Congenitally uncorrected transposition of the great arteries (congenitally uncorrected TGA), also referred to as complete transposition, is a congenital cardiac malformation characterized by atrioventricular concordance and ventriculoarterial (VA) discordance.

Summary:
Epidemiology
The incidence is estimated at 1 in 3,500-5,000 live births, with a male-to-female ratio of 1.5 to 3.2:1.
Clinical description
In 50% of cases, the VA discordance is an isolated finding. In 10% of cases, TGA is associated with noncardiac malformations. The association with other cardiac malformations such as ventricular septal defect (VSD) and left ventricular outflow tract obstruction is frequent and dictates the timing and clinical presentation, which consists of cyanosis with or without congestive heart failure. The onset and severity depend on anatomical and functional variants that influence the degree of mixing between the two circulatory systems. If no obstructive lesions are present and there is a large VSD, cyanosis may go undetected and only be perceived during episodes of crying or agitation. In these cases, signs of congestive heart failure prevail.
Etiology
The exact etiology remains unknown. Some associated risk factors (gestational diabetes mellitus, maternal exposure to rodenticides and herbicides, and maternal use of antiepileptic drugs) have been proposed. Mutations in the growth differentiation factor-1 gene (GDF1), the mediator complex subunit 13-like gene (MED13L) and the gene encoding the cryptic protein (CFC1) have been shown to be implicated in discordant VA connections, but they account for only a small minority of congenitally uncorrected TGA cases.
Diagnostic methods
The diagnosis is confirmed by echocardiography, which also provides information about the morphological details required for future surgical management.
Differential diagnosis
The differential diagnosis should include other causes of central neonatal cyanosis.
Antenatal diagnosis
Prenatal diagnosis by fetal echocardiography is feasible and useful as it may improve early neonatal management and reduce morbidity and mortality.
Management and treatment
Palliative treatment with prostaglandin E1 and balloon atrial septostomy are usually required soon after birth. Surgical correction is performed at a later stage. Usually, the Jatene arterial switch operation is the procedure of choice. Whenever this operation is not feasible, an adequate alternative surgical approach should be implemented.
Prognosis
With the advent of newer and improved surgical techniques and improved post-operative intensive care, the long-term survival is approximately 90% at 15 years of age. However, exercise performance, cognitive function and quality of life may be impaired.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr Eduardo CASTELA  - Dr Paula MARTINS


Connective tissue disorder due to lysyl hydroxylase-3 deficiency is a rare, genetic disease, caused by lack of lysyl hydrohylase 3 (LH3) activity, characterized by multiple tissue and organ involvement, including skeletal abnormalities (club foot, progressive scoliosis, osteopenia, pathologic fractures), ocular involvement (flat retinae, myopia, cataracts) and hair, nail and skin anomalies (coarse, abnormally distributed hair, skin blistering, reduced palmar creases, hypoplastic nails). Patients also present intrauterine growth retardation, facial dysmorphism (flat facial profile, low-set ears, shallow orbits, short and upturned nose, downturned corners of mouth) and joint flexion contractures. Growth and developmental delay, bilateral sensorineural deafness, friable diaphragm and later-onset spontaneous vascular ruptures are additional reported features.


Cono-spondylar dysplasia is a rare genetic primary bone dysplasia disorder characterized by early-onset severe lumbar kyphosis, marked brachydactyly and irregular, pronounced cone epiphyses of the metacarpals and phalanges. Additional reported features include developmental delay, intellectual disability, hypotonia, epileptic seizures and mild facial dysmorphism (incl. long and thin or square-shaped face, slight mid-face hypoplasia, hypertelorism, epicanthic folds, low-set ears, anteverted nostrils). Radiographic findings also reveal hypoplasia of iliac wings and anterior defect of vertebral bodies.


A group of congenital cardiac outflow tract anomalies that include such defects as tetralogy of Fallot, pulmonary atresia with ventricular septal defect, double-outlet right ventricle (DORV), double-outlet left ventricle, truncus arteriosus and transposition of the great arteries (TGA), among others. This group of defects is frequently found in patients with 22q11.2 deletion syndrome . A deletion of chromosome 22q11.2 has equally been associated in a subset of patients with various types of isolated non-syndromic conotruncal heart malformations (with the exception of DORV and TGA where this is very uncommon).


