A rare autoimmune bullous skin disease characterized by acquired, subepidermal tense bullae occurring on normal of inflamed skin and that is typically widespread (occurring in the flexor regions of the proximal arms and legs, in the armpits, groin and the abdomen) and often associated with pruritus. The evolution is typically chronic with spontaneous exacerbations and remission.

Summary:
Epidemiology
Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. It has an estimated prevalence of 1/4,000 in Europe. The incidence is reported to be increasing but currently ranges between 2-22/1,000,000 worldwide.
Clinical description
BP predominantly affects the elderly with an average age of 80 years and is significantly associated with neurological disorders. Some cases have also been described in children and young adults. The disease is characterized clinically by tight, often large, bullae with a clear content, developing primarily on the edge of erythematous plaques. Intense itching is common. Some patients may have mucosal involvement (10-20% of cases). The rare infantile forms differ from the adult form by its palmo-plantar involvement, especially in children under 1 year of age, and its greater frequency of mucosal involvement.
Etiology
BP is immunologically characterized by the production of autoantibodies directed against two structural proteins found in the dermal-epidermal junction and ensuring dermal-epidermal cohesion: BP antigen 1 (BPAG1 or AgBP230), and BP antigen 2 (BPAG2, AgBP180 or collagen XVII). The binding between the autoantibodies and these proteins leads to the separation between the dermis and the epidermis and the formation of blisters. Some drugs are associated with the onset of BP (diuretics, antiarrhythmics, neuroleptics, gliptins, immunotherapies).
Diagnostic methods
The diagnosis is based on clinical features and skin biopsy showing typical light microscopy findings (subepidermal bullae containing eosinophils and/or neutrophils, associated with a dermal infiltrate of eosinophils and /or neutrophils, or a marginalization of eosinophils along the dermal-epidermal junction) and positive direct immunofluorescence microscopy findings (linear deposits of IgG and/or C3 along the dermal-epidermal junction). Blood samples are also needed in order to search for circulating IgG anti-basement membrane autoantibodies by indirect immunofluorescence microscopy studies and anti-BP180 IgG antibodies and anti-BP230 IgG antibodies by ELISA.
Differential diagnosis
The main differential diagnoses are some forms of acquired bullous epidermolysis and anti-P200 pemphigoid. BP with mucosal involvement may look like mucous membrane pemphigoid even if mucosal involvement is rarely predominant in BP.
Management and treatment
Systemic corticosteroids (CS) (prednisone: 0.5-1 mg/kg/day) is referred as the standard treatment in most countries. The European consensus for first line treatment is with super-potent topical corticosteroids to the whole-body surface sparing the face, or applied to lesions only where the disease is localized/limited, and is followed by a maintenance or tapering schedule as required. In patients with recalcitrant BP and in those with multiple relapses, immunosuppressive drugs (methotrexate, mycophenolate mofetil) are usually used. Doxycycline can be used, especially in patients with contraindications to immunosuppressive drugs or in poor general condition. Recently, new therapeutics have been tested in particular rituximab and omalizumab whose indications remain as yet unclear.
Prognosis
BP is a serious disease. In some cases, the prognosis for BP patients is poor.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Marion CASTEL | ERN-Skin* - Pr Pascal JOLY | ERN-Skin*

                                * European Reference Network


A rare subtype of pyoderma gangrenosum disease characterized by grouped vesicles that rapidly spread and coalesce to form large bullae, which evolve into ulcerations that have an erythematous peripheral halo and central necrosis, mainly affecting the upper limbs and face. Lymphoproliferative diseases are frequently associated, thus prognosis is often compromised.


Burkitt lymphoma is a rare form of malignant mature B-cell non-Hodgkin lymphoma.

Summary:
Epidemiology
In Europe and north America it represents around half of all malignant non-Hodgkin lymphoma in children and around 2% in adults. Two incidence peaks occur: one in childhood/adolescence and the second after the age of 40 years. In Europe the standardized incidence ratio is 1/530,000 for individuals aged between 0 and 14 years and 1/670,000 for individuals aged between 15 and 19 years. Males are affected more than females.
Clinical description
Patients with HIV in whom antiviral treatment is ineffective are particularly susceptible to Burkitt lymphoma. Two forms of the disease exist: an `endemic' form (sub tropical Africa) linked to the Epstein Barr virus (EBV) that presents classically in the form of a maxillary tumor (an abdominal tumor is often present, particularly in older children), and a `sporadic' form not linked to EBV that develops mainly in the abdomen. Burkitt lymphoma can also develop in the ear, nose and throat and more rarely in other locations (orbit, kidney, bone). The tumor is very proliferative and secondarily invades the bone marrow (in about 35% of cases) and the central nervous system (in about 15% of cases). It has the appearance of tumoral meningitis or paralysis of the cranial nerves. Burkitt leukemia, with the clinical characteristics of other types of leukemia, is possible. The tumors develop from the digestive tract (mainly the intestine) and extend to the peritoneum and sometimes also the liver, pancreas, spleen, kidneys or ovaries. The most frequent clinical signs are abdominal pain, nausea, an alteration of general state and/or the appearance of lymph nodes and tumors.
Etiology
In most cases Burkitt lymphoma is associated with a specific translocation t(8;14)(q24;q32) that juxtaposes the MYC/c-Myc gene (8q24) next to the heavy chain immunoglobulin gene (14q32). In rare cases the translocation affects chromosome 2 (kappa chain in immunoglobulins) or 22 (lambda chain in immunoglobulins). The cells express surface immunoglobulins and B differentiation markers (CD19, CD20). The proliferation index of the tumor is extremely high (Ki67 > 95%). EBV influences the genesis of the endemic form of Burkitt lymphoma but the mechanisms responsible are not well understood.
Diagnostic methods
Diagnosis is based on biopsy of a mass, an effusion puncture or bone marrow that reveals the presence of tumor cells. The extent of the tumor can be evaluated using images (mainly ultrasound and scanning).
Differential diagnosis
Differential diagnoses include other forms of abdominal tumors in children (Wilms tumor and neuroblastomas, although these are retroperitoneal, and desmoplastic tumors; see these terms) and other types of lymphoma and leukemia of B and T precursors in cases with bone marrow involvement.
Management and treatment
Management should be carried out in a specialist oncology/hematology centers. Treatment is with a few months of intensive chemotherapy. The efficacy of rituximab has not yet been proven but it is the subject of several clinical trials. Burkitt lymphoma constitutes a therapeutic emergency. The key to curing the disease is a combination of rapid and individualized management (particularly adapted to the frequent metabolic problems that occur at the start of treatment) and appropriate anti-tumor treatment.
Prognosis
The current cure rate is in the order of 80-90% thanks to a difficult but relatively short treatment that is without long term sequelae.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Dr Catherine PATTE


A rare multiple congenital anomaly syndrome characterized by bilateral choanal atresia associated with characteristic cranio-facial dysmorphisms (hypertelorism with narrow palpebral fissures, coloboma of inferior eyelid with presence of eyelashes medial to the defect, prominent nasal bridge, thin lips, prominent ears), that can be accompanied by hearing loss, unilateral cleft lip, preauricular tags, cardiac septal defects and anomalies of the kidneys. Affected individuals have normal intelligence.

Summary:
Epidemiology
To date, approximately 20 families have been reported worldwide.
Clinical description
Affected individuals present with dysmorphic features from birth onwards. Bilateral choanal stenosis/atresia is potentially life threatening, and may present with respiratory distress at birth. Most patients have lower eyelid defects that can result in corneal exposure and drying. Hearing loss is frequently observed (70% of patients). Cleft lip/palate (approximately 60%) can be uni- or bilateral. Cardiac defects (approximately 30%) include persistent ductus arteriosus (PDA) and patent foramen ovale. Short stature is uncommon but when present is proportionate and mild. Intelligence is typically normal, although intellectual disability has been reported.
Etiology
The disease is usually caused by a loss of function mutation in TXNL4A (18q23) on one allele and a promotor deletion of TXNL4A on the second allele. Only one family has been described with a homozygous promotor deletion. It is still unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. A few patients are associated with mutations in POLR1A (2p11.2).
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by sequencing of the promotor and coding region of TXNL4A.
Differential diagnosis
The features of this syndrome overlaps with those of the CHARGE and Treacher Collins syndromes.
Antenatal diagnosis
Theoretically, prenatal diagnosis is possible if there is a positive family history. It is very unlikely that the diagnosis will be prenatally established without a positive family history.
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
Intubation is required for neonates presenting with respiratory distress. Surgery is required for choanal atresia. Multidisciplinary referral for evaluation of the possible ophthalmological, audiological, maxillofacial and cardiac anomalies is required. Hearing loss, eye and cardiac defects are managed according to routine procedures. The facial dysmorphism might warrant psychological therapy.
Prognosis
Quality of life is reduced due to choanal atresia, hearing loss and facial dysmorphism. Life expectancy is not reduced.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Dagmar WIECZOREK | ITHACA*

                                * European Reference Network


A rare neurologic disease characterized by an unremitting bilateral symmetrical burning sensation of the oral mucosa without clinical evidence of causative lesions. It most frequently occurs in postmenopausal women and typically affects the tongue, less often the palate, lips, or buccal mucosa. It is often associated with dysgeusia and xerostomia.


A rare patterned dystrophy of the retinal pigment epithelium characterized by abnormal accumulation of lipofuscin in a butterfly-shaped distribution at the retinal pigment epithelium level. Patients manifest with a slowly progressive loss of vision that often only becomes apparent in old age.


BVES-related limb-girdle muscular dystrophy

A rare subtype of autosomal recessive limb-girdle muscular dystrophy characterized by atrioventricular block resulting in repeated syncope episodes, elevated creatine kinase serum levels and adult-onset of slowly progressive proximal limb skeletal muscle weakness and atrophy. Muscular dystrophic changes observed in muscle biopsy include diameter variability, increased central nuclei, and presence of necrotic and regenerating fibers.


A rare autosomal dominant ectodermal dysplasia syndrome characterized by premolar aplasia, hyperhidrosis, and premature graying of the hair. Additional features may include a narrow palate, hypoplastic nails, eyebrow anomalies, a unilateral simian crease, and poorly formed dermatoglyphics.


