Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy

CARASIL is a hereditary cerebral small vessel disease characterized by early-onset gait disturbances, premature scalp alopecia, ischemic stroke, acute mid to lower back pain and progressive cognitive disturbances leading to severe dementia.

Summary:
Epidemiology
The prevalence is unknown. Less than 10 genetically proven cases have been reported, with most of them occurring in Japan where no founder haplotypes have yet been found, indicating the likely existence of unreported cases. The additional familial cases have been reported from Spain and China.
Clinical description
CARASIL has a slight male predominance. Onset varies but usually the first signs of the disease are diffuse alopecia (not always present) and gait disturbances that can often present before 30 years of age. Attacks of severe lower and mid back pain usually occur between the ages of 20-45. Some may suffer from disk herniations, nodular thickening, and severe spondylitis deformans with osteoporosis. Several cases have shown lumbago without any radiological abnormalities. Half of patients suffer from a typical lacunar stroke while the other half experiences a stepwise deterioration in brain function. Neurological symptoms include pseudobulbar palsy, hyperreflexia, vestibular symptoms, and ophthalmoplegia. Cognitive deficits begin to appear around the age of 30-40 with the first manifestation being forgetfulness. Other manifestations include emotional incontinence, personality changes (lability and irritability), disorientation to time and eventually apallic syndrome. In advanced stages emotional incontinence, abulia and akinetic mutism develop. Patients are usually bedridden 10 years after disease onset but can live for 20-30 years with the illness.
Etiology
CARASIL is caused by a mutation in the HTRA1 gene, encoding the HtrA serine peptidase 1 protein (HTRA1) which represses signaling by transforming growth factor (TGF)-beta family members. Patients with a mutation have reduced or no amounts of HTRA1 which leads to increased signaling by the (TGF)-beta family and consequently to the manifestations seen in CARASIL.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical and brain magnetic resonance (MRI) imaging findings. MRI findings are similar to those seen in CADASIL syndrome (see this term) including symmetrical distribution of white matter hypersensitivities. White matter high-signal intensity lesions and multiple lacunar infarctions are observed and are most often located in the periventricular and deep white matter. Dilation of cerebral sulci and lateral ventricles is noted in some individuals. Pathological findings show arteriosclerosis in the cerebral small arteries. Genetic testing can confirm diagnosis with a mutation in the HTRA1 gene.
Differential diagnosis
Differential diagnoses include primary angiitis of the central nervous system, Binswanger disease, CADASIL, Nasu-Hakola disease, chronic progressive multiple sclerosis and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (see these terms). As Hutchinson-Gilford progeria syndrome and Werner syndrome (see these terms) also feature premature baldness and arteriosclerosis, they must also be excluded.
Antenatal diagnosis
Antenatal diagnosis is possible for at-risk pregnancies, where one parent has a known disease-causing mutation in the family.
Genetic counseling
CARASIL is inherited autosomal recessively. Genetic counseling is recommended in families where a mutation in the HTRA1 gene has been identified.
Management and treatment
There is no cure for CARASIL syndrome. Emotional support and counseling for patients and their families is recommended. Canes or a wheelchair may be needed due to gait problems and medications such as tizanidine and baclofen may relieve spasticity. Anxiolytic medication may be prescribed for character changes. A high-salt diet and smoking should be avoided due to arteriosclerosis.
Prognosis
The prognosis is poor with the average duration of illness lasting 10 years.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Pr Osamu ONODERA


A rare, potentially life-threatening, circulatory system disease characterized by variable signs and symptoms which may include headache, seizures, altered mental status, intracranial hypertension and cavernous sinus syndrome, among others.


A rare neurologic disease characterized by significant visual dysfunction that cannot be explained by ocular abnormalities alone and is due to damage to post-chiasmatic visual pathways and structures during early perinatal development. Signs and symptoms include decreased visual acuity, visual field defects, and impairments in visual processing and attention.


Cerebro-costo-mandibular syndrome (CCMS) is characterized at birth by posterior rib gaps and orofacial anomalies reminiscent of Pierre Robin syndrome (see this term) that include palatal defects (short hard palate, absent soft palate, absent uvula), micrognathia and glossoptosis.

Summary:
Epidemiology
More than 80 cases have been reported to date; both males and females are equally affected.
Clinical description
CCMS is characterized by orofacial and costovertebral developmental anomalies. Severity is highly variable. Intrauterine growth retardation and low birth weights are common. Orofacial anomalies may include absent soft palate and a short hard palate with posterior notching, micrognathia and glossoptosis. Characteristic dorsal rib defects are sine qua non of the syndrome and often result in a bell-shaped thorax. Posterior rib gaps and rib defects are revealed by X-ray; there is no apparent continuity between the ossiﬁed ribs which are usually divided into two portions. This may lead to ''flail chest,'' a paradoxical movement of a segment of the thoracic wall due to broken ribs, which may further hamper respiration. Respiratory difficulties lead to generalized cyanosis and potential hypoxic brain injuries that may be responsible for intellectual deficit that may be observed later. Associated malformations were described in rare cases: microcephaly, absence of external ear canals and spina bifida. Those patients who survive infancy may suffer from growth retardation, scoliosis, reduced lung capacity, dental anomalies, feeding disturbances, conductive hearing loss and language disturbances. Patients who survive the first year of life are reported to survive to adulthood and to harbor a less severe form. These patients may suffer from growth retardation, scoliosis, reduced lung capacity, dentition anomalies, feeding disturbances, intellectual deficit, conductive hearing loss and language disturbance.
Etiology
No causative gene has been identified to date. It has been proposed, however, that defects in the sonic hedgehog (SHH) signaling cascade may be responsible for these developmental anomalies.
Diagnostic methods
Clinical presentation, along with typical chest X-ray findings, confirms the diagnosis.
Differential diagnosis
Differential diagnoses include trisomies 13 and 18, and Pierre Robin syndrome (see these terms).
Antenatal diagnosis
Although most cases are spontaneous, both autosomal recessive and autosomal dominant patterns of inheritance have been observed in familial cases.
Management and treatment
Orofacial anomalies responsible for breathing and feeding difficulties must be immediately addressed and severe cases must be transferred to intensive care units. Affected infants require feeding assistance and should lie in the prone position to help bring the tongue forward and liberate the trachea. Intubation or placement of a nasopharyngeal airway may be necessary. As tracheal intubation may prove impossible, a neonatal laryngeal mask airway, intermittently replaced by nasal prongs and continuous positive airway pressure, may be required. In these most severe cases, tongue-lip adhesion surgical intervention may provide a long term solution. A Haberman feeder may be of use in infants with cleft palate and nasogastric tube supplementation may be required to provide supplementary caloric intake.
Prognosis
Prognosis depends upon the severity of anomalies. The most severe forms are often fatal within the first hours after birth and 25% of all reported cases are fatal during the first month of life. This correlates significantly with greater numbers of missing ribs or gaps.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Dr Hiroyuki NAGASAWA


Cerebrofacial arteriovenous metameric syndrome type 1

A rare subtype of cerebrofacial arteriovenous metameric syndrome characterized by unilateral arteriovenous malformations involving the hypothalamus and nasal region (medial prosencephalic group). The condition manifests in childhood. Common presenting signs and symptoms are progressive neurological deficit, hemorrhage, and cosmetic complaints like facial asymmetry.


Cerebrofacial arteriovenous metameric syndrome type 3

A rare subtype of cerebrofacial arteriovenous metameric syndrome characterized by unilateral arteriovenous malformations involving the cerebellum, pons, and mandible (lateral rhombencephalic group). The condition manifests in childhood. Common presenting signs and symptoms are progressive neurological deficit, hemorrhage, and cosmetic complaints like facial asymmetry.


A group of rare, nonhereditary, complex cerebrofacial vascular malformation characterized by multiple ipsilateral arteriovenous malformations (AVMs) with a metameric distribution, affecting various territories of the face with corresponding areas of the brain. The spectrum is highly variable with three types described according to lesion distribution: CAMS 1 derives from the medial prosencephalon with concurrent involvement of hypothalamus, nose, forehead; CAMS 2 arises from the lateral prosencephalon and involves basal ganglia, optic nerve and retina and maxillo-facial region; CAMS 3 derives from the rhombencephalon and involves cerebellum and mandible.

Summary:
Epidemiology
Fewer than 100 cases have been reported in the literature to date. The sex ratio is even.
Clinical description
Cerebrofacial arteriovenous metameric syndrome (CAMS) typically presents before the third decade of life. The spectrum is highly variable and symptoms will depend on the lesion's location. The neurological symptoms vary according to the affected cerebral area (hemiparesis, hemorrhage, visual field defect ...) as the maxilla-facial symptoms vary according to the facial extension (nosebleed, maxilla-facial deformation and AVMs, hemorrhage). Focal distribution of the lesions can be seen in partial spectrum of the disease.
Etiology
While the etiology and risk factors are unknown, a somatic mutation in the neural crest prior to migration is thought to produce the vascular lesions. Recent data suggest the role of somatic mutation of the RAS-MAPK signaling pathway in the pathogenesis of cerebrofacial AVMs.
Diagnostic methods
The diagnosis is made on clinical and radiological exam; partial manifestations of the syndrome does not exclude diagnosis. Retinal AVMs are usually diagnosed by ophthalmoscopy although fluorescein angiography may be required to demonstrate smaller lesions. Intracranial lesions can be diagnosed with magnetic resonance imaging/angiography (MRI/MRA), computed tomography and digital subtraction angiography.
Differential diagnosis
Differential diagnosis includes has to be made with other types of cerebrofacial vascular metameric syndromes like Sturge-Weber syndromes that affect the venous circulations in a metameric way without any shunt, or Von Hippel-Lindau disease that corresponds to vascular tumors as hemangioblastoma that can be seen in the retina or central nervous system. Lower metameric distribution compared to CAMS will correspond to spinal arteriovenous metameric syndromes (SAMS 1-31, or Cobb syndrome).
Genetic counseling
The disease is sporadic; no familial cases have been identified.
Management and treatment
Management depends on clinical presentation and can be conservative for asymptomatic or pauci-symptomatic lesions. Treatment is typically symptomatic and may include surgery, embolization or radiosurgery. Usually, given the lesions extension, complete curative treatment is not achievable. Medical antiangiogenic treatments are under evaluation.
Prognosis
Prognosis depends on the location and progression of AVMs, and while some patients may remain asymptomatic others will experience visual and/or neurological problems, as cosmetic sequelae related to the soft tissue AVM.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Dr Julien COULIE  - Dr Georges RODESCH | VASCERN* - Dr Stanislas SMAJDA | VASCERN*

                                * European Reference Network


Cerebrofacioarticular syndrome is a rare multiple congenital anomalies syndrome characterized by mild to severe intellectual disability, a distinctive facial gestalt (blepharophimosis, maxillary hypoplasia, telecanthus, microtia and atresia of the external auditory meatus) as well as skeletal and articular abnormalities (e.g. camptodactyly of the fingers, cutaneous syndactyly, talipes equinovarus, flexion contractures of the proximal interphalangeal joints, hip or elbow subluxation, joint laxity). Affected individuals also present neonatal hypotonia, variable respiratory manifestations, chronic feeding difficulties and gray matter heterotopia.