Constitutional mismatch repair deficiency syndrome is a rare, inherited cancer-predisposing syndrome characterized by the development of a broad spectrum of malignancies during childhood, including mainly brain, hematological and gastrointestinal cancers, although embryonic and other tumors have also been occasionally reported. Non-neoplastic features, in particular manifestations reminiscent of neurofibromatosis type 1 (e.g., café-au-lait spots, freckling, neurofibromas), as well as premalignant and non-malignant lesions (such as adenomas/polpyps) are frequently present before malignancy development.


Contractures-developmental delay-Pierre Robin syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of Pierre Robin Sequence (congenital micrognathia and glossoptosis with airway obstruction and a U-shaped cleft of the soft palate) with joint contractures and developmental delay. Additional variable manifestations include talipes equinovarus, arachnodactyly, radioulnar synostosis, severe hip dysplasia, cardiac anomalies, facial dysmorphism such as crumpled ear helices, and ocular abnormalities, among others.


Contractures-ectodermal dysplasia-cleft lip/palate syndrome

A rare ectodermal dyplasia syndrome characterized by severe arthrogryposis, multiple ectodermal dysplasia features, cleft lip/palate, facial dysmorphism, growth deficiency and a moderate delay of psychomotor development. Ectodermal dysplasia manifestations include sparse, brittle and hypopigmented hair, xerosis, multiple nevi, small conical shaped teeth and hypodontia, and facial dysmorphism with blepharophimosis, deep-set eyes and micrognathia.


Contractures-webbed neck-micrognathia-hypoplastic nipples syndrome is an extremely rare, multiple congenital anomalies/dysmorphic syndrome characterized by micrognathia, a short, webbed neck, hypoplastic nipples and joint contractures (which improve over time) of the knees and elbows. In addition, sloping shoulders, mild to moderate hearing loss, mild speech impairment and facies with hypertelorism, short philtrum and tented upper lip may be associated.


Cooks syndrome is a malformation syndrome affecting the apical structures of digits and presenting with hypo/aplasia of nails and distal phalanges. More than half of digits are usually involved and the thumbs may appear digitalized.

Summary:
Epidemiology
To date, less than 20 individuals have been described in the world literature.
Clinical description
Cooks syndrome is congenital and presents with hypo/anonychia, small or absent distal phalanges and digitalization of the thumbs. Usually, the nails of digits 1-3 are progressively deformed, with anonychia congenita totalis (see this term) in the digits 4-5 and in all toes. Additional features include hypoplasia of the distal phalanges in digits 2-4 with absence of the distal phalanx of digit 5. In the feet, there is absence of all distal phalanges of digits 2-5 with hypoplasia of the distal phalanx of digit 1. Finger pads at the dorsal aspects of the affected fingers may occasionally be seen. To date, no facial dysmorphism has been associated with Cooks syndrome. Cooks syndrome is considered a clinical form of brachydactyly type B (see this term), distinct from the typical variant with sparing or duplication of the thumbs and caused by mutations in the ROR2 gene (9q22).
Etiology
The exact etiology of Cooks syndrome is still unknown but microduplications on chromosome 17q24.3 and involvement of a non-coding element of the SOX9 gene (17q24.3) have recently been associated in some patients with Cooks syndrome. The SOX9 gene is necessary for chondrocyte differentiation and cartilage formation.
Genetic counseling
An autosomal dominant mode of inheritance has been proposed. Genetic counseling may be proposed and the recurrence risk is of 50%.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Marco CASTORI


A rare multiple congenital anomalies/dysmorphic syndrome characterized by auditory canal atresia (resulting in moderate conductive hearing loss) associated with intellectual disability, ventricular septal defect, umbilical hernia, anteriorly displaced anus, various skeletal anomalies (such as mild clubfoot, long fifth fingers, proximally placed thumbs), and craniofacial dysmorphism which includes brachycephaly, prominent forehead, flattened occiput, midface hypoplasia, anteverted nares, and low set, posteriorly rotated ears with overlapping superior helix. There have been no further descriptions in the literature since 1987.


A rare, congenital, non-syndromic, heart malformation characterized by the persistence of the embryonic right valve of the sinus venosus which results in a subdivision of right atrium into two chambers. Clinical manifestations depend on the degree of right atrial septation and the size of sinoatrial orifice and vary from asymptomatic to symptoms of tricuspid valve stenosis, atrial fibrillation, cyanosis, syncope, elevated central venous pressure and right heart failure. The anomaly may be isolated or associated with other congenital heart anomalies.