C syndrome is a rare multiple congenital anomaly/intellectual disability syndrome characterized by trigonocephaly and metopic suture synostosis, dysmorphic facial features, short neck, skeletal anomalies, and variable intellectual disability.

Summary:
Epidemiology
The prevalence has been estimated to be between 1/800,000 and 1/1,000,000. Less than 60 cases have been reported so far.
Clinical description
C syndrome is a congenital disorder characterized by trigonocephaly, dysmorphic craniofacial features that include upslanting palpebral fissures, thick epicanthic folds, strabismus, depressed nasal bridge with short/thick nasal septum and columella, flat philtrum, thin vermilion borders, micrognathia, highly arched palate, buccal-gingival frenula, and multiple minor ear anomalies along with frontal midline capillary hemangioma. Cleft palate (see this term) is an occasional finding. The neck is apparently short, but this appears to be related to residual nuchal lymphedema, which may be generalized. Skeletal defects include short rhizo- and acromelic limb segments, hypermobile elbows with crepitus, polydactyly (usually postaxial), syndactyly (see these terms) of toes, sacral dimple and deformed chest. Intellectual disability may be severe, but normal intelligence quotient (IQ) has also been described in a few patients. Seizures and neonatal hypotonia have also been reported. Additional anomalies may include congenital heart malformations (50% of cases, and include interauricular communication, ventricular septal defect, tetralogy of Fallot, Eisenmenger syndrome), hernia (in particular diaphragmatic hernia), renal malformations (unilateral renal agenesis, multicystic dysplastic kidney or horseshoe kidney) (see these terms), genital anomalies (enlarged clitoris, small penis), and anal stenosis. Perinatal mortality rate appears to be around 50%.
Etiology
The etiology of C syndrome is still unknown.
Genetic counseling
Although most of the reported patients are sporadic, rare cases of familial occurrence have been described. Reports of recurrence in sibs with unaffected parents suggest that familial cases may be caused by germinal mosaicism. As recurrence in siblings has been reported, subsequent pregnancies in affected families should be monitored.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Pr John OPITZ


C11ORF73-related autosomal recessive hypomyelinating leukodystrophy

A rare leukodystrophy characterized by infantile onset of lower limb spasticity and severe developmental delay associated with delayed myelination and periventricular white matter abnormalities. Other reported signs and symptoms include microcephaly, optic atrophy, nystagmus, ataxia, or seizures.


A histological subtype of C3 glomerulopathy characterized by C3 deposition in renal tissue in the absence or near-absence of immunoglobulin deposits, in a patient with the classic clinical features of glomerulonephritis and the electron microscopic findings of predominant subendothelial, occasionally subepithelial (so-called ''humps''), and intramembranous deposits, but without the typical electron-dense deposits of dense deposit disease.


A form of primary membranoproliferative glomerulonephritis characterized by the presence in renal biopsy samples of a glomerulonephritis with sole (or at least dominant) glomerular immunofluorescence staining for C3. Non-specific alterations or proliferative patterns with C3-dominant glomerular staining are also possible. Based upon electron microscopic findings, C3 glomerulopathy (C3G) may be further classified as C3 glomerulonephritis (C3GN) or Dense deposit disease (DDD).

Summary:
Epidemiology
The estimated incidence of CG3 is 1/300,000-1,000,000. C3G appears to affect both genders equally.
Clinical description
Features of DDD tend to appear earlier than those of C3GN, usually in adolescence. However, the signs and symptoms of either disease may not begin until adulthood. All patients with C3G have proteinuria and/or hematuria; proteinuria is variable and may be nephrotic range. Patients with C3G have variable degrees of azotemia at presentation and variable rate of kidney function decline. Hypertension may be present. Occasionally, rapidly progressive (crescentic) glomerulonephritis develops. Initial clinical manifestations of C3G may be preceded by upper respiratory tract infection. Many patients with DDD, and occasionally patients with C3GN, develop drusen in Bruch's membrane of the retina. Acquired partial lipodystrophy may be noted in DDD. Serum C3 levels are typically low in C3G and other complement abnormalities may be present (e.g. elevated serum levels of sC5b-9). Serum levels of classical pathway components are usually normal, although serum C4 levels may be low in a minority at some point in the disease course. C3 nephritic factor (C3NeF) is found in approximately 80% of patients with DDD and 40% of patients with C3GN.
Etiology
Whilst the pathophysiology is not fully elucidated, dysregulation of the alternative complement pathway is well documented: low serum C3 levels associated with C3NeF are observed in most patients and a few carry auto-antibodies against complement factor H (FH) or B (FB), or mutations in complement genes (including Complement Factor H Related genes (CFHR1, 2, 3, 5), CFH and C3). Mutations in combination with common susceptibility variants are also associated with an increased risk of C3G. In patients with underlying defects in the alternative complement pathway, C3G may be triggered by a common infection.
Diagnostic methods
The diagnosis of C3G is made by kidney biopsy in a patient with suspected glomerulonephritis, and is established on histopathology findings of C3 accumulation in renal tissue in the absence, or near-absence of immunoglobulin deposits. Electron microscopy is necessary to further categorized C3G into DDD and C3GN.
Differential diagnosis
The differential diagnosis includes almost all causes of acute glomerulonephritis and nephrotic syndrome in addition to atheroembolic disease, complement-mediated thrombotic microangiopathy and acute postinfectious glomerulonephritis.
Genetic counseling
Familial cases of C3G with a monogenic cause are rare. In sporadic cases, genetic variants are reported in about 20%, although the pathogenicity of these variants is unknown. When a variant is identified, genetic testing is recommended for family members.
Management and treatment
Currently, there are limited evidence-based guidelines to inform therapeutic decisions. General measures in all patients with C3G include blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. As for those with primary C3G and nephritic-nephrotic phenotype, numerous therapeutic regimens have been tried, including the use of corticosteroids and immunosuppressants, plasmapheresis and plasma exchange. Various different treatment regimens have been reported (MMF and glucocorticoids, rituximab, and eculizumab) but the results are limited. In patients with evidence of alternative pathway of complement dysregulation, particularly if the above approach has not been successful, the use of complement inhibitory agents may be reasonable. Treatment with these agents, particularly with eculizumab, has only proven effective in approximately one-third of patients. Further agents acting upstream, at the C3 convertase level, need to be investigated in clinical trials.
Prognosis
Progression to end stage kidney disease occurs within 10 years of diagnosis in ~70% of affected children and 30-50% of affected adults. Disease recurrence in kidney transplants contributes to allograft loss in ~50% of patients within 10 years of transplantation.

                            Last update:
                            August 2021

                            - Expert reviewer(s):
                            Dr Erica DAINA | ERKNet* - Dr Marina VIVARELLI | ERKNet*

                                * European Reference Network


A new leukoencephalopathy, the CACH syndrome (Childhood Ataxia with Central nervous system Hypomyelination) or VWM (Vanishing White Matter) was identified on clinical and MRI criteria. Classically, this disease is characterized by (1) an onset between 2 and 5 years of age, with a cerebello-spastic syndrome exacerbated by episodes of fever or head trauma leading to death after 5 to 10 years of disease evolution, (2) a diffuse involvement of the white matter on cerebral MRI with a CSF-like signal intensity (cavitation), (3) a recessive autosomal mode of inheritance, (4) neuropathologic findings consistent with a cavitating orthochromatic leukodystrophy with increased number of oligodendrocytes with sometimes ``foamy'' aspect.

Summary:
Epidemiology
A total of 148 cases have been reported so far. Prevalence of this disease remains unknown.
Clinical description
Clinical symptoms are variable, from fatal infantile forms (Cree leukoencephalopathy) and congenital forms associated with extra-neurological affections, to juvenile and adult forms (ovarioleukodystrophy) characterized by cognitive and behavioural dysfunctions and by a slow progression of the disease, leading to the term of eIF2B-related leukoencephalopathies.
Etiology
This disease is linked to mutations in the five EIF2B genes encoding the five subunits of the eukaryotic initiation factor 2B (eIF2B), involved in the protein synthesis and its regulation under cellular stress. The patho-physiology of the disease would involve a deficiency in astrocytes maturation leading to an increased susceptibility of the white matter to cellular stress.
Diagnostic methods
Diagnosis relies on the detection of eIF2B mutations, predominantly affecting the EIF2B5 gene. A decrease in the intrinsic activity of the eIF2B factor (the guanine exchange activity, GEF) in lymphoblasts from patients seems to have a diagnostic value.
Management and treatment
No specific treatment exists besides the ``prevention'' of cellular stress. Corticosteroids sometimes proved to be useful in acute phases.
Prognosis
Prognosis seems to be correlated with the age of onset, the earliest forms being more severe.

                            Last update:
                            September 2007

                            - Expert reviewer(s):
                            Pr Odile BOESPFLUG-TANGUY  - Dr Anne FOGLI  - Pr Pierre LABAUGE  - Dr Florence NIEL BUETSCHI  - Pr Diana RODRIGUEZ


A rare congenital disorder of glycosylation caused by mutations in the CAD gene and characterized by epileptic encephalopathy, global developmental delay, normocytic anemia and anisopoikilocytosis. Loss of acquired skills in early childhood is present and natural disease course can be lethal in early childhood.


CADDS is a rare, genetic, neurometabolic disease characterized by severe intrauterine growth retardation, failure to thrive, profound neonatal hypotonia, severe global development delay, elevated very long chain fatty acids in plasma, and neonatal cholestasis leading to hepatic failure and death. Other features include ocular abnormalities (e.g. blindness and cataracts), sensorineural deafness, seizures, and abnormal brain morphology (notably delayed CNS myelination and ventriculomegaly).


Caffey disease is an osteosclerotic dysplasia characterized by acute inflammation with massive subperiosteal new bone formation usually involving the diaphyses of the long bones, as well as the ribs, mandible, scapulae, and clavicles. The disease is associated with fever, irritability pain and soft tissue swelling, with onset around the age of 2 months and resolving spontaneously by the age of 2 years. However, prenatal disease onset has also been described.