Cerebro-facio-thoracic dysplasia or Pascual-Castroviejo syndrome type 1 is a rare syndrome characterized by facial dysmorphism, intellectual deficit and costovertebral abnormalities.

Summary:
Epidemiology
To date, 13 cases have been reported in the literature.
Clinical description
Dysmorphic features include brachycephaly, hypertelorism, broad nasal bridge, large philtrum, triangular-shaped mouth and micrognathia. There is often synophris and a low hair line on the back. Costovertebral abnormalities are always present: short, bifid or fused ribs, bony bridges joining the posterior arches in some ribs, hemi vertebrae. Intellectual deficit is constant but the severity varies and patients also have cerebral abnormalities: cortical atrophy, hypoplasia of the corpus callosum and cerebellar vermis.
Etiology
It is most likely that the condition is hereditary, transmitted as an autosomal recessive trait.
Antenatal diagnosis
Antenatal diagnosis is possible by ultrasonographic monitoring for cerebral, costal or vertebral malformations.

                            Last update:
                            January 2010


Cerebro-oculo-nasal syndrome is a multisystem malformation syndrome that has been reported in about 10 patients. The clinical features include bilateral anophthalmia, abnormal nares, central nervous system anomalies, and neurodevelopmental delay.

Summary:
Clinical description
Additional features include brachycephaly (the nose may have a proboscis-like appearance) and other facial anomalies such as large forehead, flat supraorbital ridges, ocular hypertelorism, epicanthic folds, downslanting palpebral fissures, sparse and medially absent eyebrows, sparse eyelashes, malar hypoplasia, large philtrum, high-arched palate possibly associated with atypical cleft lip and a single maxillary central incisor, posteriorly rotated ears with hypoplastic tragus and large conchae. Non facial anomalies have also been reported: postaxial polydactyly, genital hypoplasia.
Antenatal diagnosis
No case of prenatal diagnosis has been reported.
Genetic counseling
All cases reported so far have been sporadic, suggesting that the syndrome may be due to a new dominant mutation.

                            Last update:
                            March 2006


Cerebrotendinous xanthomatosis (CTX) is an anomaly of bile acid synthesis (see this term) characterized by neonatal cholestasis, childhood-onset cataract, adolescent to young adult-onset tendon xanthomata, and brain xanthomata with adult-onset neurologic dysfunction.

Summary:
Epidemiology
More than 300 patients have been reported worldwide. Prevalence is estimated to be approximately 1/50,000 among Caucasians.
Clinical description
The initial clinical manifestation may be neonatal cholestasis or chronic diarrhea from infancy. In 75% of cases, cataract is the first finding, often appearing in childhood. Infants may present with cholestasis and liver dysfunction. Xanthomata may appear in the 2nd or 3rd decade of life, in the Achilles and other tendons (elbow, hand, patella, neck). Some patients show intellectual impairment from infancy, but most have normal or subnormal intellectual function until puberty. Adult-onset progressive neurologic dysfunction includes dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, seizures, and neuropathy. Dementia occurs in the 20s in over 50% of cases. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicidal tendencies may be prominent. Pyramidal signs and/or cerebellar ataxia are present in the 20s or 30s. Patients may experience extrapyramidal manifestations (dystonia and atypical parkinsonism), and peripheral neuropathy.
Etiology
CTX is caused by mutations in the sterol 27-hydroxylase gene (CYP27A1; 2q33-qter). Sterol 27-hydroxylase catalyzes the first step in the oxidation of the side-chain of sterol intermediates in the bile acid synthesis (BAS) pathway. Defective enzymatic function disrupts bile acid synthesis leading to cholesterol and cholestanol deposits, which result in a degenerative process.
Diagnostic methods
Mass spectrometry analysis of urine enables early diagnosis in children by showing characteristic bile alcohol metabolites. Diagnosis in adults is based on two of the following criteria: intractable diarrhea, presenile cataracts, tendinous xanthomata and neurologic abnormalities, and abnormal amounts of cholestanol in serum and tendons. Plasma cholesterol concentration may be low or normal. MRI shows bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter. Molecular genetic testing in a certified laboratory may be used to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include other causes of xanthomata such as sitosterolemia and hyperlipemia (especially type IIa, also known as familial hypercholesterolemia [see these terms]), and for infants presenting with cholestasis, all other causes of neonatal cholestasis.
Antenatal diagnosis
Antenatal diagnosis can be established by analysis of embryonic tissue when there has been a previously identified sibling.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to affected families.
Management and treatment
First-line treatment is based on chenodeoxycholic acid (CDCA) replacement therapy, which normalizes BAS and cholestanol concentrations, and improves neurological symptoms. Inhibitors of HMG-CoA reductase may also be used alone or in combination with CDCA, although they may induce muscle damage. Cataract extraction is typically required by age 50 years. Cholic acid treatment has also been used. It is not as effective as CDCA in suppressing BAS and the production of cholestanol, but lacks the hepatotoxicity of CDCA.
Prognosis
Early diagnosis and treatment are crucial to prevent progressive accumulation of cholestanol and cholesterol: disease progression may be halted and in some cases reversed. Treated patients may have a normal lifespan. In untreated patients, life expectancy is 50 to 60 years. Some early deaths in infancy have also been reported.

                            Last update:
                            September 2011

                            - Expert reviewer(s):
                            Pr James HEUBI


Cernunnos-XLF deficiency is a rare form of combined immunodeficiency characterized by microcephaly, growth retardation, and T and B cell lymphopenia.

Summary:
Epidemiology
Prevalence is unknown. To date, five cases have been reported.
Clinical description
Patients present in childhood with growth retardation, microcephaly, uro-genital and bone malformations, dysmorphic features, including ''bird-like'' facial dysmorphism, and features of combined immunodeficiency including recurrent opportunistic, viral and bacterial infections. Some patients may also present with autoimmune cytopenia (anemia and thrombocytopenia). Patients share several clinical features with Nijmegen breakage syndrome and LIG 4 deficiency (see these terms).
Etiology
This disease is caused by mutations in the NHEJ1 (or Cernunos) gene (2q35). The resulting defect of Cernunnos/XLF, a core protein of the non-homologous end-joining (NHEJ) pathway, affects the major mechanism of DNA double-strand break repair.
Diagnostic methods
Diagnosis is based on the combination of clinical features with evidence of B and T cell lymphocytopenia with normal levels of natural killer (NK) cells. Fibroblasts also exhibit increased radiosensitivity.
Differential diagnosis
Differential diagnoses include Nijmegen breakage syndrome and LIG4 syndrome (see these terms).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is based on antibiotic treatment of infections, immunoglobulin replacement, antiviral prophylaxis and allogeneic hematopoietic stem-cell transplantation (HSCT). Radiotherapy as part of conditioning regimens should be avoided. Reduced intensity conditioning regimens are favored.
Prognosis
Without treatment, the immunodeficiency may result in severe infection, sepsis and early death.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


A type of hereditary congenital cataract, distinguished by bluish and white opacifications in the superficial layers of the fetal lens nucleus and adult lens nucleus, and characterized by reduced visual acuity in childhood, eventually necessitating extraction of the lens.


A rare, congenital anomaly of the great arteries characterized by cranially situated aortic arch ascending into the neck above the clavicles. Most patients remain asymptomatic, some present with a murmur and a pulsatile neck mass, stridor, dyspnea, recurrent bronchitis, dysphagia or signs and symptoms of a stenosis/aneurism of the aortic arch. Other congenital heart anomalies are frequently associated, including abnormalities of arch laterality and branching, aortic coarctation or aneurysm.


Cervical dermoid cyst is a rare, benign cutaneous neoplasm containing keratinized epithelium and dermal derivatives, such as hair follicles, sweat and sebaceous glands, smooth muscle or fibroadipose tissue which usually manifests as a slow-growing, painless mass in the submandibular or sublingual space. Depending on the location, and especially after sudden enlargement, it can cause dyspnea, dysphagia or dysphonia.


Cervical hypertrichosis-peripheral neuropathy syndrome

A rare genetic syndrome characterized by the association of congenital hypertrichosis in the anterior cervical region with peripheral sensory and motor neuropathy. Associated features may include retinal anomalies, spina bifida, kyphoscoliosis and hallux valgus, and developmental delay (one case). There have been no further descriptions in the literature since 1993.


A rare extraskeletal chondroma located in the head and neck region, histologically typically characterized by lobules of mature, adult hyaline cartilage with chondrocytic cells identifiable in lacunae, and prominent fibrosis. Malignant transformation has not been described.


A rare ectodermal dysplasia syndrome characterized by the association of sparse, woolly, curly hair, ankyloblepharon, and nail dysplasia. Additional reported features include abnormal oral frenula, bifid tongue, lip pits, adhesions between upper and lower lips, hypertelorism and flat nasal bridge, alveolar synechia, and imperforate vagina.


A clinical variant of iridocorneal endothelial (ICE) syndrome, characterized by very few iris abnormalities but more severe corneal edema and less severe secondary glaucoma than seen in the other two ICE syndrome variants: Cogan-Reese syndrome and essential iris atrophy.


Chapare hemorrhagic fever, caused by the Chapare virus (a new arenavirus), discovered from a small outbreak in Cochabamba, Bolivia between 2003 and 2004, is an acute viral hemorrhagic fever characterized by fever, myalgia, arthralgia, and multiple hemorrhagic signs. About a third of untreated cases go on to develop more severe symptoms with delirium, coma and convulsions and death (in one case). No other cases have been reported since.


A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the triad of patent ductus arteriosus (PDA), facial dysmorphism (wide-set eyes, downslanting palpebral fissures, mild ptosis, flat midface, flat nasal bridge and upturned nasal tip, short philtrum with a triangular mouth, and thickened, everted lips) and hand anomalies (aplasia or hypoplasia of the middle phalanges of the fifth fingers).