A rare, congenital, non-syndromic, heart malformation characterized by the presence of a thin, fibromuscular membrane subdividing the left atrium into an upper and lower chamber. The upper chamber receives blood from the pulmonary veins and the lower chamber is attached to the left atrial appendage. Therefore, the membrane blocks the orifice of the mitral valve and leads to obstruction of the left ventricular inflow. It may be asymptomatic or present in infancy with tachypnea, dyspnea, hemoptysis, chest pain, syncope, pulmonary edema, pulmonary hypertension, or heart failure, depending on the degree of obstruction. The anomaly may be isolated or associated with other congenital heart anomalies.


Corneal dystrophy-perceptive deafness syndrome

Corneal dystrophy-perceptive deafness (CDPD) or Harboyan syndrome is a degenerative corneal disorder characterized by the association of congenital hereditary endothelial dystrophy (CHED; see this term) with progressive, postlingual sensorineural hearing loss.

Summary:
Epidemiology
To date, 24 cases from 11 families of various origins (Asian Indian, South American Indian, Sephardi Jewish, Brazilian Portuguese, Dutch, Gypsy, Moroccan and Dominican) have been reported.
Clinical description
The ocular manifestations in CDPD include diffuse bilateral corneal edema occurring with severe corneal clouding, blurred vision, visual loss and nystagmus. They are apparent at birth or within the neonatal period and are indistinguishable from the ocular findings characterizing autosomal recessive CHED (CHED2). Hearing deficit in CDPD is slowly progressive and is typically identified in patients between 10 and 25 years of age. There are no reported cases with prelingual deafness, however, significant hearing loss in children as young as 4 years old has been detected by audiometry, suggesting that hearing may be affected early in the disease course, even at birth.
Etiology
CDPD is caused by mutations in the SLC4A11 gene located at the CHED2 locus on chromosome 20p13-p12, indicating that CHED2 and CDPD are allelic disorders. A total of 62 different SLC4A11 mutations have been reported in 98 families (92 with CHED2 and six with CDPD).
Diagnostic methods
Diagnosis is based on clinical criteria, detailed ophthalmological assessment and audiometry. Molecular confirmation of the clinical diagnosis is feasible.
Differential diagnosis
A variety of genetic, metabolic, developmental and acquired diseases presenting with clouding of the cornea should be considered in the differential diagnosis (Peters anomaly, sclerocornea, limbal dermoids and congenital glaucoma; see these terms). Audiometry must be performed to differentiate CDPD from CHED2. Autosomal recessive types of CHED (CHED2) and CDPD should be carefully distinguished from the less severe autosomal dominant type, CHED1.
Genetic counseling
More than 50% of the reported CDPD cases have been associated with parental consanguinity and all reported cases have been consistent with autosomal recessive transmission.
Management and treatment
The ocular abnormalities in patients with CDPD may be treated with topical hyperosmolar solutions. However, corneal transplantation (penetrating keratoplasty) represents the definitive treatment. Corneal transplantation results in substantial visual gains and has a relatively good surgical prognosis. Audiometric monitoring should be offered to all patients. Hearing aids may be necessary in adolescence.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Pr Marc ABRAMOWICZ  - Dr Julie DESIR


A heterogeneous group of bilateral, genetically determined, non-inflammatory eye diseases that are usually restricted to the cornea. The designation is imprecise but remains in use because of its clinical value.