Summary:
Epidemiology
To date <100 cases have been described in the literature.
Clinical description
Caffey disease is characterized by periosteal new bone formation which leads to cortical thickening (hyperostosis) of the affected bone. The bone lesions are often asymmetric with a characteristic involvement of the mandible (70-90% of cases), clavicle, ribs and scapula (20-30%), skull, ilium, long bones. Typically the disease presents with fever and/or pallor, joint swelling (adjacent to involved bones), pain and irritability between birth and age 5 months (average age of onset is 9 weeks). When the mandible is affected, infants may refuse to eat, leading to failure to thrive. The pain may be severe enough to result in pseudo paralysis and individual nerve involvement may result in true localized palsies. The swelling becomes wood hard and fixes to underlying tender bone, but edematous soft tissue remains freely mobile and is never discolored. A prenatal form exists that presents before 35 weeks gestation and is potentially lethal. It is characterized by corticial hyperostosis, bowing or angulation of the long bones and presence of polyhydramnios and fetal lung disease.
Etiology
Autosomal dominant Caffey disease is caused by a mutation in the COL1A1 gene (17q21.33). Additional genetic or environmental conditions may be required for the manifestation of the disease. In addition to the autosomal dominant form, several Caffey cases have been described, in which no COL1A1 mutation could be identified.
Diagnostic methods
Diagnosis is based on clinical features and radiologic findings of subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses), ribs, scapulae, clavicles, and mandible in a child age 2 months to 5 years. Magnetic resonance imaging of bone can also detect inflammatory signals in adjacent muscle, connective tissue, and in the bone marrow. Laboratory findings include elevated erythrocyte sedimentation and alkaline phosphatase levels along with increased C-reactive protein and immunoglobulin levels. Diagnosis is confirmed by genetic screening.
Differential diagnosis
Differential diagnosis includes osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, mucopolysaccharidosis type 2 and Hurler syndrome (see these terms), non-accidental childhood injury, hypervitaminosis A, prostaglandin E1 exposure, bone malignancies, osteomyelitis and parotitis.
Antenatal diagnosis
Prenatal and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family. On rare occasions, hyperostosis can be detected by ultrasound late in the 3rd trimester of pregnancy, even for the autosomal dominant form.
Genetic counseling
Caffey disease either occurs sporadically or is inherited in an autosomal dominant manner with incomplete penetrance. The prenatal form is thought to be inherited in an autosomal recessive manner.
Management and treatment
Management is mainly supportive and includes use of non-steroidal anti-inflammatory drugs or corticosteroids to improve inflammation and pain, antipyretics, and analgesics in the short term to decrease fever and to relieve pain. Yearly evaluation of linear growth, dental health, joint range of motion re-extensibility, possible hernias and fracture history is recommended.
Prognosis
Caffey disease usually has a favorable prognosis as it spontaneously resolves by the age of 2 years. However, the disease sometimes recurs in childhood or adolescence. Moreover, adults who had Caffey disease in childhood may manifest joint laxity, skin hyperextensibility, hernias, and an increased risk for bone fractures and/or deformities.

                            Last update:
                            April 2015

                            - Expert reviewer(s):
                            Pr Harald JÜPPNER


A rare, superficial fibromatosis characterized by non-malignant, locally invading, fibrosing tumour of differentiated fibroblasts, slowly growing subcutaneously, occurring predominantly distally on the extremities, especially the hands and feet. Histologic examination shows a multinodular pattern with large areas of calcification and fibrosis, and the presence of elongated spindle cells with hyperchromatic plump vesicular nuclei interspersed within fine bands of collagen.


A rare, life-threatening, non-inflammatory vasculopathy characterized clinically by progressive and painful skin lesions associated with calcification of cutaneous arterial microvessels. Calciphylaxis predominantly affects patients with end-stage kidney disease (ESKD) on dialysis.


A rare vascular calcification disorder typically characterized by occlusion of microvessels in the cutaneous tissue resulting in painful cutaneous lesions. The disorder is often life-limiting.

Summary:
Epidemiology
Calciphylaxis typically affects patients with end-stage kidney disease (ESKD) treated with dialysis. Incidence amongst patients on hemodialysis varies worldwide, ranging from 0.35 % in the USA to less than 0.03% in Japan. A report suggests an increasing incidence in the USA. The incidence in kidney-transplant recipients and in patients without ESKD, including among those with earlier stages of chronic kidney disease, is unknown. Approximately 60 to 70% of patients with calciphylaxis are women.
Clinical description
The average age at the time of diagnosis is reported between 50 to 70 years; very few patients are children. Patients with calciphylaxis typically present with painful skin lesions. The pain is typically severe and there is associated tactile hyperesthesia. The initial manifestations may include skin induration, plaques, nodules, livedo, or purpura. The initial lesions rapidly progress to stellate ulcers with black eschars. Sepsis originating from the resultant wounds is considered the most common cause of death. Rarely, diffuse precipitation of calcium in viscera occurs (mainly in the heart or lungs, but also in the stomach or kidneys) which may lead to fibrosis and thrombosis, and eventually 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. More than 70% of patients with calciphylaxis require hospitalization for severe ulcers.
Etiology
The exact pathogenesis of calciphylaxis remains unclear. In addition to ESKD, warfarin use has been described as a major risk factor for calciphylaxis.
Diagnostic methods
Diagnosis is suspected on clinical presentation. Skin biopsy may facilitate exclusion of conditions that mimic calciphylaxis.
Differential diagnosis
Differential diagnosis includes warfarin necrosis, peripheral arterial disease, and oxalosis.
Management and treatment
There is no approved treatment for calciphylaxis. Treatment focuses on pain control, wound management, and mitigation of risk factors. Off label treatments like sodium thiosulfate are frequently used clinically.
Prognosis
Quality of life of patients with calciphylaxis is extremely poor. Once calciphylaxis develops then the patients suffer from substantial morbidity related to pain, wounds and limited mobility, and many die within the first year of disease onset.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                            Dr Sagar NIGWEKAR


Calpain-3-related limb-girdle muscular dystrophy D4

A rare autosomal dominant limb-girdle muscular dystrophy characterized by adult onset of proximal muscle weakness, pain, and wasting predominantly affecting the proximal leg, lumbar paraspinal, and medial gastrocnemius muscles. Upper limb involvement may also be observed in some cases. Serum creatine kinase is often, but not always, elevated, and muscle biopsy shows non-specific myopathic changes. The severity of the disease is variable, although most patients remain ambulatory.


Calpain-3-related limb-girdle muscular dystrophy R1

A subtype of autosomal recessive limb girdle muscular dystrophy characterized by a variable age of onset of progressive, typically symmetrical and selective weakness and atrophy of proximal shoulder- and pelvic-girdle muscles (gluteus maximus, thigh adductors, and muscles of the posterior compartment of the limbs are most commonly affected) without cardiac or facial involvement. Clinical manifestations include exercise intolerance, a waddling gait, scapular winging and calf pseudo-hypertrophy.


Calvarial doughnut lesions-bone fragility syndrome

A rare primary bone dysplasia with decreased bone density disorder characterized by multiple doughnut-shaped hyperostotic or osteosclerotic calvarial lesions (manifesting with cranial lumps) associated with numerous pathologic fractures, elevated serum alkaline phosphatase levels and osteopenia.


A disorder that is characterised by the association of a non-progressive congenital ataxia, severe intellectual deficit, optic atrophy and structural anomalies of the skin vessels. It has been described in five children from a large consanguineous Lebanese family. Short stature and microcephaly were also reported. Transmission is autosomal recessive.


Campomelia, Cumming type, is characterized by the association of limb defects and multivisceral anomalies.

Summary:
Epidemiology
The syndrome has been reported in eight infants from four different families.
Clinical description
Skeletal features include tetramelic campomelia and short long bones. Extraskeletal manifestations may include cervical lymphocele, generalized hydrops, polycystic kidneys, pancreas and liver, fibrotic liver or pancreas, polysplenia, heterotaxia (see this term), lung hypoplastia, short bowel. All newborns reported so far were either stillborn or died shortly after birth.
Genetic counseling
In one of the affected families, three sibs with identical features born to first-cousin parents have been reported, suggestive of autosomal recessive mode of inheritance.

                            Last update:
                            July 2009

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM


A rare skeletal dysplasia characterized by peculiar facial anomalies, Pierre Robin sequence, cleft palate, shortening and bowing of long bones. Sexual ambiguity or female external genitalia is possible in individuals with a male karyotype.

Summary:
Epidemiology
Although epidemiological data is limited, prevalence at birth has been suggested at approximately 1/40,000-80,000.
Clinical description
The clinical features include a relatively large head, Pierre Robin sequence with cleft palate, flat face, laryngotracheomalacia, respiratory distress, 11 pairs of ribs, ambiguous genitalia or normal female external genitalia in an individual with a 46,XY karyotype. It also includes dislocated hips, short bowed femura and tibiae (lower limbs more frequently than upper limbs), pretibial skin dimples (bowing of the lower leg is often associated with a skin dimple over the apex of curve) and clubfeet. A few cases of a variant syndrome, referred to as ``acampomelic campomelic dysplasia'' have been described. This variant can be distinguished by the lack of long bone curvature. Many infants die in the neonatal period; additional problems identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive kyphoscoliosis, and hearing impairment. In some cases developmental delay is described.
Etiology
The disorder is autosomal dominant; however, most cases are due to heterozygous de novo mutations in the SOX9 gene (localized to 17q24). In rare individuals the disorder is caused by chromosomal recombination (deletion or translocation) involving the region 17q24.
Diagnostic methods
Diagnosis in based on peculiar facial anomalies (flat face, long philtrum, micrognathia), short stature and specific radiological findings (bowed femura and tibiae, dislocated hip, hypoplastic scapulae, hypoplastic and nonmineralized thoracic vertebral pedicles).
Differential diagnosis
In the prenatal period, differential diagnoses include osteogenesis imperfecta type 2 and 3, hypophosphatasia and thanatophoric dysplasia and Stuve-Wiedemann syndrome; after birth, spondyloepiphyseal dysplasia congenita (SEDC), diastrophic dysplasia and Larsen syndrome may be considered.
Antenatal diagnosis
Diagnosis is generally suspected prenatally during the second trimester ultrasound examination, based on the observation of delayed growth associated with bowed femura and tibiae. Prenatal genetic testing can be performed through chorionic villus sampling or amniocentesis when there is a suspicion of the diagnosis or in familial cases where an abnormality of the chromosomal region has already been identified.
Genetic counseling
Most cases arise sporadically and in these cases the recurrence risk in siblings of a proband is at estimated 2% (due to germline mosaicism). Approximately 5% of cases are a result of chromosomal recombination involving the region 17q24 and, in rare cases, there may be familial transmission. For this reason, genetic counseling is recommended for couples potentially at risk.
Management and treatment
Treatment is symptomatic and follows standard protocols for cleft palate, clubfeet, hip subluxations, cervical instability and kyphoscoliosis. In individuals with a 46,XY karyotype and undermasculinization of the genitalia, the gonads should be removed due to the increased risk for gonadoblastoma. Hearing aids for those with hearing impairment.
Prognosis
Newborns suffering from campomelic dysplasia often die soon after birth as a result of respiratory insufficiency, but about 10 % of individuals survive. Complications (such as kyphoscoliosis, recurrent respiratory infections, hearing loss, light to moderate learning difficulties, small size and hip dislocation) can arise as the patients age.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Dr Maria Francesca BEDESCHI | ITHACA*