Summary:
Epidemiology
Approximately 100 individuals from 13 families have been reported in the medical and scientific literature.
Clinical description
Typical facial features include wide-set eyes, downslanting palpebral fissures, mild ptosis, flat midface, flat nasal bridge, upturned nasal tip, a short philtrum, a triangular mouth, and thickened (patulous) everted lips. Hand abnormalities include aplasia or hypoplasia of the middle phalanges of the fifth fingers but can also be as minimal as fifth finger clinodactyly, which can be a normal finding and overlaps with numerous other syndromes. Less common features associated with Char syndrome include additional heart defects (such as interventricular communication or complex congenital defects), additional hand abnormalities (such as interstitial polydactyly, distal symphalangism of the fifth fingers, fusion of the distal interphalangeal joints), polythelia, foot anomalies (interphalangeal joint fusion, clinodactyly, interstitial polydactyly, or syndactyly), strabismus, mild to moderate developmental delay, prominent occiput, persistence of the deciduous teeth in the absence of permanent dentition, and somnambulism.
Etiology
Causal mutations have been identified in the TFAP2B gene (chromosome 6p12.3), encoding a member of the AP-2 family of transcription factors. TFAP2B sequence analysis detects pathogenic variants in approximately 50% of affected individuals. The pathogenic variant p.Pro63Arg is associated with a less severe phenotype with mild facial dysmorphism, PDA and absence of hand anomalies. TFAP2B mutations have also been reported in familial patent arterial duct.
Diagnostic methods
The diagnosis is established by the presence of the key clinical features.
Differential diagnosis
The associated facial features associated are not often confused with those observed in other disorders. The primary differential diagnosis includes other heart-hand syndromes (including Holt-Oram syndrome, Tabatznik syndrome, and heart-hand type III).
Antenatal diagnosis
Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the pathogenic variant in the family. In at-risk pregnancies, prenatal ultrasound examination may identify abnormal hands or feet, as well as complex congenital heart defects. PDA is a normal fetal feature and cannot be used as a diagnostic marker in utero.
Genetic counseling
The pattern of inheritance is autosomal dominant but may arise de novo. Where the parent is affected, the sibling recurrence risk is 50%. In sporadic cases, the sibling recurrence risk is very low (<1%) due to the theoretical possibility of gonadal mosaicism in a parent.
Management and treatment
The major focus for management and treatment is the cardiovascular involvement. Management of PDA after the immediate newborn period is determined by the degree of shunting from the aorta to the pulmonary artery. Surgical ligation or ductal occlusion with catheterization are treatment options. Early special care for the dysmorphia and hand anomalies is not required but plastic surgery may be considered later in life. The outcomes of plastic surgery for the facial features are unknown. Preventive pediatric care should be offered for the associated anomalies (including visual problems and developmental delay).
Prognosis
The prognosis depends on the potential presence of associated heart malformations. Early intervention of the additional anomalies can improve outcomes.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Dr Bruce GELB


Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominant demyelinating peripheral neuropathies characterized by distal weakness and atrophy, sensory loss, foot deformities, and slow nerve conduction velocity.

Summary:
Epidemiology
The prevalence of CMT1 is estimated to be between 1/7,000 and 1/5,000, with CMT1A representing 70% of cases.
Clinical description
Age of onset of CMT1 varies widely and ranges from infancy to the fourth or subsequent decades of life. Typically, patients become symptomatic between the first and the second decade of life; however, the full clinical picture may appear later. Clinical severity is variable, ranging from extremely mild disease, which goes unrecognized, to considerable weakness and disability. Affected individuals typically develop distal weakness, symmetric atrophy of muscles (mainly peroneal), and reduced-to-absent tendon reflexes. Sensory deficits of position, vibration, and pain/temperature commonly occur in the feet and later in the hands. Pes cavus (or planus) with hammer toes is often present since childhood. Variable scoliosis may develop during adolescence.
Etiology
CMT1A can be caused by 1.4 Mb duplications or by point mutations in the PMP22 gene (17p12). CMT1E is caused by point mutations in the PMP22 gene (17p12). CMT1B is associated with MPZ (1q22) gene mutations. CMT1C, CMT1D and CMT1F (see these terms) are associated with pathogenic variants in LITAF (16p13.3), EGR2 (10q21.1) and NEFL (8p21.2), respectively.
Diagnostic methods
Diagnosis of CMT1 is based on progressive peripheral motor and sensory neuropathy; slow nerve conduction velocity (NCV) with motor NCV <38 m/s in upper limbs; and positive family history (however, sporadic presentations may occur, due to de novo mutations). Genetic testing is the gold standard for diagnosis.
Differential diagnosis
Differential diagnosis includes other genetic neuropathies, especially X-linked CMT, autosomal dominant CMT2, CMT4, and hereditary neuropathy with liability to pressure palsies (see these terms). CMT1 identification may be challenging when there is no family history and acquired demyelinating neuropathies must also be taken into account.
Antenatal diagnosis
Preimplantation genetic diagnosis may be an option for families in which the pathogenic variant has been identified.
Genetic counseling
Transmission is autosomal dominant with complete penetrance and genetic counseling is recommended.
Management and treatment
Treatment is multidisciplinary and includes use of special shoes, inserts and/or ankle foot orthoses; forearm crutches, canes, and wheelchairs for the most severe cases, as needed for mobility; surgery for severe pes cavus, as needed; exercise for muscle strengthening, as tolerated; stretching to prevent Achilles' tendon shortening; and regular foot examination for pressure sores. Occupational therapy focused on strategies/tools to help patients with daily living activities is useful, especially for those with hand weakness.
Prognosis
CMT1 is slowly progressive and affected individuals experience long plateau periods without obvious deterioration. Most patients remain ambulatory throughout life and have a normal lifespan.

                            Last update:
                            March 2016

                            - Expert reviewer(s):
                            Dr Davide PAREYSON  - Dr Chiara PISCIOTTA


Charcot-Marie-Tooth disease type 1B (CMT1B) is a form of CMT1 (see this term), caused by mutations in the MPZ gene (1q22), that presents with the manifestations of peripheral neuropathy (distal muscle weakness and atrophy, foot deformities and sensory loss). The phenotype is variable depending on the particular mutation. Two distinct presentations have been described: (1) an early infantile onset severe phenotype with delayed walking and motor nerve conduction velocities (MNCV) <10 m/s, often referred to as Dejerine-Sottas syndrome (see this term), or (2) a much later onset phenotype (>age 40), with normal or mildly slowed MNCV and more frequent hearing loss and pupillary abnormalities. CMT1B can also cause the classical CMT phenotype in about 15% of total CMT1B cases.


A rare, autosomal dominant, hereditary, demyelinating motor and sensory neuropathy which may present either as a classic Charcot-Marie-Tooth disease phenotype with distal motor weakness and wasting, gait difficulties, parethesias, decreased vibration and pain sensation, or as a milder, predominantly sensory form with transient paresthesias, decreased sensation and distal pain in upper or lower limbs, without significant motor weakness. Pes cavus is a common feature, and additional symptoms may include hand tremor and decreased or absent deep tendon reflexes.


Charcot-Marie-Tooth disease type 1D (CMT1D) is a form of CMT1 (see this term), caused by mutations in the EGR2 gene (10q21.1), with a variable severity and age of onset (from infancy to adulthood), that usually presents with gait abnormalities, progressive wasting and weakness of distal limb muscles, with possible later involvement of proximal muscles, foot deformity and severe reduction in nerve conduction velocity. Additional features may include scoliosis, cranial nerve deficits such as diplopia, and bilateral vocal cord paresis.


A rare subtype of CMT1 characterized by a variable clinical presentation. Onset within the first two years of life with a delay in walking is not uncommon; however, onset may occur later. CMT1E is caused by point mutations in the PMP22 (17p12) gene. The disease severity depends on the particular PMP22 mutation, with some cases being very mild and even resembling hereditary neuropathy with liability to pressure palsies, while others having an earlier onset with a more severe phenotype (reminiscent of Dejerine-Sottas syndrome) than that seen in CMT1A, caused by gene duplication. These severe cases may also report deafness and much slower motor nerve conduction velocities compared to CMT1A patients.


Charcot-Marie-Tooth disease type 1F (CMT1F) is a form of CMT1, with a variable clinical presentation that can range from severe impairment with onset in childhood to mild impairment appearing during adulthood. CMT1F is characterized by a progressive peripheral motor and sensory neuropathy with distal paresis in the lower limbs that varies from mild weakness to complete paralysis of the distal muscle groups, absent tendon reflexes and reduced nerve conduction. CMT1F represents the ''demyelinating'' form of CMT2E and is caused by mutations in the NEFL gene (8p21.2).


Charcot-Marie-Tooth disease, type 2B1 (CMT2B1, also referred to as CMT4C1) is an axonal CMT peripheral sensorimotor polyneuropathy.

Summary:
Epidemiology
It has been described exclusively in families originating from North-Western Africa (northwest Algeria and the east of Morocco).
Clinical description
Onset occurs in the second decade of life. The disease course and severity are variable, even between affected members of the same family. In general, the disease manifests as distal muscle weakness and atrophy that progress gradually to the proximal muscles. Involvement of the upper and lower limbs has been reported. Sensory impairment may also be present but foot deformities are either moderate or absent. Proximal muscle atrophy of the pelvic and scapular girdle may occur later in the disease course.
Etiology
CMT2B1 is caused by a p.R644C missense mutation in the lamin A/C protein (encoded by the LMNA gene, 1q22).
Genetic counseling
CMT2B1 is transmitted in an autosomal recessive manner.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Carmen ESPINÓS  - Pr Francesc PALAU


Charcot-Marie-Tooth disease, type 2B2 (CMT2B2, also referred to as CMT4C3) is an axonal CMT peripheral sensorimotor polyneuropathy that has been described in a large consanguineous Costa Rican family of Spanish ancestry.

Summary:
Clinical description
Onset occurs in adulthood (between 26 and 42 years of age) with symmetric moderate to severe weakness of the distal muscles, predominantly affecting the lower extremities. Marked sensory deficits were also reported.
Etiology
CMT2B2 is transmitted in an autosomal recessive manner and the disease-causing gene was mapped to chromosome 19q13.3 (MED25).

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Carmen ESPINÓS  - Pr Francesc PALAU


A rare axonal hereditary motor and sensory neuropathy characterized by infantile onset of slowly progressive distal motor weakness and atrophy (more severe in legs and moderate in arms) with mildly delayed motor development, hypotonia, and distal sensory impairment of all sensory modalities.