Summary:
Epidemiology
Prevalence of the corneal dystrophies is variable but these conditions are rare. An indication of the precise number of each of the specific types of corneal dystrophies is unknown as all cases are not reported or recorded in a registry.
Clinical description
Clinically, the corneal dystrophies can be divided into three groups based on the sole or predominant anatomical location of the abnormalities. Some affect primarily the corneal epithelium and its basement membrane or Bowman layer and the superficial corneal stroma (superficial corneal dystrophy), the corneal stroma (stromal corneal dystrophy), or Descemet membrane and the corneal endothelium (posterior corneal dystrophy) (see these terms). Most corneal dystrophies have no systemic manifestations and present with variable shaped corneal opacities in a clear or cloudy cornea and they affect visual acuity to different degrees.
Etiology
Different corneal dystrophies are caused by mutations in the CHST6, COL8A2, KRT3, KRT12, PIP5K3, SLC4A11, TACSTD2, TCF4, TGFBI, and UBIAD1 genes. Knowledge about the genetic mutations responsible for these disorders has led to a better understanding of their basic defect and to molecular tests for their precise diagnosis. Genes for other corneal dystrophies have been mapped to specific chromosomal loci, but have not yet been identified.
Diagnostic methods
As clinical manifestations vary widely with the different entities, corneal dystrophies should be suspected when corneal transparency is lost or corneal opacities occur spontaneously, particularly in both corneas, and especially in the presence of a positive family history or in the offspring of consanguineous parents. Clinical diagnosis is based on the age of onset and the clinical appearance of the cornea on slit-lamp biomicroscopy. When corneal tissue is excised, it should be examined by light microscopy and transmission electron microscopy (TEM) as this can establish the precise diagnosis of many corneal dystrophies. In dystrophies for which the genetic mutation has been identified, molecular genetic testing can confirm diagnosis.
Differential diagnosis
Main differential diagnoses include various causes of monoclonal gammopathy, lecithin-cholesterol-acyltransferase deficiency, Fabry disease, cystinosis, tyrosinemia type 2, systemic lysosomal storage diseases (mucopolysaccharidoses, lipidoses, mucolipidoses), and several skin diseases (X-linked ichthyosis, keratosis follicularis spinolosa decalvans) (see these terms).
Antenatal diagnosis
A prenatal diagnosis of corneal dystrophies caused by known genetic mutations is theoretically possible but is not justified ethically for these non-life-threatening conditions.
Genetic counseling
Corneal dystrophies may have an autosomal dominant, autosomal recessive or X-linked recessive Mendelian mode of inheritance. Since the clinical characteristics and mode of inheritance of each of the well-defined corneal dystrophies are well established, genetic counseling can be offered to patients, particularly to provide genetic counseling on treatments and prognoses.
Management and treatment
The management of the corneal dystrophies varies with the specific disease. Some are treated medically or with methods that excise or ablate the abnormal corneal tissue, such as deep lamellar endothelial keratoplasty (DLEK) and phototherapeutic keratectomy (PTK). Other less debilitating or asymptomatic dystrophies do not warrant treatment.
Prognosis
The prognosis varies from minimal effect on vision to corneal blindness, with marked phenotypic variability.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare corneal disorder characterized by inflammation of the corneal endothelium with corneal edema, keratic precipitates, mild to moderate anterior chamber reaction, and subsequent visual disturbances. It is often associated with increased intraocular pressure. Based on the distribution of the lesions, a linear, sectorial, disciform, and diffuse form can be distinguished.


Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

A rare opthalmic disorder characterized by corneal opacification and dyskeratosis (which may cause visual impairment), associated with systemic features including palmoplantar hyperkeratosis, laryngeal dyskeratosis, pruritic hyperkeratotic scars, chronic rhintis, dyshidrosis and/or nail thickening.


A rare multiple congenital anomalies syndrome characterized by facial dysmorphism, hypertrichosis, mild to profound intellectual disability, intrauterine growth restriction (IUGR) and/or postnatal growth restriction, feeding difficulties, abnormalities of the hands and feet (ranging from severe reductional limb abnormalities, oligodactyly, to brachymetacarpia of the first metacarpus). Variable visceral malformations may be present.