                                * European Reference Network


Camptobrachydactyly is an extremely rare brachydactyly syndrome, characterized by short broad hands and feet with brachydactyly associated with congenital flexion contractures of the proximal and/or distal interphalangeal joints of the fingers, as well as syndactyly of feet. Polydactyly, septate vagina and urinary incontinence were also occasionally reported. Camptobrachydactyly has been described in 18 members of 1 family, suggesting an autosomal dominant inheritance. There have been no further descriptions in the literature since 1972.


Camptodactyly of fingers is a rare, genetic, non-syndromic, congenital limb malformation disorder characterized by a painless, non-traumatic, non-neurogenic, often bilateral, permanent flexion contracture at the proximal interphalangeal joint of a postaxial finger, resulting in permanent volar inclination of the affected digit. The fifth finger is always involved, but additional digits might also be affected.


Camptodactyly syndrome, Guadalajara type 1 is a rare syndrome consisting of growth retardation, facial dysmorphism, camptodactyly and skeletal anomalies.

Summary:
Epidemiology
To date only eight cases have been reported in the literature.
Clinical description
Dysmorphic features include flat face, epicanthic folds, telecanthus, small downturned mouth, small ears with attached lobule and abnormal dental eruption and occlusion. Some patients had psychomotor development delayed.
Genetic counseling
The reported cases suggest the condition is hereditary and is transmitted as an autosomal recessive trait.

                            Last update:
                            October 2010


Camptodactyly syndrome, Guadalajara type 2 is an extremely rare multiple congenital anomaly syndrome characterized by distinctive intrauterine growth retardation, skeletal dysplasia with multiple malformations including camptodactyly of all fingers, bilateral hallux valgus, short second, fourth and fifth toes, hypoplastic patella, microcephaly, low-set ears, short neck, cuboid-shaped vertebral bodies, pectus excavatum, hip dislocation, and hypoplastic pubic region and genitalia. Camptodactyly syndrome, Guadalajara type 2 has been described in two sisters and is most likely transmitted in an autosomal recessive manner. There have been no further descriptions in the literature since 1985.


Camptodactyly syndrome, Guadalajara type 3 is a rare, genetic bone development disorder characterized by hand camptodactyly associated with facial dysmorphism (flat face, hypertelorism, telecanthus, symblepharon, simplified ears, retrognathia) and neck anomalies (short neck with stricking pterygia, muscle sclerosis). Additional features include spinal defects (e.g. cervical and dorso-lumbar spina bifida occulta), congenital shortness of the sternocleidomastoid muscle, flexed wrists and thin hands and feet. Brain structural anomalies, multiple nevi, micropenis and mild intellectual disability are also observed. Imaging reveals increased bone traveculae, cortical thickening of long bones and delayed bone age.


A rare, genetic, rheumatologic disease characterized by congenital or early-onset camptodactyly and symmetrical, polyarticular, non-inflammatory, large joint arthropathy with synovial hyperplasia, as well as progressive coxa vara deformity and, occasionally, non-inflammatory pericarditis.


Camptodactyly-fibrous tissue hyperplasia-skeletal anomalies syndrome

An extremely rare chondrodysplastic malformation syndrome characterized by the combination of arachnodactyly, becoming evident at around the age of 10, camptodactyly, and scoliosis. Additional reported manifestations include a mild intellectual disability and a mild facial dysmorphism including a broad nose and flaring nostrils. There have been no further descriptions in the literature since 1972.


Camptodactyly-joint contractures-facial skeletal defects syndrome

A rare multiple congenital anomalies syndrome characterized by the association of camptodactyly, multiple eye defects (fibrosis of the medial rectus muscle, severe myopia, ptosis and exophthalmos), scoliosis, flexion contractures and facial anomalies (arched eyebrows, facial asymmetry with an abnormal skull shape, a prominent nose, small mouth, low-set and dysplastic ears, and a low nuchal hairline).


Camptodactyly-tall stature-scoliosis-hearing loss syndrome is characterised by camptodactyly, tall stature, scoliosis, and hearing loss (CATSHL). It has been described in around 30 individuals from seven generations of the same family. The syndrome is caused by a missense mutation in the FGFR3 gene, leading to a partial loss of function of the encoded protein, which is a negative regulator of bone growth.


Camptodactyly-taurinuria syndrome is a congenital malformation syndrome characterized by the association of a permanent camptodactyly of the fingers (see this term) with the over excretion of taurine in the urine. Camptodactyly mainly affects the little finger, although any finger may be involved. The disease has been described in 17 affected patients from 4 unrelated families. An autosomal dominant inheritance has been suggested. There have been no further descriptions in the literature since 1966.


Camurati-Englemann disease (CED) is a rare, clinically variable bone dysplasia syndrome characterized by hyperostosis of the long bones, skull, spine and pelvis, associated with severe pain in the extremities, a wide-based waddling gait, joint contractures, muscle weakness and easy fatigability. Camurati-Englemann disease (CED) is a rare, clinically variable bone dysplasia syndrome characterized by hyperostosis of the long bones, skull, spine and pelvis, associated with severe pain in the extremities, a wide-based waddling gait, joint contractures, muscle weakness and easy fatigability.

Summary:
Epidemiology
The prevalence is unknown but more than 300 cases have been reported to date. CED has been described in various ethnic groups, and males and females are affected equally.
Clinical description
Most of the clinical signs are related to hyperostosis and sclerosis. The age of onset and severity are highly variable, even within the same family. The average age of onset is about 13 years and almost always before 30 years. Patients generally present with pain in the extremities, waddling gait, easy fatigability, and muscle weakness. Pain may be severe, constant and aching and is exacerbated by cold weather and physical activity. Other signs include decreased muscle mass, joint contractures, and sometimes marfanoid body habitus. Later in life, severely affected individuals may present facial abnormalities such as frontal bossing and enlarged mandible, as well as facial paralysis. Other signs of musculoskeletal involvement include lumbar lordosis, kyphosis, scoliosis, coxa valga, genu valgum, and flat feet. Involvement of the orbit may lead to proptosis, papilledema, epiphora, glaucoma, and subluxation of the globe. Conductive and/or sensorineural hearing loss is found in less than 20% of patients. Occasional associated systemic features include anemia, leukocytopenia, and hepatosplenomegaly. Rare signs include sensory loss, slurred speech, dysphagia, cerebellar ataxia, anorexia, decreased subcutaneous tissue, hyperhidrosis of the extremities, delayed dentition, extensive dental caries, delayed puberty, hypogonadism and bladder incontinence.
Etiology
In more than 90% of patients, mutations in the transforming growth factor TGFB1 gene (19q13.1) are detected.
Diagnostic methods
Diagnosis of CED is based on the clinical and radiographic signs and can be confirmed by molecular genetic testing. CED should be suspected in patients with proximal muscle weakness and hyperostosis of one or more of the long bones on radiographic imaging. The radiographic hallmark of the disorder is bilateral, sometimes symmetrical, periosteal and endosteal bony sclerosis of the diaphyses of long bones resulting in cortical thickening. Skull, spine and pelvic involvement may be found on radiographic examination.
Differential diagnosis
Camurati-Engelmann disease has characteristic clinical and radiological findings, reducing the need for extensive differential diagnosis. Disorders to consider include craniodiaphyseal dysplasia, autosomal dominant Kenny-Caffey syndrome, juvenile Paget disease, Ghosal hematodiaphyseal dysplasia, Worth type autosomal dominant osteosclerosis, sclerosteosis and hyperostosis corticalis generalisata (see these terms).
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is possible when the disease-causing mutation has been identified in a family.
Genetic counseling
CED is inherited as an autosomal dominant trait with reduced penetrance. The number of cases caused by de novo mutations is not known. Reduced penetrance complicates genetic counseling.
Management and treatment
No disease-modifying treatment is available. Corticosteroids are reported to relieve the symptoms of CED. Analgesics and non-pharmacological methods can be used to treat pain. NSAIDs and bisphosphonates have been found to be ineffective.
Prognosis
CED is a progressive disorder and prognosis is poor. Depending on the severity, quality of life is impaired by pain and reduced mobility.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Pr Wim VAN HUL


Canavan disease (CD) is a neurodegenerative disorder; its spectrum varies between severe forms with leukodystrophy, macrocephaly and severe developmental delay, and a very rare mild/juvenile form characterized by mild developmental delay.