Charcot-Marie-Tooth disease, type 2H (CMT2H, also referred to as CMT4C2) is an axonal CMT peripheral sensorimotor polyneuropathy associated with pyramidal involvement.

Summary:
Epidemiology
So far, it has been described in 13 members of a large Tunisian family.
Clinical description
Onset occurred during the first decade of life with progressive distal atrophy involving both the upper and lower limbs, associated with a mild pyramidal syndrome (brisk patellar and upper limb reflexes, absent ankle reflexes and unattainable plantar reflexes).
Etiology
CMT2H is transmitted in an autosomal recessive manner and the disease-causing locus has been mapped to 8q13-21.1. This region contains the GDAP1 gene, which has been implicated in the demyelinating disease CMT4A, and in the axonal disease CMT4C4 or CMT2K (see these terms).

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Carmen ESPINÓS  - Pr Francesc PALAU


Charcot-Marie-Tooth disease type 2P is a rare, genetic, axonal hereditary motor and sensory neuropathy disorder characterized by adulthood-onset of slowly progressive, occasionally asymmetrical, distal muscle weakness and atrophy (predominantly in the lower limbs), pan-modal sensory loss, muscle cramping in extremities and/or trunk, pes cavus and absent or reduced deep tendon reflexes. Gait anomalies and variable autonomic disturbances, such as erectile dysfunction and urinary urgency, may be associated.


A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by early-onset axial hypotonia, generalized muscle weakness, absent deep tendon reflexes and decreased muscle mass. Electromyography reveals decreased motor nerve conduction velocities with markedly reduced sensory and motor amplitudes.


A rare subtype of axonal hereditary motor and sensory neuropathy characterized by progressive distal muscle weakness and atrophy of both the lower and upper limbs, absent or reduced deep tendon reflexes, mild sensory loss, foot drop, and pes cavus leading eventually to wheelchair dependance. Some patients present with early hypotonia and delayed motor development. Scoliosis and variable autonomic disturbances may be associated.


A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by adult onset of slowly progressive distal muscle weakness and atrophy, sensory impairment, and decreased or absent deep tendon reflexes predominantly in the lower extremities. Patients present gait disturbances but remain ambulatory. Mild involvement of the upper limbs may be seen.


A disorder that belongs to the genetically heterogeneous group of CMT peripheral sensorimotor polyneuropathy diseases.

Summary:
Epidemiology
The prevalence of all forms of CMT is around 1 in 3,330; however, CMT4 is less common and often limited to certain ethnic groups.
Clinical description
The term CMT4 is classically applied to autosomal recessive demyelinating forms of CMT, although current trends point towards a reclassification of CMT4 forms to include autosomal recessive axonal types. CMT4 patients present with the typical CMT phenotype characterized by progressive, distally accentuated weakness and atrophy of muscles innervated by the peroneal nerve in the lower limbs, followed by weakness and atrophy of hands, sensory loss, and characteristic foot abnormalities. CMT4 is usually more severe than other forms of CMT and onset occurs earlier. The disease may arise in early infancy with hypotonia or may manifest in later infancy with toe walking. The most common symptoms are walking difficulties with steppage gait or pes cavus. Hammer toes are frequent and other skeletal deformities, such as scoliosis, are often observed. Sensory signs are usually less prominent than motor signs. The most frequent finding is distal loss of sensation to touch, pain, and vibration in the lower limbs. Deep tendon reflexes are reduced or absent in most patients with demyelinating CMT4. To date, 15 forms of CMT4 have been described, including eleven demyelinating (CMT4 types A, 4B1, 4B2, 4C, 4D, 4E, 4F, 4G, 4H, 4J and CCFDN; see these terms) and four axonal forms (CMT4 types 4C1, 4C2, 4C3 and 4C4; see these terms).
Etiology
So far, fourteen genes and two loci have been described associated with these fifteen CMT variants and the roles and functions of the proteins encoded by these CMT4 genes are diverse.
Diagnostic methods
The diagnostic approach includes clinical examinations (natural history of the disease, and neurological and systemic examinations), together with definition of the inheritance pattern, electrophysiological studies and a nerve biopsy for selected patients. Identification of the disease-causing mutation supports the clinical and electrophysiological diagnosis. Definitive diagnosis is extremely difficult because the phenotype is similar throughout the spectrum of clinical types, both demyelinating and axonal.
Genetic counseling
Genetic counseling should be offered to the parents of an affected individual and prenatal diagnosis should be proposed when the disease is well diagnosed and the disease-causing mutation in the family has been identified.
Management and treatment
There is currently no cure for CMT and treatment is only symptomatic: physical therapy and orthopedic management for musculoskeletal dysfunction; pulmonary evaluation, ventilatory support, and scoliosis correction for respiratory dysfunction; and pain control, antidepressants and anticonvulsants for sensory dysfunction.
Prognosis
The prognosis for the different types of CMT4 varies and depends on the clinical severity. In general CMT is a slowly progressive neuropathy, causing eventual disability but, in the absence of secondary complications, does not generally reduce life expectancy. However, early-onset and severe respiratory complications associated with some forms of CMT4 (notably CMT4C4, CMT4B1, CMT4B2 and CMT4E) may lead to a poorer prognosis with early death in some cases.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Carmen ESPINÓS  - Pr Francesc PALAU


Charcot-Marie-Tooth disease type 4A (CMT4A) is a subtype of Charcot-Marie-Tooth disease type 4 characterized by early-onset (infancy to early childhood) of severe, rapidly progressing demyelinating, axonal, or intermediate sensorimotor neuropathy usually affecting first, and more severely, the distal lower extremities and later the proximal muscles and upper extremities. Nerve conduction velocities range from very slow to normal. Apart from the typical CMT phenotype (distal muscle weakness and atrophy, sensory loss, frequent pes cavus foot deformity), patients commonly present delayed motor development, vocal cord paresis, mild sensory loss, abolished deep tendon reflexes, and skeletal deformities.


Charcot-Marie-Tooth disease type 4B1 (CMT4B1) is a subtype of Charcot-Marie-Tooth disease type 4 characterized by an early childhood-onset of severe, demyelinating sensorimotor neuropathy, various degrees of complex myelin outfoldings seen on peripheral nerve biopsy, very slow, and often undetectable, nerve conduction velocities, and the typical CMT phenotype (i.e. distal muscle weakness and atrophy, sensory loss, and frequent pes cavus). Other reported features include facial weakness, vocal cord paresis, respiratory difficulties, and skeletal deformities (e.g. chest deformities, claw hands, pes equinovarus).


Charcot-Marie-Tooth disease type 4B2 (CMT4B2) is a subtype of Charcot-Marie-Tooth type 4 characterized by a severe, early childhood-onset of demyelinating sensorimotor neuropathy, early-onset glaucoma, focally folded myelin sheaths in the peripheral nerves, severely reduced nerve conduction velocities, and the typical CMT phenotype (i.e. distal muscle weakness and atrophy, sensory loss, and frequent pes cavus). Severe visual impairment leading to visual loss has also been reported.


Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is a subtype of Charcot-Marie-Tooth type 4 characterized by a childhood onset of slowly progressing, demyelinating sensorimotor neuropathy, focally folded myelin sheaths in nerve biopsy, reduced nerve conduction velocities (less than 38 m/s), and the typical CMT phenotype (i.e. distal muscle weakness and atrophy, and sensory loss).


Charcot-Marie-Tooth disease type 4C (CMT4C) is a subtype of Charcot-Marie-Tooth type 4 characterized by childhood or adolescent-onset of a relatively mild, demyelinating sensorimotor neuropathy that contrasts with a severe, rapidly progressing, early-onset scoliosis, and the typical CMT phenotype (i.e. distal muscle weakness and atrophy, sensory loss, and often foot deformity). A wide spectrum of nerve conduction velocities are observed and cranial nerve involvement and kyphoscoliosis have also been reported.


Charcot-Marie-Tooth disease type 4D (CMT4D) is a subtype of Charcot-Marie-Tooth disease type 4 characterized by a childhood-onset of severe, progressive, demyelinating sensorimotor neuropathy manifesting with distal muscle weakness and atrophy, sensorineural hearing impairment leading to deafness (usually in third decade), severely reduced nerve conduction velocities, and skeletal, especially foot, deformities. Tongue atrophy has also been reported.


Charcot-Marie-Tooth disease type 4E (CMT4E) is a congenital, hypomyelinating subtype of Charcot-Marie-Tooth disease type 4 characterized by a Dejerine-Sottas syndrome-like phenotype (incl. hypotonia and/or delayed motor development in infancy), extremely slow nerve conduction velocities, potential respiratory dysfunction, cranial nerve involvement, and the typical CMT phenotype, i.e. distal muscle weakness and atrophy, sensory loss, and foot deformity.


Charcot-Marie-Tooth disease type 4F (CMT4F) is a severe, demyelinating subtype of Charcot-Marie-Tooth disease type 4 characterized by the childhood onset of a slowly-progressing typical CMT phenotype (i.e. distal muscle weakness and atrophy, as well as pes cavus) that presents severe sensory loss (frequently with sensory ataxia), moderately to severely reduced motor nerve conduction velocities and almost invariable absence of sensory nerve action potentials, and delayed motor milestones.


Charcot-Marie-Tooth disease type 4G (CMT4G) is a subtype of Charcot-Marie-Tooth disease type 4 characterized by early childhood onset of progressive distal muscle weakness and atrophy, delayed motor development, prominent distal sensory impairment, areflexia, moderately reduced nerve conduction velocities, and foot and hand deformities in Balkan (Russe) Gypsies.


Charcot-Marie-Tooth disease type 4H is a subtype of Charcot-Marie-Tooth disease type 4 characterized by onset before two years of age of severe, slowly progressive, demyelinating sensorimotor neuropathy manifesting with delayed motor development (walking), unsteady gait, distal muscle weakness and atrophy (more prominent in the lower limbs), areflexia, mild symmetrical stocking-distribution hypoesthesia, and skeletal malformations (incl. kyphoscoliosis, short neck, pes cavus and pes equinus). Severely reduced nerve conduction velocities are associated.


Charcot-Marie-Tooth disease type 4J is a subtype of Charcot-Marie-Tooth disease type 4 characterized by childhood- to adulthood-onset of variably severe, rapidly progressive, axonal and demyelinating sensorimotor neuropathy typically manifesting with delayed motor development, proximal and distal asymmetric muscle weakness and atrophy of the lower and upper extremities, severe motor dysfunction with mildly reduced sensory impairment, and areflexia. Nerve conduction velocities range from very mildly to severely reduced.


