.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by pre- and postnatal growth restriction, microcephaly, mild to severe intellectual disability, sensorineural hearing loss with cochlear abnormalities, and facial dysmorphism (with small and elongated face, bifrontal narrowing, epicanthus, short nose, small nares, dysplastic ears, and short neck). Additional variable features include limb malformations, cardiac anomalies, abnormal skin pigmentation, and recurrent infections, among others.


A rare primary lymphedema characterized by extensive, multisegmental lymphedema, associated with persistent, widespread infections with various genital high- and low-risk human papillomaviruses, resulting in multifocal anogenital dysplasia. Laboratory examination shows abnormalities in lymphocyte subsets, in particular CD4+ T-cells. Epidermal nevi and capillary malformations have also been reported.


A rare, benign, epidermal disease characterized by a solitary, asymptomatic, verrucous, skin-coloured to red-brown papule or nodule, which contains a central pore and keratotic plug, occuring most frequently on the scalp, face and neck (rarely, in the mouth, under the nail plate or on the mons pubis). Occasionally, lesions may be multiple and/or pruritic. Histologically, a well-circumscribed, cup-shaped, keratin-filled invagination, with prominent acantholytic dyskeratosis, suprabasilar clefts and villi projecting into the clefts, is observed.