Summary:
Epidemiology
The disease has been reported worldwide, but is more frequent in Ashkenazi Jewish populations. The incidence of severe CD in the non-Jewish population has been estimated at approximately 1:100,000 births. If both parents are of Ashkenazi Jewish descent, the incidence is 1:6,400 to 1:13,500 births. The main form of CD is the severe form.
Clinical description
Two forms of CD are clinically distinguishable: severe Canavan disease with onset in the neonatal period or infancy, and mild Canavan disease diagnosed in children (see these terms).In the severe form, patients have severe hypotonia, developmental delay and other neurologic impairments, and a very high N-acetyl-L-aspartic acid (NAA) concentration in urine, blood and cerebrospinal fluid. In mild Canavan disease, there can be mild developmental delay, problems with speech or achievement at school and urine NAA is slightly elevated.
Etiology
CD is caused by mutations in the ASPA gene (17p13.3), coding for the aspartoacylase enzyme. Numerous mutations have been identified, and subsequent enzymatic activity is either low or totally absent. In Ashkenazi Jews, two common mutations have been identified. Mild forms of Canavan disease are usually compound heterozygotes with one mild and one severe mutation.
Prognosis
Prognosis is variable. In severe Canavan disease, life expectancy is reduced with average survival until 10 years or occasionally longer. In mild Canavan disease, life expectancy is usually normal and the prognosis is good.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Kimberlee MATALON  - Dr Reuben MATALON


A rare paraneoplastic disease of the eye characterized by the presence of extraocular malignancy and circulating autoantibodies against retinal proteins.

Summary:
Epidemiology
Cancer-associated retinopathy (CAR) is a rare visual syndrome and its prevalence is still unknown. Females are affected twice as commonly as men. The average age of a CAR patient is about 66 years old.
Clinical description
The disease is progressive; visual symptoms and sudden vision loss can manifest before diagnosis of cancer. The disease is highly heterogeneous and patients differ in their clinical presentation and antibody profiles. Different antiretinal antibodies frequently coexist in a single patient, creating antibody-profiles related to the syndrome, with each disease progression stage having its own unique autoantibody signature. Patients typically present with rapidly progressive visual loss, scotomas, dyschromotopsia, nyctalopia, photoaversion, and prolonged dark adaptation. Although the disease is bilateral, initial asymmetry is not uncommon. Deterioration of visual acuity and visual field changes (scotoma, or central constriction) are common, attenuated retinal arteriole, in addition to the presence of serum autoantibodies against retinal proteins, are crucial for diagnosis. The electroretinogram (ERG) typically shows marked reduction or loss of rod and cone-mediated responses. The most common malignancies related to CAR are carcinomas, including breast carcinomas, small cell carcinoma of the lung, non-small cell carcinoma, endometrial, ovarian, cervical, prostate, and colon carcinomas, and cutaneous melanomas.
Etiology
The exact etiology remains unknown but an autoimmune mechanism may contribute to the development of retinal degeneration. No known genetic association has been reported.
Diagnostic methods
Initial absence of clinical findings makes the diagnosis challenging. The diagnostic evaluation should include electroretinography (ERG) in patients with unexplained visual glare and subacute visual loss. Optical coherence tomography (OCT) is useful to provide information on the presence of cystoid macular edema (CME) and loss of outer retinal layers, which may include disruption of the ellipsoid zone (EZ). Areas around the macula can show loss of inner and outer segments. The presence of CME is associated to decreased ERG amplitudes and faster EZ loss. Predisposed cancer patients may develop autoantibodies cross-reacting with photoreceptor proteins.
Differential diagnosis
The main differential diagnosis is non-paraneoplastic autoimmune retinopathy. Other differential diagnoses include white dot syndrome spectrum disorders, retinal degenerative disorders (such as retinitis pigmentosa and cone-rod dystrophy), posterior uveitis, acute zonal occult outer retinopathy (AZOOR) and retinal toxicities from medications such as chemotherapy agents and vitamin deficiencies.
Management and treatment
Early diagnosis and treatment are critical to lower the risk of irreversible immunological damage to the retinal cells. Treatment involves modulation of the immune system to reduce autoimmune response and systemic antibody levels. Importantly, care for patients with cancer should be consulted with oncologist prior to applying immunosuppressive therapies. Patients with less severe retinal disease or earlier disease can benefit from rituximab monotherapy or with an adjunctive antimetabolite, which may be also added to other immunosuppression like intravenous methylprednisolone, sodium succinate and hydroxyzine as a pretreatment regimen before each rituximab infusion. Response to treatments varies when patients were treated at late stages of retinal disease. Cyclophosphamide or IVIg adjunctive therapies can be applied to patients with more severe or rapidly advancing disease.
Prognosis
The ophthalmological prognosis varies depending on the clinical course of CAR, ranging from progressive visual loss to blindness. The overall prognosis varies depending on the type of cancer present. It is difficult to achieve an improvement in vision in patients who had advanced disease before immunosuppressive treatments were initiated.

                            Last update:
                            August 2023

                            - Expert reviewer(s):
                            Dr Grazyna ADAMUS


A rare chronic immune-mediated polyneuropathy characterized by a progressive disabling neuropathy with marked gait disturbance primarily due to sensory ataxia with concurrent cranial neuropathies (internal or external ophthalmoplegia, dysphagia, dysarthria, or facial weakness) and anti-disialosyl IgM antibodies.

Summary:
Epidemiology
The disease is rare with less than 100 cases reported in the literature. The disease predominantly affects males with a ratio of 3:1 (males:females).
Clinical description
The condition appears in adult or elderly age with a median age at onset of 55 years. The clinical picture comprises a chronic neuropathy with marked sensory ataxia and hyporeflexia/areflexia. Patients have relatively preserved motor function in the limbs, although some may develop distal weakness. The clinical manifestations may be fixed, progressive or relapsing-remitting. Electrophysiology and nerve pathology show demyelinating, axonal, or combined demyelinating and axonal features. Nerve ultrasound shows regional nerve enlargement, a finding consistent with acquired demyelination.
Etiology
The etiology remains incompletely characterized. Evidence suggests direct damage to dorsal root ganglia (DRG) and to the nodal axolemma. It is generally accepted that antibodies against gangliosides are pathogenic. The IgM accounting for the anti-ganglioside activity is almost invariably in the form of an IgM paraprotein, which may also have cold agglutinin activity.
Diagnostic methods
The diagnosis is based on the identification of typical clinical and electrodiagnostic features, IgM antibodies to disialosyl antibodies (i.e. GD1b), cold agglutinins and an IgM monoclonal gammopathy.
Differential diagnosis
Differential diagnosis includes other inflammatory peripheral neuropathies, particularly chronic inflammatory demyelinating polyneuropathy, as well as vascular and demyelinating brainstem lesions.
Management and treatment
Rituximab and/or intravenous immunoglobulin (IVIg) are effective in most patients. IVIg may prevent relapses in responsive patients while rituximab may be most effective in halting disease progression. While there is no clear evidence to support a disease-specific dosing regimen for either agent, commonly utilized regimens for other forms of immune-mediated peripheral nervous system disease have been effective.
Prognosis
The functional outcome is generally guarded-to-poor with the majority of patients suffering some degree of permanent disability from the sensory ataxia that defines the illness.

                            Last update:
                            March 2019

                            - Expert reviewer(s):
                            Dr Robert BUCELLI  - Dr ROCIO GARCIA-SANTIBANEZ


Cantu syndrome is a rare disorder characterized by congenital hypertrichosis, osteochondrodysplasia, cardiomegaly, and dysmorphism.

Summary:
Epidemiology
To date, fewer than 30 cases have been reported.
Clinical description
Dysmorphic features include macrocephaly and a coarse facial appearance with thick eyebrows, prominent supraorbital ridges, broad nasal bridge, anteverted nares, long and large philtrum, prominent mouth with full lips and macroglossia. Affected individuals have hypertrichosis with thick scalp hair extending onto the forehead and generalized increased body hair. Cardiomegaly is found in the majority of patients and pericardial effusions have been present occasionally. Additional findings in most patients included thickened calvarium, broad ribs and metaphyseal widening of long bones with enlarged medullary canals. Mild intellectual deficiency has been described in several patients.
Etiology
Most cases appear to be sporadic but a few familial cases, with predominantly autosomal dominant inheritance, have been reported.

                            Last update:
                            January 2010


Cap myopathy is a very rare congenital myopathy presenting a weakness of facial and respiratory muscles associated with craniofacial and thoracic deformities, as well as weakness of limb proximal and distal muscles. Onset is at birth or in childhood, weakness progression is slow but may lead to a severe and even fatal prognosis.


A rare colorectal disease characterized by multiple inflammatory polyps that predominantly affect the rectosigmoid area and that manifests primarily as rectal bleeding with abnormal transit, constipation and diarrhea.

Summary:
Epidemiology
To date, around 67 cases have been described in the world literature. Females seem to be more affected than males.
Clinical description
The mean age at presentation is 49 years (range 5-79 years) with clinical manifestations including constipation alternating with periods of mucous and bloody diarrhea, associated with rectal bleeding, chronic straining with defecation, tenesmus, abdominal pain, fatigue, and loss of appetite and weight. Some patients may also show lower limb edema due to a protein-losing enteropathy.
Etiology
The etiology of Cap polyposis (CP) is still unclear but various causes including lower colonic mucosal prolapse, mucosal ischemia, inflammation, abnormal colonic motility, repeated trauma to the colonic mucosa caused by straining, infections (such as Helicobacter pylori infection), and immune disorders have been proposed.
Diagnostic methods
The diagnosis of CP relies on colonoscopy which reveals multiple polyps with white muco-fibrinoid caps and a normal intervening mucosa. The lesions are mainly located in the rectum and sigmoid colon. Pathological examination shows a polypoid lesion with an ulcerated cap of fibrin and mucus, elongated tortuous crypts filled with mucoid exudate, and possibly smooth muscle fibers in the mucosa. Laboratory findings may reveal hypoproteinemia, hypoalbuminemia, and severe anemia with low hemoglobin concentration. C-reactive protein (CRP) levels or white blood cell counts are mostly within the normal reference range.
Differential diagnosis
Differential diagnosis includes juvenile polyposis syndrome, Cronkhite-Canada syndrome (see these terms), amoebic dysentery, mucosal prolapse syndrome, and inflammatory bowel disease, primarily ulcerative colitis (with inflammatory polyps).
Management and treatment
CP has been treated empirically using sulfasalazine, 5-aminosalicylic acid, orally or anally administered steroids, metronidazole, quinolone,  Helicobacter pylori  eradication therapy and infliximab. For cases refractory to treatment, polypectomy (for fewer than 10 polyps) or surgical resection (for greater numbers of polyps) may be successful. Patients with predominant straining/constipation symptoms can be treated with laxatives.
Prognosis
CP is not a premalignant condition. The clinical course of CP ranges from spontaneous remission to a disease course requiring surgical resection of the affected bowel segments. However, the recurrence rates are high, particularly if numerous polyps are present.