Charcot-Marie-Tooth disease-deafness-intellectual disability syndrome is a rare demyelinating hereditary motor and sensory neuropathy characterized by early-onset, slowly progressive, distal muscular weakness and atrophy with no sensory impairment, congenital sensorineural deafness and mild intellectual disability (with absence of normal speech development). The absence of large myelinated fibers on sural nerve biopsy is equally characteristic of the disease.


CHARGE syndrome is a multiple congenital anomaly syndrome characterized by the variable combination of multiple anomalies, mainly Coloboma; Choanal atresia/stenosis; Cranial nerve dysfunction; Characteristic ear anomalies (known as the major 4 C's).

Summary:
Epidemiology
The incidence is estimated to be 1/12,000 - 15,000 live births.
Clinical description
The syndrome shows a variable clinical picture, even within a family, depending on the associated anomalies. It presents in the neonatal period with cyanosis due to choanal atresia (60-70%, bony/membranous, unilateral/bilateral) and/or cyanotic heart disease (75-80%; e.g. conotruncal heart malformations, aortic arch defects; see these terms). Coloboma, more likely retinal, is present in 75-90% and can be in conjunction with microphthalmia and lead to vision loss. Ear anomalies (95-100%) include low-set lop or cup-shaped outer ear with deficient cartilage of the outer pinna and a triangular concha, middle ear ossicle malformations, leading to chronic serous otitis media, and sensorineural hearing loss. Cranial nerve abnormalities are frequent and include abnormalities of the olfactory, facial, auditory, vestibular nerves and those involved in swallowing. Central nervous system (CNS) defects involve cerebral atrophy, corpus callosum agenesis, posterior fossa anomalies and cerebellar hypoplasia. Genital hypoplasia and delayed puberty are observed. Failure to thrive is often related to the severe sucking/swallowing problems. Motor delay (due to balance problems), speech delay and delay in fine motor skills are also noted. Dysmorphic facial features include square face, prominent forehead, prominent nasal bridge and asymmetry from the facial palsy. Upper airway defects (e.g. congenital laryngomalacia, congenital tracheomalacia; see these terms), tracheoesophageal fistula (TEF) and gastroesophageal reflux are common. Endocrine dysfunction (growth hormone deficiency, hypogonadotropic hypogonadism) and immune abnormalities (e.g. severe combined immune deficiencies, isolated T-cell lymphopenia) are also observed. Chest infections are frequent. Patients may manifest an autistic like behavior associated with attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) and anxiety.
Etiology
In most cases, CHARGE syndrome is due to heterozygous mutations in CHD7 (8q12.2) encoding the chromodomain helicase DNA-binding protein.
Diagnostic methods
Diagnosis is initially clinical. Any of the major 4 C's criteria should prompt the physician to screen for additional anomalies. Magnetic resonance imaging of the temporal lobe demonstrates absent or hypoplastic semi-circular canals (most predictive feature of the CHD7 mutation). Diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes Abruzzo-Erickson syndrome, Kallmann syndrome, 22q11.2 deletion syndrome, VACTERL/VATER association, Kabuki syndrome, renal coloboma syndrome, Cat-eye syndrome, Joubert syndrome, BOR syndrome, 5q11.2 microdeletion syndrome (see these terms) and other chromosomal microdeletion syndromes.
Antenatal diagnosis
Prenatal diagnosis involves detection by ultrasound in the 2nd trimester of polyhydramnios, CNS, heart and genitourinary malformations, ear anomalies. Molecular studies can be performed.
Genetic counseling
CHARGE syndrome is either sporadic (97%) or shows an autosomal dominant transmission. There is a 1-2% risk of gonadal mosaicism.
Management and treatment
Management requires a multi-disciplinary approach (involving dieticians, gastroenterologists, endocrinologists, cardiologists) that associates surgical management, services for persons with vision and hearing loss (deaf/blind services), occupational therapy, physiotherapy, speech/language therapy, cochlear implant, behavior therapy and psychological counseling.
Prognosis
Mortality is high during the neonatal period often due to the combination of cyanotic heart disease, TEF, choanal atresia, T-cell deficiency and brain anomalies. Mortality and morbidity in the post-neonatal period are often related to post-anesthesia events and feeding problems resulting in aspiration pneumonia.

                            Last update:
                            March 2015

                            - Expert reviewer(s):
                            Dr Kim BLAKE  - Dr Chitra PRASAD


A rare multiple congenital anomalies/dysmorphic syndrome characterized by the common manifestations found in oromandibular-limb hypogenesis syndromes(OLHS) group such as hypoplasia of the mandible, variable limb anomalies like syndactylyl and ectrodactyly, small mouth, cleft palate and hypodontia, accompanied by other clinical signs such as facial paralysis, facial asymmetry, hypertelorism, hypoglossia/aglossia, absent or conically crowned incisors and, ectromelia. There have been no further descriptions in the literature since 1976.


CHD3-related developmental delay-speech delay-intellectual disability-abnormalities of vision-facial dysmorphism syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by moderate to severe intellectual disability, developmental delay, macrocephaly, speech delay, and hypotonia. Dysmorphic facial features include a high, broad, and/or prominent forehead, laterally sparse eyebrows, widely spaced and deeply-set eyes, narrow palpebral fissures, low-set ears, full/prominent cheeks, midface hypoplasia, thin upper lip, and a pointed chin. Additional variable manifestations include joint laxity, abnormality of vision (including hypermetropia, strabismus, and cerebral visual impairment), genital abnormalities in males, and inguinal, umbilical, or hiatal hernia.


A rare skin disease of unknown origin characterized by macrocheilia and secretions of thick saliva from swollen labial minor salivary glands.

Summary:
Epidemiology
Cheilitis glandularis (CG) prevalence is unknown. Less than a 100 cases have been reported to date, predominantly in adult males, and more rarely in adult females.
Clinical description
The clinical picture of CG consists of variable degrees of macrocheilia accompanied by the presence of red, dilated ostia of minor salivary glands on the vermilion area. A thick, mucoid material can be obtained from these ostia by manual expression. This viscous saliva often sticks to the vermilion causing discomfort to the patient. Hardening of superficial and deep tissues, including minor salivary glands, may occur. Rarely they may suppurate and drain a purulent discharge (cheilitis apostematosa profunda). Changes occur more frequently on the lower lip, but the upper lip is occasionally affected. Because of the macrocheilia, the vermilion is more exposed to ultra-violet radiation, which may lead to chronic actinic cheilitis and squamous cell carcinoma of the lower lip in rare cases.
Etiology
Cheilitis glandularis occurs more frequently in fair skinned adults and albino patients seem particularly prone, suggesting an influence of sunlight exposure. Nonetheless, the actual cause of CG remains unknown. Some consider CG as an inflammatory glandular disease while others think it merely represents a clinical reaction pattern to external trauma (mechanic, actinic) with no relation to salivary involvement as salivary glands have been found to be normal in some patients. Recently, changes in the immunohistochemical expression of water flow channels have been demonstrated in cases of CG.
Diagnostic methods
Diagnosis is mostly clinical. Histopathologic findings in the vermilion vary from spongiotic changes to chronic actinic epithelial damage, including superficial squamous cell carcinoma. Changes in minor salivary glands include chronic sialadenitis with dilated acinar lobules and ducts. Excretory ducts are ectatic and ductal metaplasia can be observed.
Differential diagnosis
Differential diagnosis may include cheilitis granulomatosa, cutaneous lupus erythematosus, angioedema, atopic cheilitis, actinic cheilitis, cheilitis artefacta, exfoliative cheilitis, ointment pseudo-cheilitis and benign and malignant minor salivary gland tumours (e.g. cystadenoma, cystadenocarcinoma and mucoepidermoid carcinoma).
Management and treatment
Mild cases do not require specific treatment. A lower lip vermilionectomy followed by careful dissection of the minor labial salivary glands is recommended for symptomatic and/or albino patients and is the only curative treatment for CG. Intralesional corticosteroids and oral antibiotics are ineffective. Long-term follow up is recommended, especially in very fair-skinned or albino patients, as the risk of labial squamous cell carcinoma is higher in these patients.
Prognosis
With proper treatment and surveillance, the prognosis is good.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Dr Marcello NICO


Cherubism is a rare, self-limiting, fibro-osseous, genetic disease of childhood and adolescence characterized by varying degrees of progressive bilateral enlargement of the mandible and/or maxilla, with clinical repercussions in severe cases.

Summary:
Epidemiology
The prevalence of cherubism is unknown and is difficult to determine because of the wide clinical spectrum. About 300 cases have been reported in various ethnic groups worldwide. The disorder affects males and females equally.
Clinical description
Patients are normal at birth and most develop some degree of symmetrical mandibular and maxillary enlargement between two and five years of age. These lesions are considered aggressive, non-aggressive or quiescent depending on their clinical behavior, with each type corresponding to a particular age group (early childhood, adolescence or adulthood). In the early stages of the disease, patients may present with lymph node enlargement. The clinical manifestations are highly variable, from subclinical cases to severe enlargement causing visual, respiratory, speech, mastication, and swallowing complications. In severe cases, the fibro-osseous lesions may invade the orbital walls causing lower lid retraction, displacement of the globe, proptosis or diplopia. Respiratory complications are infrequent but can include obstructive sleep apnea, upper airway obstruction and obliteration of the nasal airway. Dental abnormalities include disrupted arrangement of primary dentition, absent teeth, rudimentary molars, premature exfoliation of primary dentition, and displacement of permanent dentition by the cystic lesions. Malocclusion is commonly found. Other organs and systems are usually not affected. Lesions progress slowly until puberty and then start to stabilize and regress through bone remodeling until the age of about 30. At this age, facial abnormalities are generally no longer visible. Cherubism can also be part of Ramon syndrome, neurofibromatosis 1 and fragile X syndrome (see these terms).
Etiology
Cherubism is caused by missense mutations in the SH3BP2 gene (4p16.3) in approximately 80% of cases, suggesting genetic heterogeneity. The exact mechanism underlying fibrous expansion has not been elucidated. Experimental data points to possible auto-inflammatory disease.
Diagnostic methods
The diagnosis is based on clinical signs, patient age, family history and radiographic findings, and can be confirmed by molecular genetic testing. Histology shows spindle cells embedded in interstitial collagen fibers and osteoclastic giant-cells.
Differential diagnosis
Differential diagnosis includes Noonan-like syndrome, hyperparathyroidism-jaw tumor syndrome, fibrous dysplasia of bone (see these terms), brown tumor of hyperparathyroidism, and central giant-cell granuloma.
Antenatal diagnosis
Prenatal diagnosis is possible when the disease-causing mutation has been detected in the family.
Genetic counseling
About 50% of cases are familial and the others appear to be related to de novo mutations. Cherubism is considered to be an autosomal dominant trait but there are reports suggesting autosomal recessive transmission. Genetic counseling is recommended for affected families.
Management and treatment
Clinical and radiographic monitoring is recommended during the growth phase of lesions. Since the disorder is usually self-limiting, surgery is not always recommended. However, surgical intervention involving resection, curettage or contouring may be required in patients with functional manifestations or for esthetic reasons and to improve quality of life. Surgery is generally indicated once lesions have become quiescent and does not alter disease progression. Careful attention should be paid to the psychological aspects related to disfigurement during childhood and adolescence.
Prognosis
Despite the possible severity of signs and symptoms, the condition is benign and the prognosis very good, with rare reports of residual deformity.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Berivan BASKIN


A rare infectious disease characterized by acute onset of high fever associated with debilitating polyarthralgia and usually accompanied by an erythematous skin rash (that may progress to vesiculobullous lesions in children) caused by the mosquitoe-borne Chikungunya virus. Myalgia, severe headache, and lymphadenopathy are frequently associated. Chronically the disease may cause recurrent, long-term polyarthralgia, arthritis, fatigue, and depression.