Summary:
Epidemiology
In Europe, the prevalence at birth of Cornelia de Lange syndrome (CdLS) is estimated at 1/80,000.
Clinical description
Distinctive facial features include: well-defined arched eyebrows, synophrys, long eyelashes, short nose, concave nasal ridge, anteverted nares, micrognathia, long smooth philtrum, and downturned corners of the mouth with a thin upper lip. Feeding difficulties and failure to thrive are frequently complicated by gastroesophageal reflux. Global developmental delay, in particular speech delay evolves towards intellectual disability ranging from mild to profound. Various behavioral disorders have been reported (anxiety, autistic traits/autism, shyness, compulsive obsessional disorder, self-injurious behavior, psychiatric disorders). Hearing loss is possible as well as various cardiac, renal, skeletal, gastrointestinal, and genital malformations.
Etiology
Causative pathogenic variants in six genes involved in structural or regulatory components of the cohesin complex have been identified. NIPBL variants (5p13.2) are the most common cause (70% of patients). Less frequently involved genes include: SMC1A (Xp11.22-p11.21) associated with an X-linked form of CdLS, SMC3 (10q25) missense variants associated with a non-classical phenotype, RAD21 (8q24.11) mainly non-classical phenotype, HDAC8 (Xq13.1) implicated in an X-linked CdLS with some distinctive features, and BRD4 (19p13.12) recently associated with non-classical or mild CdLS. Genotype-phenotype correlations can be made to a certain extent, severe forms are more frequently associated with NIPBL.
Diagnostic methods
Diagnosis is often suspected on clinical presentation and a clinical diagnosis can be confirmed for the classical phenotype if full criteria are met. The diagnosis is confirmed by genetic testing for up to 70% of patients presenting a classical phenotype. Gene panels should at least include the causal genes as wells as genes from differential diagnoses (e.g. ANKRD11). Somatic mosaicism occurs quite frequently in CdLS (15%) and saliva or buccal cell swabs should be considered as preferred sample for genetic testing.
Differential diagnosis
Hypertrichosis is common in other syndromes that affect chromatin/transcription regulation genes such as Coffin Siris Syndrome, Wiedemann Steiner Syndrome, Rubinstein Taybi syndrome, CHOPS syndrome, etc. Other differential diagnoses include mucopolysaccharidosis, fetal alcohol syndrome, and Smith Lemli Opitz syndrome among others. There are overlapping features between KBG syndrome and mild or atypical CdLS.
Antenatal diagnosis
Prenatal ultrasound examination may show IUGR, organ malformations (diaphragmatic hernia, limb defects), increased nuchal thickness, and abnormal facial profile. Prenatal genetic testing can be proposed when the pathogenic variant has been previously identified in a family member.
Genetic counseling
Most cases are sporadic. Occasionally, familial transmission occurs, following an autosomal dominant pattern. Genetic counseling can be difficult in milder forms given some inter-individual variability. Germline mosaicism explains recurrence cases when the pathogenic variant is not detected in parents. X-linked forms (SMC1A, HDAC8) require specific genetic counseling.
Management and treatment
There is no cure for the disorder but psychoeducational care is necessary. Failure to thrive and gastroesophageal reflux require specific care: tube feeding, gastrotomy and Nissen anti-reflux intervention. Screening for multi-visceral or sensorineural complications helps to improve quality of life.
Prognosis
Life expectancy with appropriate care is typically unaltered but follow-up data is lacking. Life expectancy can be reduced in case of severe or untreated organ malformations. Quality of life is mostly altered by severe limb defects, behavioral disorders and psychiatric disorders. Hearing impairment can be difficult to diagnose and has been reported to improve with time in some adults.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Alice GOLDENBERG | ITHACA* - Dr Gabriella VERA | ITHACA*

                                * European Reference Network


A rare, genetic, ectodermal dysplasia syndrome characterized by corneal epithelial changes (ranging from roughening to nodular irregularities), diffuse palmoplantar hyperkeratosis with thickened, erythematous, scaly lesions affecting the elbows, knees and knuckles, distal onycholysis, brachydactyly accompanied by a single transverse palmar crease, short stature, premature birth, and increased susceptibility to tooth decay. Ocular symptoms include photophobia, reduced night vision, burning and watery eyes, and varying visual acuity. There have been no further descriptions in the literature since 1984.


Coronary arterial fistulas are a connection between one or more of the coronary arteries and a cardiac chamber or great vessel.

Summary:
Epidemiology
Their exact incidence is unknown but the defect is rare and usually occurs in isolation.
Clinical description
The majority of these fistulas are congenital in origin although they may occasionally be detected after cardiac surgery. They do not usually cause symptoms or complications in the first two decades of life, especially when small. After this age, the frequency of both symptoms and complications increases. Complications include 'steal' from the adjacent myocardium, thrombosis and embolism, cardiac failure, atrial fibrillation, rupture, endocarditis/endarteritis and arrhythmias. Thrombosis within the fistula is rare but may cause acute myocardial infarction, paroxysmal atrial fibrillation and ventricular arrhythmias. Spontaneous rupture of the aneurysmal fistula causing haemopericardium has also been reported.
Diagnostic methods
Whilst two-dimensional echocardiography helps to differentiate between the different shunts, coronary angiography is the main diagnostic tool for the delineation of the anatomy.
Differential diagnosis
The main differential diagnosis is patent arterial duct, although other congenital arteriovenous shunts need to be excluded.
Management and treatment
Surgery was the traditional method of treatment but nowadays catheter closure is recommended using a variety of closure devices, such as coils. With the catheter technique, the results are excellent with infrequent complications.