                            Last update:
                            May 2016

                            - Expert reviewer(s):
                            Pr Jean-Alain CHAYVIALLE  - Pr Jean-Christophe SAURIN


This syndrome is characterised by the association of multiple capillary malformations (CM) with an arteriovenous malformation (AVM) and arteriovenous fistulas.

Summary:
Epidemiology
So far, it has been described in multiple members of six families.
Clinical description
The CMs are atypical: they are small, round-to-oval in shape and pink-red in colour. AVMs may be cutaneous, subcutaneous, intramuscular, intraosseous or cerebral. The association of CM with arteriovenous fistulas or Parkes-Weber syndrome (see this term) was reported in some cases.
Etiology
The syndrome is caused by heterozygous mutations in the RASA1 gene (5q13.3), encoding RAS p21 protein activator 1.

                            Last update:
                            April 2008


CAR T cell therapy-associated cytokine release syndrome

A rare systemic condition affecting patients undergoing chimeric antigen receptor (CAR) T-cell therapy and characterized by a systemic inflammatory response due to massive activation of leukocytes with subsequent cytokine release. It can present with a variety of signs and symptoms ranging from mild, flu-like symptoms (such as fever, fatigue, headache, rash, arthralgia, and myalgia) to severe life-threatening manifestations including vascular leakage, disseminated intravascular coagulation, shock, and multiple organ failure. Respiratory manifestations are common and range from cough and tachypnea to acute respiratory distress syndrome (ARDS).


Carbamoyl-phosphate synthetase 1 deficiency

A rare, severe disorder of urea cycle metabolism typically characterized by either a neonatal-onset of severe hyperammonemia that occurs few days after birth and manifests with lethargy, vomiting, hypothermia, seizures, coma and death or a presentation outside the newborn period at any age with (sometimes) milder symptoms of hyperammonemia.

Summary:
Epidemiology
The worldwide prevalence ranges between 1/526,000-1,300,000 live births.
Clinical description
In the neonatal-onset form of carbamoyl-phosphate synthetase 1 deficiency (CPS1D), patients are usually healthy at birth but after few days they begin to manifest with lethargy and unwillingness to feed. Severe hyperammonemia continues and manifests with vomiting, hypothermia, hypotonia, seizures, coma, and can lead to death. Outside the newborn period, patients can present at any time in life. Risk factors for manifestation include catabolic stressors such as fasting and intercurrent illness. Manifestations include hyperammonemia with irritability, lethargy, headache, seizures, confusion, avoidance of high-protein meals, axial hypotonia and cognitive disability.
Etiology
CPS1D is due to mutations in the CPS1 gene (2p) that encodes carbamoyl-phosphate synthetase I (CPS1), an enzyme located in the mitochondrial matrix of hepatocytes and epithelial cells of intestinal mucosa that controls the first step of the urea cycle where ammonia is converted into carbamoyl-phosphate. Mutations in this gene lead to an interruption in the urea cycle and excess nitrogen is not converted to urea for excretion by the kidneys, leading to hyperammonemia.
Diagnostic methods
Diagnosis is based mainly on clinical findings and laboratory test results. Biochemical findings include severe hyperammonemia with very low plasma levels of citrulline and arginine, high plasma levels of glutamine, increased transaminases and low or normal levels of orotic acid in the urine. Molecular genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnoses mainly include other urea cycle disorders and organic acidurias. Amino acid profiles will distinguish CPS1D from argininosuccinic aciduria, citrullinemia type I and arginase deficiency while orotic acid in urine should help to distinguish from ornithine transcarbamylase deficiency. Another more recent differential diagnosis is hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation on both alleles.
Genetic counseling
CPS1D is inherited in an autosomal recessive manner; there is a 25% risk of inheriting the disease where both parents are unaffected carriers.
Management and treatment
Patients presenting with a hyperammonemic coma must be treated immediately in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration methods), ammonia scavenger therapy implemented, catabolism reversed (through glucose and lipid infusions) and special care taken to reduce the risk of neurological damage (EEG surveillance and treatment of seizures, if necessary). A life-long diet low in natural protein, supplements of essential amino acids, citrulline and arginine as needed, nitrogen scavenger therapy (sodium benzoate and/or sodium or glycerol phenylbutyrate) and appropriate nutritional support to avoid catabolic stress are recommended. Early liver transplantation for those with neonatal-onset CPS1D can correct metabolic abnormalities but does not reverse any neurological complications. Valproic acid should be avoided.
Prognosis
Prognosis depends on disease severity but is considered bleak in patients with early neonatal disease. With early diagnosis and optimal treatment started without any delay, the prognosis improves. Episodes of hyperammonemic coma of long duration are associated with a poor neurological outlook.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Johannes HÄBERLE


Carcinofibroma of the corpus uteri is an extremely rare subtype of mixed müllerian tumor characterized by the presence of a uterine neoplasm which simuntaneously presents a malignant epithelial component (carcinomatous glands) and a benign mesenchymal component. Clinical presentation typically includes dysfunctional vaginal bleeding, abnormal vaginal discharge and/or lower abdominal pain.


A rare neoplastic disease characterized by the occurrence of a hormonal syndrome resulting from secretion of humoral factors (including polypeptides, vasoactive amines, and prostaglandins) from a functional neuroendocrine tumor (particularly from the midgut), typically manifesting with increased bowel movements and diarrhea, episodic vasoactive flushes (particularly of the face), hypotension, tachycardia, venous telangiectasia, dyspnea, and bronchospasms, as well as long-term fibrotic changes in the mesentery, retroperitoneum, and of the cardiac valves.


Carcinoma of esophagus, salivary gland type

A rare gastroesophageal tumor characterized by a typically submucosal tumor occurring usually in the middle to distal esophagus and histologically characterized as either mucoepidermoid (intimate mixture of mucus, intermediate, and epidermoid cells) or as adenoid cystic carcinoma (biphasic admixture of duct‐lining epithelial and myoepithelial cells with tubular, cribriform, solid, or basaloid growth patterns). Patients may be asymptomatic or may present with progressive dysphagia, heartburn, retrosternal pain and/or weight loss.


Esophageal carcinoma (EC) is a tumor arising in the epithelial cells lining the esophagus and can be divided into two subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC).

Summary:
Epidemiology
The estimated annual incidence of EC in Europe is approximately 1/13,300.
Clinical description
The disease usually presents between the ages of 50-70 years. It is often asymptomatic until it has reached an advanced disease stage with the first symptoms usually being difficulty in swallowing (dysphagia), especially present when swallowing dry foods. Unintentional weight loss is also common. Manifestations of back or chest pain, hoarseness of voice, unexplained coughing, protracted hiccups, and severe reflux may be presenting or associated symptoms. More rarely, neck swelling from adenopathies may be the initial manifestation.
Etiology
The etiology is unknown but many risk factors for esophageal cancer have been identified. Alcohol abuse, smoking, lye ingestion, radiation therapy and achalasia are associated with ESCC. EAC is associated with Barrett's esophagus (see this term), which is intestinal metaplasia (replacement of normal esophageal epithelia by intestinal epithelia), associated with chronic gastroesophageal reflux disease. EAC has also been associated with obesity, in particular visceral obesity and metabolic syndromes which are more common in men than in women.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Dr Claire DONOHOE  - Dr John REYNOLDS


Carcinoma of gallbladder and extrahepatic biliary tract

Carcinoma of the gallbladder (GBC) is the most common and aggressive form of biliary tract cancer (BTC; see this term) usually arising in the fundus of the gallbladder, rapidly metastasizing to lymph nodes and distant sites.

Summary:
Epidemiology
Annual incidence rates vary from 1/100,000 to 1/ 4,350 between different ethnic groups and geographical regions. It is rare in developed Western countries but has a high incidence in Japan (1/19,000), northern India, Chile and certain regions of Eastern Europe.
Clinical description
GBC is a rare neoplasm occurring more often in females (3-4:1 female to male ratio) with an average age of onset of 65 years. Most patients are asymptomatic until the disease is advanced but presenting symptoms include abdominal pain (usually in the upper right quadrant), nausea, vomiting, jaundice, anorexia and weight loss. Gallstones are often present in patients with GBC. GBC is extremely aggressive and invasion of the lymph nodes, liver and other organs occurs rapidly in many cases.
Etiology
The exact etiology is unknown. Genetic susceptibility elicited by chronic inflammation of the gallbladder leading to dysplasia and malignant change is one possibility. Risk factors associated with GBC include a history of gallstones, cholelithiasis, porcelain gallbladder, bacterial infections, high caloric diet and an anomalous pancreaticobiliary junction. A family history of GBC is also a risk factor supporting the hypothesis that genetic and environmental factors both play a role in disease susceptibility. The APOB gene is the only gene identified so far with a direct link to GBC. Mutations in the genes KRAS, INK4a, p53 and EGFR have all been implicated in the pathogenesis of GBC.
Diagnostic methods
Diagnosis is based on laboratory tests and imaging studies. Blood tests measuring liver enzymes and tumor marker levels are conducted. There is often an increase in CEA and CA 19-9 tumor markers, especially at an advanced stage. Ultrasound and computed tomography (CT) scans show any masses or enlargement of the gallbladder. Tumor masses are usually found in the neck and body of the gallbladder. The TNM staging system is used to stage GBC and to determine the treatment and prognosis given. Patients are then given a stage based on the International Union Against Cancer (UICC) staging system. Histopathologically most GBCs are adenocarcinomas with various histopathological subtypes. Less frequently there can be squamous cell carcinoma, sarcoma, lymphoma (see this term) or melanoma.
Differential diagnosis
GBC is often misdiagnosed as other types of adenocarcinoma and other benign gallbladder diseases such as chronic cholecystitis and adenomyomatosis.
Management and treatment
The only curative treatment is complete surgical resection. If obstructive jaundice is present then biliary drainage with stenting is necessary. For T1 tumors a simple or radical (in T1b tumors) open cholecystectomy is recommended and is usually curative. Unfortunately GBC is rarely discovered at such an early stage. T2 tumors are best managed with an en bloc resection of the liver bed. T3 tumors require a selective radical resection depending on the organs affected. T4 tumors are considered unresectable or associated with high surgical morbidity. Chemotherapy can be given to those with unresectable T3 or T4 tumors or metastatic disease in hopes of improving survival and quality of life. Gemcitabine combined with cisplatin therapy is the standard treatment for unresectable biliary tract cancers. Less toxic molecular-targeted agents are now being tested as possible future treatments.
Prognosis
As GBC is often detected only at an advanced disease stage, the prognosis is poor with 5-year survival rates of approximately 20%.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Dr Junji FURUSE


Carcinoma of the ampulla of Vater is a rare malignant tumor originating from the ampulla of Vater that can present with symptoms of general fatigue, loss of appetite, weight loss, nausea, vomiting, abdominal pain and, most commonly, painless obstructive jaundice. The tumor is believed to arise from duodenal, biliary or pancreatic epilthelium, resulting in the respective histological types. In general, carcinoma of the ampulla of Vater has a better prognosis (5-year survival rate of 45%) than cancers of the distal bile duct and pancreas.