A rare, chronic cutaneous lupus erythematosus disease characterized by red or violaceous, initially pruritic (evolving to painful) papules and plaques located on acral areas (especially dorsal aspects of fingers and toes, while the nose and ear involvement is uncommon), exacerbated by cold and damp conditions, with fissuring and ulceration occasionally observed. Coexistence of discoid lupus erythematosus lesions elsewhere on the body and occasional progression to systemic lupus erythematosus may be associated. Histological examination and direct immunofluorescence studies reveal nonspecific inflammatory lupus erythematosus changes while results of cryoglobulin and cold agglutinin studies are negative.


A rare developmental defect during embryogenesis characterized by unilateral inflammatory and scaling skin lesions with ipsilateral visceral and limb anomalies.

Summary:
Epidemiology
Less than 60 cases have been reported to date, mainly in female patients.
Clinical description
CHILD syndrome (CS) patients present at birth or shortly thereafter with unilateral yellow ichthyosiform nevi in the form of patches halting abruptly at the midline, with an affinity to skin folds (ptychotropism), generally sparing the face. A claw-like onychodystrophy and periungual hyperkeratosis are common, and ipsilateral bald patches may be present. This is accompanied by ipsilateral limb defects, ranging from shortened metacarpals and phalanges to the absence of an entire limb. Additional malformations may include the absence of ribs, vertebrae and long bones, and scoliosis and joint contractures. During the first months of life, punctate calcification of cartilage (stippled epiphyses) may be noted on X-rays. Ipsilateral renal defects have been reported (unilateral hydronephrosis, renal agenesis). Most patients present with normal intellectual development, although unilateral CNS defects have often been reported including unilateral hypoplasia of cranial nerves and the spinal cord, lissencephaly and cerebellar malformation. The involvement may be right or left-sided, but mild contralateral lesions are often noted. Over two-thirds of cases have presented with right-sided involvement, perhaps due to more severe cardiac involvement causing prenatal death in left-sided cases. Lung hypoplasia has also been reported in several cases. Hearing loss, optic atrophy, absence of some facial muscles, thrombocytosis, congenital bilateral hip dislocation, unilateral hypoplasia of the thyroid gland, adrenal glands, ovaries and fallopian tubes have been reported in single cases.
Etiology
NSDHL (Xq28) encodes a protein responsible for cholesterol biosynthesis, mutations are typically lethal in males. X-inactivation creates a mosaic of cells lacking the enzyme in females, disrupting embryonic development and leading to a highly variable spectrum of anomalies.
Diagnostic methods
In most cases, the striking lateralization of all lesions, also noted on X-rays, is a strong diagnostic clue. Skin lesion histology reminiscent of psoriasis reveals hyperkeratosis and parakeratosis with inflammatory infiltrates. Biopsies from papillomatous lesions involving the body folds, however, show highly characteristic verruciform xanthoma in the form of lipid-laden histiocytes in the papillary dermis. Ultrasound of viscera, echocardiogram and full brain MRI are required to complement X-rays and identify all anomalies. Genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnoses include X-linked dominant chondrodysplasia punctata, linear nevus sebaceous syndrome and inflammatory linear verrucous epidermal nevus.
Antenatal diagnosis
Genetic testing from chorionic villus samples is available; certain anomalies may be identified during routine sonograms.
Genetic counseling
Transmission is X-linked dominant. Sporadic cases have been reported, but extreme X-inactivation may mask the phenotype. Mothers should be examined for the presence of minimal symptoms and tested for a NSDHL mutation. Carriers have a 50% risk of transmission to daughters, but cannot transmit to live-born sons.
Management and treatment
Lung and heart anomalies are potentially fatal and may require immediate surgical intervention. Renal anomalies may also require draining or removal of the affected kidney. Orthopedic braces or corrective surgery may be necessary. Contralateral autologous skin grafts have been successfully performed. Skin lesions are best treated by topical application of a lotion or ointment containing lovastatin or simvastatin (in combination with cholesterol).
Prognosis
Prognosis is highly variable and based upon skeletal or cardiac anomalies. Cases of minimal involvement carry the risk of a severe disease in offspring.

                            Last update:
                            February 2023

                            - Expert reviewer(s):
                            Pr Aldona PIETRZAK  - Pr Matthias SCHMUTH | ERN-Skin*

                                * European Reference Network


Childhood absence epilepsy (CAE) is a familial generalized pediatric epilepsy, characterized by very frequent (multiple per day) absence seizures, usually occurring in children between the ages of 4 and 10 years, with, in most cases, a good prognosis.

Summary:
Epidemiology
CAE accounts for 10% to 17% of all cases of epilepsy diagnosed in school-aged children. Incidence has been estimated at 1/50,000-1/12,500 in the United States. Females are usually more affected than males.
Clinical description
CAE usually occurs in children between the ages of 4 and 10 years, with a peak between 5 and 7 years. The disease is characterized by frequent (multiple per day) absence seizures with an abrupt onset and offset. Photosensitivity is reported in 18% of CAE patients. In rare cases, CAE is also associated with an increased rates of adverse behavioral, psychiatric, language, and subtle cognitive comorbidities (including attention problems, anxiety, depression, social isolation and low self-esteem). These cognitive concerns are frequently complicated by attention deficit hyperactivity disorder (ADHD). Intellectual disability may also be observed. Onset of absence seizures under the age of 4 years is observed in a rare subset of CAE patients, a proportion of whom have encephalopathy due to GLUT1 deficiency (see this term).
Etiology
Although CAE is genetically determined, the precise mode of inheritance and genes involved remain largely unidentified. Mutations in the genes NIPA2 (15q11.2) which encodes a magnesium transporter; CACNA1H (16p13.3) which encodes a T-type calcium channel are reported to be susceptibility genes in Chinese Han population; GABRA1 (5q34), GABRB3 (15q12), GABRG2 (5q34) which encode gamma-aminobutyric acid (GABA) receptors; JRK (8q24.3) which encodes a putative DNA-binding protein; and SLC2A1 (1p34.2) which encodes a facilitated glucose transporter, may be implicated in CAE. Mutations in CLCN2 (3q27.1) which encodes a chloride channel, may be a susceptibility locus in a subset of CAE.
Diagnostic methods
Diagnosis relies on the clinical features and electroencephalographic findings of bilateral, synchronous symmetrical spike waves, usually 3 Hz, on a normal background activity.
Differential diagnosis
Differential diagnosis includes epilepsy with myoclonic absences, Jeavons syndrome, juvenile absence epilepsy, perioral myoclonia with absences, juvenile myoclonic epilepsy, encephalopathy due to GLUT1 deficiency as well as absences associated with chromosomal anomalies (ring chromosome 20, 15q13.3 microdeletion syndrome) (see these terms).
Management and treatment
Treatment of CAE involves the use of antiepileptic drugs such as ethosuximide, valproate, and lamotrigine. However, lack of response is common. Levetiracetam (alternative choice for patients with CAE and photosensitivity) or topiramate are options for refractory absence seizures but may not be successful.
Prognosis
In 56-65% of affected children, a 5-year remission rate off antiepileptic drugs is observed. Terminal remission generally occurs 3-8 years after the onset of CAE. However, in the remaining 30% of children, seizures persist either as absences alone (10-15%), absences with either generalized tonic-clonic or myoclonic seizure (5-15%), or evolution to juvenile myoclonic epilepsy (5-15%).

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                            Dr Gabrielle RUDOLF


Childhood disintergrative disorder is a rare pervasive developmental disorder with a disease onset before the age of three and characterized by a dramatic loss of behavioral and developmental functioning after atleast two years of normal development. Manifestations of the disease include loss of speech, incontinence, communication and social interaction problems, stereotypical autistic behaviors and dementia.


Childhood encephalopathy due to thiamine pyrophosphokinase deficiency is a rare inborn error of metabolism disorder characterized by early-onset, acute, encephalopathic episodes (frequently triggered by viral infections), associated with lactic acidosis and alpha-ketoglutaric aciduria, which typically manifest with variable degrees of ataxia, generalized developmental regression (which deteriorates with each episode) and dystonia. Other manifestations include spasticity, seizures, truncal hypotonia, limb hypertonia, brisk tendon reflexes and reversible coma.


Benign childhood occipital epilepsy, Gastaut type is a rare, genetic neurological disorder characterized by childhood to mid-adolescence onset of frequent, brief, diurnal simple partial seizures which usually begin with visual hallucinations (e.g. phosphenes) and/or ictal blindness and may associate non visual seizures (such as deviation of the eyes, oculoclonic seizures), forced eyelid closure and blinking and sensory hallucinations. Post-ictal headache is common while impairment of consciousness is rare.


Childhood-onset autosomal recessive myopathy with external ophthalmoplegia

A rare, genetic, non-dystrophic myopathy disease characterized by childhood-onset severe external ophthalmoplegia, typically without ptosis, associated with mild, very slowly progressive muscular weakness and atrophy, involving the facial, neck flexor and limb (upper > lower, proximal > distal) muscles. Muscle biopsy shows type 1 fiber uniformity, absent, or abnormally small, type 2A fibers, increased variability of fiber size, internalized nuclei and/or fatty infiltration.


Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia

A rare, genetic, autosomal recessive cerebellar ataxia disease characterized by slowly progressive spinocerebellar ataxia developing during childhood, manifesting with gait and limb ataxia, postural tremor, dysarthria, sensory alterations (e.g. decreased vibration sense), eye movement anomalies (i.e. nystagmus, saccadic pursuit, oculomotor apraxia), upper and lower limb fasciculations, and hyperreflexia with Babinski signs. Brain imaging reveals cerebellar, pontine, vermian and medullar atrophy.


Childhood-onset basal ganglia degeneration syndrome

A rare genetic neurodegenerative disease characterized by sudden onset of progressive motor deterioration and regression of developmental milestones. Manifestations include dystonia and muscle spasms, dysphagia, dysarthria, and eventually loss of speech and ambulation. Brain MRI shows predominantly striatal abnormalities. The disease is potentially associated with a fatal outcome.


Childhood-onset benign chorea with striatal involvement

A rare genetic hyperkinetic movement disorder characterized predominantly by chorea of variable severity, associated with bilateral striatal abnormalities on cerebral MRI. The disease is scarcely progressive, and cognitive performance is preserved in the majority of cases, although mild cognitive delay has also been reported.


A rare, moderate form of hypophosphatasia (HPP) characterized by onset after six months of age and widely variable clinical features from low bone mineral density for age, to unexplained fractures, skeletal deformities, and rickets with short stature and waddling gait.

Summary:
Epidemiology
The prevalence is unknown. About 130 cases have been reported to date.
Clinical description
Patients develop manifestations after six months of age and generally before five years of age. Clinical manifestations cover a wide spectrum. Commonly, patients have rickets leading to short stature, with delay in walking and a waddling gait, and bone and joint pain. Skeletal deformities may include dolichocephalic skull and enlarged joints. Other common features are signs of intracranial hypertension and failure to thrive. Diaphyseal and metaphyseal fractures are common. Some affected children have premature loss of deciduous teeth, starting with incisors and then loss of other teeth with intact roots, before five years of age. The disease may follow an intermittent course with remission and recurrence in later life. There may be some clinical overlap between childhood-onset HPP and moderately severe infantile HPP.
Etiology
Mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia.
Diagnostic methods
Diagnosis is based on clinical presentation, alkaline phosphatase assay and confirmed by genetic testing.
Differential diagnosis
Osteogenesis imperfecta is the most common differential diagnosis of HPP.
Genetic counseling
Autosomal recessive and autosomal dominant patterns of inheritance are reported, potentially explaining clinical variability. Genetic counseling is recommended for affected individuals.
Management and treatment
Treatment has traditionally been supportive rehabilitative strategies to minimize functional limitations, and surgery to manage some fractures. However, there is evidence that enzyme replacement therapy with asfotase alfa, approved for pediatric onset HPP (Europe and USA), improves function in childhood-HPP.
Prognosis
Affected individuals may have significant disease, with poor mobility, chronic pain, and short stature. In addition, significant rickets, long bone deformity, and non-traumatic fractures are possible. Fractures may heal poorly and can reoccur.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Severine BACROT  - Dr Etienne MORNET


Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder

A rare genetic neurodegenerative disease characterized by childhood onset of slowly progressive motor and cognitive regression, resulting in intellectual disability and loss of language and ambulation, associated with the appearance of dystonia, parkinsonism, chorea, or rigidity. Ataxia, dysarthria, and seizures have also been reported. Head circumference percentiles may decline over time. Brain imaging shows progressive cerebral and cerebellar atrophy, in some patients also thinning of the corpus callosum.


Childhood onset nemaline myopathy, or mild nemaline myopathy is a type of nemaline myopathy (NM; see this terms) characterized by distal muscle weakness, and sometimes slowness of muscle contraction.

Summary:
Epidemiology
The annual incidence of NM has been estimated at 1/50,000 live births.
Clinical description
Childhood onset NM might represent 10-15% of total cases. Onset is around 10 years of age, with initial presentation of symmetric weakness of ankle dorsiflexion and foot drop, or a general slowness of muscle contraction. All movements at the ankle and more proximal limb muscles may be disturbed. Weakness is slowly progressive. Facial, respiratory and cardiac muscles are generally normal, but patients are unable to jump or run because of muscle weakness or slowness.
Etiology
This form of NM is caused by mutations in the ACTA1 (1q42.13), NEB (2q22), TPM2 (9p13.3) or TPM3 (1q21.2) genes.
Genetic counseling
Transmission follows an autosomal dominant pattern.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Monique RYAN


Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome

A progressive muscular dystrophy characterized by co-existence of limb-girdle weakness and diffuse joint contractures without cardiomyopathy. Patients present lower limb weakness progressing to involve also upper limbs and axial muscles and eventually leading to permanent loss of ambulation, widespread joint contractures in the limbs and sometimes the spine, and variable respiratory involvement. Morphological changes in muscle biopsies include rimmed vacuoles, increased internal nuclei, cytoplasmic bodies, and a dystrophic pattern.


Childhood-onset spasticity with hyperglycinemia is a rare neurometabolic disease characterized by a childhood onset of progressive spastic ataxia associated with gait disturbances, hyperreflexia, extensor plantar responses and non-ketotic hyperglycinemia typically revealed by biochemical analysis. Additional signs of upper extremity spasticity, dysarthria, learning difficulties, poor concentration, nystagmus, optic atrophy and reduced visual acuity may also be associated.


CHIME syndrome is a rare ectodermal dysplasia syndrome characterized by ocular colobomas, cardiac defects, ichthyosiform dermatosis, intellectual disability, conductive hearing loss and epilepsy.

Summary:
Epidemiology
Prevalence is unknown. To date, CHIME syndrome has been described in 8 cases.
Clinical description
CHIME syndrome is characterized by early-onset migratory ichthyosiform dermatosis, bilateral ocular coloboma, conductive hearing loss, seizures, intellectual disability, and characteristic facial features: brachycephaly, mild upslanting of the palpebral fissures, pale blue irides, hypertelorism, flat midface and philtrum, anteverted nostrils, thin upper lip, and excessive creases around a wide mouth. Ears are low-set with thick overfolded helices. Teeth are widely spaced and square in shape. Less constant findings are cleft palate or a less severe equivalent (bifid uvula and/or submucous cleft), cardiac defects (tetralogy of Fallot or transposition of the great vessels), pectus excavatum and supernumerary nipples.
Etiology
CHIME syndrome is caused by mutations in the glycosylphosphatidylinositol gene PIGL located to 17p12-p11.2.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            October 2013


A rare, usually sporadic, congenital nose and cavum anomaly characterized by respiratory distress relieved by crying and rhinorrhea that presents at birth. It is caused by blockade of the nose on both sides by bony or soft tissue formed during embryological development.


A rare, usually, sporadic congenital anomaly that is more commonly seen in females than in males (2:1), where the nose is blocked by bony or soft tissue formed during embryologic development on only one side (more commonly on the right side) and which is characterized by nasal obstruction and rhinorrhea, usually presenting at birth but that may go undetected until a respiratory infection aggravates the condition.


Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by choanal atresia, athelia or hypoplastic nipples, branchial arch abnormalities, external ear malformations, hearing loss, thyroid abnormalities, delayed or absent pubertal development, and short stature. Developmental delay / intellectual disability are variably reported.


Choanal atresia (CA) is a congenital anomaly of the posterior nasal airway characterized by the obstruction of one (unilateral) or both (bilateral) choanal aperture(s), with clinical manifestations ranging from acute respiratory distress to chronic nasal obstruction.

Summary:
Epidemiology
CA has a birth prevalence of approximately 1/11,630 in Europe and it follows a ''2:1'' ratio, namely female to male and unilateral to bilateral CA.
Clinical description
CA is a congenital disorder that consists of a unilateral or bilateral bony or membranous septum between the nose and nasopharynx. In bilateral CA (see this term), neonates present at birth with acute respiratory distress requiring orotracheal intubation or placement of an oropharyngeal cannula. Nasotracheal intubation is not possible. Neonates with bilateral CA can also present with a history of multiple failed extubation attempts, especially in those with secondary airway issues. Spontaneous survival with a bilateral CA is possible but exceptional. In unilateral CA (see this term), infants can be asymptomatic often until the first respiratory infection. The most common presentation is persistent unilateral nasal obstruction or persistent mucoid rhinorrhea. CA can either occur in an isolated form or associated with other congenital deformities such as in CHARGE syndrome, Crouzon disease, Down syndrome, Treacher-Collins syndrome, 22q11.2 deletion syndrome (see these terms) or polydactyly. Bilateral CA is more common in patients with other congenital anomalies while unilateral CA occurs more frequently in isolated cases.
Etiology
The following hypotheses are thought to result in developmental failure of the nasal cavity to communicate with the nasopharynx: persistence of the buccopharyngeal membrane from the fetal foregut; abnormal persistence of mesoderm forming adhesions in the nasochoanal region; abnormal persistence of the nasobuccal membrane of Hochstetter; or misdirection during neural crest cell migration. Prenatal exposure to maternal hyperthyroidism treated with methimazole may also be associated with CA development.
Diagnostic methods
Initial clinical evaluation includes introduction of a 6 or 8 French suction catheter via the nostrils, methylene blue dye test, cotton wisp test, and laryngeal mirror test. Flexible nasal endoscopy after mucous suctioning allows direct visualization of the atretic plate in the choana. Definitive evaluation is achieved with a computerized tomography scan which shows thickening of the medial portion of the pterygoid plates and enlargement of the posterior portion of the vomer, with or without membranous involvement. Tomography may also detect an associated malformation of semi-circular canals as found in CHARGE syndrome.
Differential diagnosis
Differential diagnoses include isolated pyriform aperture stenosis, nasolacrimal duct cyst (see these terms), turbinate hypertrophy, septal dislocation and deviation, antrochoanal polyp or nasal neoplasm.
Management and treatment
The goal of initial treatment for infants with bilateral CA is to maintain an adequate airway via the oral route. An oral airway or a feeding nipple with large holes to facilitate air flow can be used. If a patient still fails to maintain an adequate airway, endotracheal intubation must be performed. A tracheostomy may be required in patients with severe comorbidities but it is not necessary in cases of isolated (even bilateral) CA. Definitive surgical correction by nasal endoscopic approach is performed when appropriate and when feasible (weight >2kg). Given the relatively low morbidity of unilateral CA, definitive treatment is delayed until a later age (>18 months of age), when possible, as the chance of successful surgical repair increases with age.
Prognosis
CA (mainly the bilateral form) is a life-threatening condition and treatment cannot be delayed. In both unilateral and bilateral cases, restenosis necessitating reoperation is common.