Carcinosarcoma of the cervix uteri is a rare, malignant, mixed epithelial and mesenchymal tumor, located in the cervix uteri, composed of an admixture of carcinomatous and sarcomatous elements. It usually presents with abnormal vaginal bleeding and a round, well-defined, grey to yellowish-white, pedunculated polypoid mass protruding through the cervical canal. Association with HPV infection (especially serotype 16) has been frequently reported.


Carcinosarcoma of the corpus uteri is a rare, malignant, mixed epithelial and mesenchymal tumor of the uterine body composed of high-grade carcinomatous and sarcomatous elements. It may present with vaginal bleeding, abnormal vaginal discharge, abdominal pain and/or pelvic mass, with a polypoid tumor sometimes protruding through the cervical canal. Association with Tamoxifen therapy, long-term unopposed estrogen use and previous pelvic radiotherapy has been reported.


Cardiac anomalies-heterotaxy syndrome is characterised by non-compaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect. Laterality sequence anomalies are also present. So far, the syndrome has been described in nine members from three generations of the same family. Transmission is autosomal dominant and linkage to chromosome 6p24.3-21.2 was reported.


Cardiac anomalies-short stature-joint hypermobility-facial dysmorphism syndrome

A rare multiple congenital anomalies syndrome characterized by the combination of cardiac anomalies (most commonly mitral valve defects and cardiomyopathy), short stature, facial dysmorphism and sometimes mild developmental delay.

Summary:
Epidemiology
70 individuals have been described in literature: 34 individuals with TAB2 variants, 36 individuals with TAB2 deletions.
Clinical description
Almost all individuals present with a specific facial appearance including: broad forehead, hypertelorism, up/downslanting palpebral fissures, ptosis, low set ears, broad/short neck, and half of the individuals have a face suggestive for Noonan syndrome. Cardiac disease is seen in most individuals and includes mainly mitral valve defects, sometimes in combination with another valve defect, and (dilated) cardiomyopathy. Cardiomyopathy can be present from birth or develop between infancy and adulthood. Other cardiovascular defects are variably reported, including dysplasia of the tricuspid, aortic and pulmonary valves, atrial and/or ventricular septal defects, coarctation of the aorta and thoracic aneurysms. Short stature is often disproportionate (short limbs). Connective tissue abnormalities can include joint hypermobility, umbilical and inguinal hernias, pes planus, pectus excavatum and other skeletal and/or skin abnormalities. Some individuals have mild developmental delay. More severe developmental delay can be seen in larger deletions (>6.47 Mb) containing TAB2, but was never reported in individuals with TAB2 variants. Hearing loss and vision problems are also reported. Hypotonia is reported in individuals with TAB2 deletions, but rarely in TAB2 variants.
Etiology
This syndrome is caused by heterozygous pathogenic variants in the TAB2 gene, or by chromosome 6 deletions including TAB2 (6q25.1). Both TAB2 variants and deletions including TAB2 lead to a highly comparable phenotype.
Diagnostic methods
Diagnosis is based on clinical examination, and cytogenetic and molecular studies.
Differential diagnosis
The differential diagnosis includes Noonan syndrome/RASopathies, cardiospondylocarpofacial syndrome (MAP3K7 gene), cardiac valvular dysplasia (FLNA gene), connective tissue disorders with cardiac valve involvement such as Loeys Dietz type 3 (SMAD3 gene) or 5 (TGFB3 gene).
Antenatal diagnosis
Detection of the TAB2 variant or deletion by chorion villus biopsy or amniocentesis should be discussed with adults carrying the deletion or variant.
Genetic counseling
Transmission is autosomal dominant. TAB2 deletions often arise de novo, but are also reported in families (largest known familial deletion: 8.67 Mb) and therefore should be excluded in parents before counselling a low recurrence risk. Genetic counselling should be offered to all individuals with a TAB2 variant or deletion. For patients with a heterozygous TAB2 variant or deletion, each pregnancy carries a 50% risk of transmission to offspring. Sibling recurrence in de novo mutations may occur due to mosaicism, but has not been reported.
Management and treatment
Regular cardiac evaluation and evaluation of overall development, hearing, vision and connective tissue abnormalities is recommended for all affected individuals. Cardiac follow-up is needed as valvular heart disease, thoracic aneurysm and cardiomyopathy may manifest later in life. Surgical intervention for cardiac anomalies may be required. The relevance of growth hormone therapy for short stature in this syndrome is not clear and should be studied further.
Prognosis
Life expectancy can be limited due to severe cardiac disease. Three children died due to dilated cardiomyopathy and four adults died between the age of 40-60 from the (late) effects of structural heart disease.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                             A. [Aafke] ENGWERDA | ITHACA* - Dr W.S. [Mieke] KERSTJENS-FREDERIKSE | ITHACA*

                                * European Reference Network


Congenital cardiac diverticulum (CCD) is a very rare congenital malformation characterized by a muscular appendix emerging from the left ventricular apex, rarely from the right ventricle or from both chambers, with clinical manifestations ranging from asymptomatic to life-threatening hemodynamic collapse.

Summary:
Epidemiology
CCD is a very rare malformation. Exact prevalence and incidence data are not available. About 0.4% or 1 of 250 cardiac necropsy cases showed this malformation. In the literature, the combined number of aneurysm/diverticle reports is 418 cases. Incidence of 1/2700 on echocardiographic studies (0.04% of the population) has been reported. A very slightly higher incidence has been reported in males compared to females (1.05:1.0).
Clinical description
Congenital cardiac diverticulum is often associated with other cardiac abnormalities (midline defects) but is mostly an isolated anomaly. It is mostly found in infants and children and occasionally as an incidental finding in adults. The left ventricular apex is the most common location, but right ventricular diverticula are also reported. Two types of CCD are described: fibrous CCD which may be asymptomatic or associated with thromboembolic events, and muscular CCD with normal myocardial contraction which is frequently associated with other congenital anomalies and may cause rupture, aortic insufficiency, endocarditis, heart failure and tachyarrhythmia. Other clinical manifestations may include dyspnea, palpitation, and chest pain. Fetal death has also been described because of intrauterine diverticulum rupture. Congenital aneurysms are composed of collagenous or connective tissue and are associated with akinesis or dyskinesis. Acquired forms of cardiac diverticulum/aneurysm are common, particularly after myocardial infarction.
Etiology
The etiology of congenital cardiac diverticulum is not known. Hemodynamic factors may play a role. In the 4th embryonic life there are outpouchings in the early wall of the left ventricle which later enlarge ventriclular cavity volume. Failure during this process could be responsible for the development of aneurysms.

                            Last update:
                            March 2015


A rare form of Ehlers-Danlos syndrome (EDS) characterized by soft skin, skin hyperextensibility, easy bruisability, atrophic scar formation, joint hypermobility and severe, progressive cardiac valvular defects comprising mitral and/or aortic valve insufficiency.


A rare, multiple congenital anomalies syndrome with intellectual disability commonly characterized by facial dysmorphism (e.g. sagittal craniosynostosis, hypertelorism, strabismus, low-set dysplastic ears, retrognathia or micrognathia, mandibular ankyloses, cleft palate, aplasia uvulae), congenital heart defects (e.g. atrioventricular septal defect, anomalous venous return), genital anomalies (e.g. cryptorchidism, microphallus), as well as growth delay and intellectual disability. In some cases, tracheobronchial anomalies, large joint contractures, syndactyly, rib anomalies and hypoplastic kidneys are reported. Rarely, no cardiac anomaly may be reported.


A rare, multiple congenital anomalies syndrome characterized by craniofacial dysmorphology, congenital heart disease, dermatological abnormalities (most commonly hyperkeratotic skin and sparse, curly hair), neurological manifestations (hypotonia, seizures), failure to thrive and intellectual disability.

Summary:
Epidemiology
Around 300 cases have been published in the literature to date. Prevalence has been estimated at 1/810,000 people in Japan. However prevalence is believed to be higher.
Clinical description
Cardiofaciocutaneous (CFC) syndrome displays wide phenotypic variability. Polyhydramnios is often reported. Neonates present at birth with relative macrocephaly, short webbed neck and distinctive dysmorphic craniofacial features (i.e. coarse facial appearance, large forehead, low-set ears, ptosis, downslanting of eyes, epicanthal folds, short nose with depressed nasal bridge, prominent philtrum, high arched palate, thick lower lip). Cardiac abnormalities, if present, may not be diagnosed until later, and include valvular pulmonary stenosis, interauricular communication and hypertrophic cardiomyopathy. Feeding difficulties, leading to failure to thrive, gastroesophageal reflux (GER), vomiting and constipation often appear in infancy but improve in childhood. Growth failure leading to short stature is sometimes due to a growth hormone deficiency. Dermatological manifestations include sparse, thin, and curly hair; dry, hyperkeratotic and hyperelastic skin (on arms, legs and face); general hyperpigmentation; progressively forming nevi; ichthyosis; palmoplantar keratoderma; café au lait spots; lymphedema; and hemangiomas. Severe eczematous lesions are frequently seen. Hypertelorism, strabismus, nystagmus, optic nerve hypoplasia and astigmatism can lead to decreased vision and acuity. Recurrent otitis media has also been reported. Neurological abnormalities (hypotonia, learning difficulties and developmental delay (motor and speech, mainly)) are seen in all children. In 50% of cases, seizures can also be present.
Etiology
CFC syndrome is considered a RASopathy and is due to mutations in one of the 4 genes: BRAF (7q34) (in 75% of CFC cases), MAP2K1 (15q22.1-q22.33), MAP2K2 (19p13.3), and KRAS (12p12.1), which encode proteins of the sarcoma/mitogen-activated protein kinase (RAS/MAPK) signaling pathway. This signaling pathway participates in the regulation of cell differentiation, proliferation, migration, and apoptosis.
Diagnostic methods
Clinical diagnosis is based mainly on the presence and frequency of the characteristic clinical traits and the sporadic occurrence of the disease. Molecular genetic testing, preferably multigene panel testing, including all known RASopathy genes, is preferable. If unavailable, sequential gene testing is recommended, starting from BRAF, exons 6, 12 and 11 being the most commonly mutated.
Differential diagnosis
Differential diagnoses include Costello Syndrome (CS) and Noonan Syndrome, which have overlapping phenotypes with CFC syndrome. CFC syndrome, unlike CS, does not appear to have an increased risk of malignancies.
Antenatal diagnosis
Prenatal testing is possible in families with a known mutation.
Genetic counseling
All bona fide cases reported to date are due to de novo dominant mutations. Due to sporadic nature of the disease, the sibling recurrence risk is very small.
Management and treatment
Management requires a multidisciplinary team. Infants may require nasogastric or gastrostomy feeding or a Nissen fundoplication when severe GER is present. Monitoring by a cardiologist is necessary and heart surgery may be required to repair specific defects. Monitoring by a neurologist is needed for the patients presenting seizures. Regular ophthalmology exams as well as corrective lenses or surgery can improve vision. Standard treatment of skin conditions is recommended. Referral to an endocrinologist may also be needed. Early occupational, physical and/or speech therapy promotes motor and speech development.
Prognosis
Prognosis is highly variable and is dependent on clinical manifestations. Life-expectancy can be close to normal or reduced (if severe heart and/or neurological manifestations are present).

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Maria Ines KAVAMURA


A rare, cardiac condition characterized by severely decreased cardiac output, hypoperfusion and end-organ dysfunction, in the presence of adequate intravascular volume. The clinical presentation is variable and may range from subtle hemodynamic alterations to overt cardiovascular collapse. Commonly reported features include dyspnea, crackles, elevated jugular venous pressure, altered mental state, abnormal pulse pressure, oliguria, cold extremities, and increased serum lactate levels.


Cardiomyopathy-cataract-hip spine disease syndrome

A rare triad of dilated cardiomyopathy, premature cataract, and articular disease of the hips and spine characterized by hip joint degeneration, irregular intervertebral disks, and platyspondyly. The ocular abnormalities are often the first symptoms to arise. There have been no further descriptions in the literature since 1985.


Cardiomyopathy-hypotonia-lactic acidosis syndrome is characterised by hypertrophic cardiomyopathy, muscular hypotonia and the presence of lactic acidosis at birth. It has been described in two sisters (both of whom died within the first year of life) from a nonconsanguineous Turkish family. The syndrome is caused by a homozygous point mutation in the exon 3A of the SLC25A3 gene encoding a mitochondrial membrane transporter.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by growth retardation, short stature, feeding difficulty and failure to thrive, cardiac anomalies (septal defects and/or valve dysplasia), joint laxity, short extremities, brachydactyly, carpal and tarsal fusion, cervical vertebral fusion, inner ear malformation with bilateral conductive hearing loss, and dysmorphic facial features (such as hypertelorism, upslanting palpebral fissures, posteriorly rotated ears, anteverted nares, and long philtrum). Additional variable manifestations include gastroesophageal reflux and genitourinary anomalies, among others.


Carey-Fineman-Ziter (CFZ) syndrome is a rare condition characterized by the association of hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre-Robin sequence (micrognathia, glossoptosis, and high-arched or cleft palate), unusual face, and growth delay.

Summary:
Epidemiology
Less than 20 cases have been reported the literature, including two pairs of sibs.
Clinical description
Most patients had non-specific peripheral (myopathy) or central (brain anomaly) causes of hypotonia. Some had a non-specific myopathy, with consequent severe scoliosis. Other features, reported in one or two patients with CFZ, included brain anomalies (ventriculomegaly, reduced white matter, neuronal heterotopias, small foci of necrosis with microcalcifications, small pons and brainstem with enlarged pre-pontine and pontocerebellar cisterns), absence of the pectoralis major muscle with an ulnar deviation of the hand (Poland sequence), laryngostenosis, unexplained intermittent arterial hypertension with facial flushing and sweating, hydronephrosis, glanular hypospadias, and talipes equinovarus. Intelligence may be normal but mental disability has been reported. One patient also presented with a gastrointestinal disturbance with biopsy-proven villous atrophy.
Diagnostic methods
Diagnosis can be made on the basis of clinical features, but magnetic resonance imaging (MRI) is necessary to detect the brain anomalies.
Genetic counseling
Although CFZ syndrome has been reported in two pairs of sibs, suggesting an autosomal recessive mode of inheritance, the recurrence risk does not seem to be as high as 25%.
Management and treatment
Scoliosis necessitated rod placement in one patient during adolescence, and in another case induced restrictive lung disease and death from pneumonia at 37 years of age.

                            Last update:
                            April 2006


Parkinsonism with dementia of Guadeloupe is characterised by symmetrical bradykinesia, predominantly axial rigidity, postural instability with early falls and cognitive decline with prominent features of frontal lobe dysfunction.

Summary:
Epidemiology
Prevalence is unknown, but a higher number of cases have been described in the French West Indies.
Etiology
This form of atypical parkinsonism may be related to exposure to tropical plants containing mitochondrial complex I inhibitors.
Differential diagnosis
Guadelupian parkinsonism may actually be a tauopathy identical or closely related to progressive supranuclear palsy (see this term).
Management and treatment
Most patients are L-dopa unresponsive.

                            Last update:
                            December 2007


Carney complex-trismus-pseudocamptodactyly syndrome is a rare genetic heart-hand syndrome characterized by typical manifestations of the Carney complex (spotty pigmentation of the skin, familial cardiac and cutaneous myxomas and endocrinopathy) associated with trismus and distal arthrogryposis (presenting as involuntary contraction of distal and proximal interphalangeal joints of hands evident only on dorsiflexion of wrist and similar lower-limb contractures producing foot deformities).


A rare endocrine disease characterized by lentigines with a specific peri-orifical distribution, blue nevus, myxomas, various endocrine tumors including primary pigmented nodular adrenocortical disease (PPNAD), acromegaly, thyroid tumors, and a wide range of other tumors.

Summary:
Epidemiology
Carney complex (CNC) is a rare disease with more than 750 cases reported in the scientific and medical literature.
Clinical description
Lentigines with a specific peri-orifical distribution, blue nevus (particularly epithelioid blue nevus), and cutaneous myxomas, with a classical distribution in the eyelids, nipples, external ear canal or genitalia, are frequent and very suggestive of the diagnosis. The most common endocrine gland manifestations are of Cushing syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD), large cell calcifying Sertoli cell tumors, thyroid tumors, and acromegaly. Myxomas can also be observed in the heart and breast. Cardiac myxomas are diagnosed at a median age of 50 but may occur in early childhood, can develop in any cardiac chamber, and may be multiple and/or recurrent.
Etiology
In more than 70% of cases, CNC is related to mutations of the PRKAR1A gene coding for regulatory subunit R1alpha of protein kinase A. The mutation c.709-7del6 is mostly associated with isolated PPNAD, and the mutation c.491-492del is associated with more frequent cardiac myxomas, lentigines and thyroid tumors. Deleterious PDE11A variants have been described in patients with PRKAR1A mutations, with more frequent PPNAD and testicular tumors. A germline triplication mutation involving PRKACB, the gene encoding the catalytic subunit beta of the protein kinase A, has been described in a young woman with acromegaly, lentigines and myxomas who did not harbor a PRKAR1A mutation.
Diagnostic methods
Diagnosis is made if two major features are present (e.g. peri-orifical lentigines, myxomas, PPNAD), or one major feature with a supplementary criterion such as a PRKAR1A mutation or an affected first-degree relative. Patients with CNC, or with a genetic predisposition to CNC, should have regular screening for manifestations of the disease. Clinical work-up for all the manifestations of CNC should be performed at least once a year in all patients and should start in infancy.
Differential diagnosis
The heterogeneity of the manifestations of CNC implies that differential diagnosis should be discussed for each of its numerous manifestations: i.e. differential diagnosis of PPNAD can be the others causes of adrenal Cushing syndrome; PPNAD can be isolated without others manifestations of CNC and no genetic variant of PRKAR1A, or be part of a classic CNC associated with another main feature like lentiginosis and/or myxoma.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in one of the 2 parents.
Genetic counseling
About 70% of the cases are familial with an autosomal dominant transmission. Genetic analysis should be proposed to all patients with CNC. In a second step, a genome-wide study may be discussed. Genetic counseling should be proposed in families with a known disease-causing mutation.
Management and treatment
Cardiac myxomas require surgical removal. Treatment of the other manifestations of CNC should be discussed and may include follow-up, surgery, or medical treatment depending on the location of the tumor, it's size, existence of hormonal excess or volume-related clinical signs, and the suspicion of malignancy. Bilateral adrenalectomy is the most common treatment for CS due to PPNAD.
Prognosis
Cardiac myxoma complications and other tumors development can greatly impact the lifespan of CNC patients.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Pr Jérôme BERTHERAT | Endo-ERN*

                                * European Reference Network