                            Last update:
                            February 2016

                            - Expert reviewer(s):
                            Pr Nicolas LEBOULANGER


Cholangiocarcinoma (CCA) is a biliary tract cancer (BTC, see this term) originating in the epithelium of the biliary tree, either intra or extra hepatic.

Summary:
Epidemiology
The prevalence is unknown but it accounts for approximately 3% of gastrointestinal tumors and 10-15% of all hepatobiliary malignancies.
Clinical description
CCA can occur in the intra or extra-hepatic biliary tract. A specific type of extra-hepatic CCA known as a Klatskin tumor (see this term) occurs at the junction where the left and right hepatic bile ducts meet the common bile duct (CBD). It is slightly more prevalent in males than females (1.3:1.0) and usually presents in the fifth to seventh decade of life. Clinical manifestations are not usually noted until an advanced disease stage. Extra-hepatic CCA manifests with signs of cholestasis (jaundice, pale stools, dark urine, pruritus), malaise, weight loss and/or progressive weakness. Intra-hepatic CCA may present with an abdominal mass or with non-specific symptoms of decreased appetite, weight loss, abdominal pain and malaise.
Etiology
The etiology is unknown and most cases of CCA occur sporadically. Risk factors include primary sclerosing cholangitis (see this term), secondary sclerosing cholangitis, chronic typhoid carriage, parasitic infections (Opisthochis viverrini and Clonorchis sinensis), exposure to thorotrast (x-ray contrast medium) and choledochal cysts, all of which cause chronic biliary inflammation.
Diagnostic methods
Diagnosis is suspected on clinical and laboratory findings. Serum carbohydrate antigen (CA) 19-9 is the glycoprotein tumor marker most often used in the diagnosis of CCA. It is found to be elevated in 85% of patients. Increased CEA levels are also noted. Extra-hepatic tumors cause increased levels of alkaline phosphate (ALP), conjugated bilirubin and gamma-glutamyl transpeptidase (GGT) while intra-hepatic have only slightly elevated ALP levels. Abdominal imaging, visualization of the biliary tree and biopsies of the lesion are necessary for diagnosis. Magnetic resonance cholangiopancreatography (MRCP) provides information on intrahepatic metastases, biliary anatomy and tumor extension and is used in the staging of CCA. It has been advocated to replace endoscopic retrograde cholangiopancreatography (ERCP), a more invasive method. Visualization of the biliary tree and samples through brush cytology or bile duct biopsies are obtained with ERCP. A needle biopsy is performed in those with a liver mass. Extra-hepatic CCA is further divided into anatomical subtypes according to the Bismuth classification and a disease stage is given. Ultrasound, and contrast enhanced helical computerized computed tomography (CT) can be used in visualizing the extent of disease.
Differential diagnosis
Intra-hepatic CCA is often mistaken for metastatic adenocarcinoma. Carcinoma of the gallbladder (see this term), benign strictures and Mirizzi syndrome should be excluded.
Management and treatment
Surgical resection is the only potentially curative treatment for CCA but recurrences after surgery are frequent. Unfortunately CCA is often diagnosed as unresectable because of local extension and/or metastases. Distal CCA arising from the CBD is often treated by pancreatoduodenectomy. More proximal CCA needs hepatic resection. Palliative management involves biliary drainage by inserting metal stents in the biliary tree to release the blockage. Adjuvant chemotherapy after surgery or palliative chemotherapy for unresectable CCA is indicated. Gemcitabine combined with cisplatin therapy is the standard treatment for unresectable biliary tract cancers, including CCA.
Prognosis
As proximal CCA is usually not diagnosed until a late stage of disease, prognosis is poor with 5-year survival rates of 20-50% after resection and almost 0% in unresectable tumors. Death is often due to biliary sepsis, cancer cachexia, malnutrition and liver failure.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Dr Junji FURUSE


A rare biliary tract disease characterized by congenital fusiform or cystic dilatation of intra- and/or extrahepatic bile ducts. Females are much more often affected than males. Clinical signs and symptoms include abdominal pain, jaundice, presence of a palpable abdominal mass, nausea, vomiting, or fever. Depending on the age of the patient, the condition may be complicated by stone formation, hepatomegaly, rupture with subsequent bile peritonitis, cholangitis, cholecystitis, biliary strictures, pancreatitis, or secondary biliary cirrhosis. The risk of malignancy, particularly cholangiocarcinoma, is significantly increased.


Cholera is an infectious disease, caused by intestinal infection with Vibrio cholerae, characterized by massive watery diarrhea and severe dehydration that can lead to shock and death if left untreated.

Summary:
Epidemiology
Cholera is endemic to over 50 countries (defined as having reported cholera cases for the last 3 years with evidence of local transmission), mainly in Asia and Africa. In addition, outbreaks have occurred throughout Africa, Asia, the Middle East, South and Central America, and the Caribbean. Worldwide, it is estimated that there are 1-4 million cases per year. In Europe, the disease is extremely rare, occurring as isolated, imported cases.
Clinical description
Once ingested, the incubation period ranges from 12 hours to 5 days. The majority of infected individuals will be asymptomatic, a smaller percentage will develop mild to moderate symptoms, and only a small proportion will develop severe dehydration. Cholera afflicts children and adults equally during epidemics among immunologically-naive populations but in endemic populations, children are more affected. Onset of severe cholera begins with profuse watery diarrhea with a ''rice water'' appearance, usually accompanied by vomiting. Some may experience abdominal cramping and discomfort but fever is extremely rare. Signs of dehydration and electrolyte imbalance soon occur and include sunken eyes, lethargy, dry mouth, decreased skin turgor, wrinkled hands and feet, and cold clammy skin. Kussmaul breathing and muscle cramping are seen in some. In children, seizures, altered consciousness, and coma can occur due to severe hypoglycemia. If left untreated, cholera can lead to severe dehydration, shock, and death within hours.
Etiology
Cholera is due to an infection with Vibrio cholerae, a Gram negative rod bacteria that grows best in coastal waters and estuaries and is spread by the fecal-oral route. Over 200 serogroups exist but only 2 cause epidemic cholera: O1 and O139. The O1 serogroup is additionally subdivided into the Ogawa and Inaba serotypes. Once ingested, V. cholerae colonizes the small intestine where it releases cholera toxin that results in secretory diarrhea. The disease is associated with poor sanitation resources and lack of access to adequate water.
Diagnostic methods
Diagnosis is based on the sudden onset of severe diarrhea as well as recent exposure to the bacteria.  V. cholerae can be isolated from stool samples on selective media, followed by biochemical tests along with serogrouping and serotyping. The comma-shaped, motile bacteria can also be identified by examining fresh stool under dark field microscopy. Immunoassays that detect cholera toxins or  V. cholerae O1 and O139 lipopolysaccharides in the stool are also available.
Differential diagnosis
Mild cases can be confused with other causes of gastroenteritis such as Escherichia coli and rotavirus infections.
Management and treatment
Treatment involves immediate rehydration with oral rehydration solutions (preferred when possible) containing salt and glucose or rice-based rehydration solutions and/or isotonic intravenous (IV) solutions. Individuals with severe cholera require an average of 200 ml/kg of fluids within the first 24 hours (may need >350 ml/kg). The initial fluid deficit should be replaced within 3-4 hours of presentation. Antibiotics such as tetracyclines, fluoroquinolones and macrolides are beneficial in moderate to severe cases and should be chosen based on availability and local resistance patterns. A high energy diet should be established once dehydration has been corrected to prevent malnutrition and complications. Access to safe drinking water and adequate sanitation prevents the spread of cholera. Two oral killed cholera vaccines are available, WC-rBS (whole-cell/recombinant B-subunit oral cholera vaccine; licensed in the EU) and BivWC (bivalent whole-cell oral cholera vaccine; used in endemic settings), which are given as 2 or 3 doses and provide 60-85% protection for 2-3 years. Children less than 5 years old, however, receive less protection from vaccination and for a shorter duration than adults.
Prognosis
With proper treatment, the prognosis is good with a mortality rate of <0.2%. If untreated, the mortality rate can reach 50-70%.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Alaina RITTER


Cholestasis-lymphedema syndrome is a rare genetic disorder characterized by neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and severe chronic lymphedema which mainly affects the lower limbs. Patients often present with fat malabsorption leading to failure to thrive, fat soluble vitamin deficiency with bleeding, rickets, and neuropathy. In 25% of cases, cirrhosis occurs during childhood or later in life.


A form of lysosomal acid lipase deficiency characterized by progressive cholesterol esters and triglyceride accumulation in tissues and organs typically presenting with hepatosplenomegaly, liver dysfunction and/or dyslipidemia.


Chondrodysplasia punctata, tibial-metacarpal type

A rare, non-rhizomelic, chondrodysplasia punctata syndrome characterized, radiologically, by stippled calcifications and disproportionate, short metacarpals and tibiae (with characteristic overshoot of the proximal fibula), clinically manifesting with severe short stature, bilateral shortening of upper and lower limbs, flat midface and nose, in the absence of cataracts and cutaneous anomalies. Neonatal tachypnea, hydrocephalus and mild developmental delay have been seldomly associated. Additional radiologic features include bowed long bones, platyspondyly and/or vertebral clefts.


Chondrodysplasia punctata, Toriello type is a rare, non-rhizomelic, primary bone dysplasia syndrome characterized by calcific stippling of epiphyses in association with minor facial abnormalities, short stature and ocular colobomata. In addition, patients present chondrodysplasia punctata, brachycephaly, flat facial profile with small nose, flat lower eyelids and low-set ears, developmental delay, brachytelephalangy and deep palmar creases. Complex congenital cardiac disease and central nervous system anomalies (including partial absence of corpus callosum, small vermis, enlargement of the cisterna magna and/or of the anterior horns of the lateral ventricles) have been reported.


Chondrodysplasia with joint dislocations, gPAPP type

A rare, genetic, primary bone dysplasia characterized by prenatal onset of disproportionate short stature, shortening of the limbs, congenital joint dislocations, micrognathia, posterior cleft palate, brachydactyly, short metacarpals and irregular size of the metacarpal epiphyses, supernumerary carpal ossification centers and dysmorphic facial features. In addition, hearing impairment and mild psychomotor delay have also been reported.