                            Last update:
                            December 2006

                            - Expert reviewer(s):
                            Dr Shakeel QURESHI


A rare coronary artery congenital malformation characterized by congenital, partial or total occlusion of the left or right coronary artery orifice, associated with hypoplasia of the proximal segment of the corresponding coronary artery. It may present with failure to thrive, dyspnea, syncope, angina pectoris, ventricular tachycardia, myocardial ischemia and/or sudden death.


A rare congenital anomaly of the coronary sinus characterized by its stenosis at the ostium, lumen, or origin, typically leading to dilation of the vessel. Symptoms are variable and can include palpitations, tachypnea, dyspnea, chest pain, fatigue, and cyanosis. The malformation may be associated with other cardiac anomalies, such as coronary artery-coronary sinus fistula, unroofed coronary sinus, atrial septal defect, coronary sinus-left atrium fistula, total anomalous pulmonary venous connection, and ventricular septal defect.


Corpus callosum agenesis-abnormal genitalia syndrome is a rare, genetic developmental defect during embryogenesis syndrome characterized by agenesis of the corpus callosum, mild to severe neurological manifestations (intellectual disability, developmental delay, epilepsy, dystonia), and urogenital anomalies (hypospadias, cryptorchidism, renal dysplasia, ambiguous genitalia). Additionally, skeletal anomalies (limb contractures, scoliosis), dysmorphic facial features (prominent supraorbital ridges, synophris, large eyes) and optic atrophy have been observed.


Corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome is a developmental anomalies syndrome characterized by coloboma of the iris and optic nerve, facial dysmorphism (high forehead, microretrognathia, low-set ears), intellectual deficit, agenesis of the corpus callosum (ACC), sensorineural hearing loss, skeletal anomalies and short stature.


Corpus callosum agenesis-macrocephaly-hypertelorism syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by agenesis of the corpus callosum, borderline or mild intellectual disability, macrocephaly, and dysmorphic facial features (broad forehead, widely spaced eyes). Chiari type I malformation has also been reported in association.


Corpus callosum agenesis-neuronopathy syndrome

A rare neurodegenerative disorder characterized by severe progressive sensorimotor neuropathy beginning in infancy with resulting hypotonia, areflexia, amyotrophy and variable degrees of dysgenesis of the corpus callosum. Additional features include mild-to-severe intellectual and developmental delays, and psychiatric manifestations that include paranoid delusions, depression, hallucinations, and 'autistic-like' features. Affected individuals are usually wheelchair restricted in the second decade of life and die in the third decade of life. The disease is inherited as an autosomal recessive trait.


Cortical blindness-intellectual disability-polydactyly syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by congenital, total, cortical blindness, intellectual disability, postaxial polydactyly of the hands and feet, pre- and postnatal growth delay, psychomotor developmental retardation, and mild facial dysmorphism (incl. prominent forehead, short nose, long philtrum, high-arched palate, and microretrognathia). Recurrent respiratory and intestinal infections, as well as moderate hypertonia and hyperreflexia, are also associated. There have been no further descriptions in the literature since 1985.


Cortical dysgenesis with pontocerebellar hypoplasia due to TUBB3 mutation

A rare, genetic, non-syndromic cerebral malformation due to abnormal neuronal migration disease characterized by the association of cortical dysplasia and pontocerebellar hypoplasia, manifesting with global developmental delay, mild to severe intellectual disability, axial hypotonia, strabismus, nystagmus and, occasionally, optic nerve hypoplasia. Brain imaging reveals variable malformations, including frontally predominant microgyria, gyral disorganization and simplification, dysmorphic and hypertrophic basal ganglia, cerebellar vermis dysplasia, brainstem/corpus callosum hypoplasia, and/or olfactory bulbs agenesis.


A rare neurologic disease characterized by multifaceted motor system dysfunctions and cognitive defects such as asymmetric rigidity, bradykinesia, limb apraxia, and visuospatial dysfunction.

Summary:
Epidemiology
The prevalence of Corticobasal syndrome (CBS) is unknown.
Clinical description
The disease shows a wide clinical variability between patients with many developing a relatively pure motor syndrome, and others displaying a combination of motor and cognitive deficits. Disease onset is insidious and usually occurs in the 6th to 7th decade of life with symptoms typically being unilateral at first, and the arm being more commonly affected than the leg. It may begin primarily as a movement disorder with rigidity, bradykinesia and tremor, in association with frontal signs, cortical sensory loss, alien limb phenomenon, stimulus induced myoclonus and progressive limb apraxia, which may become bilateral, though usually asymmetrical, as the disease progresses. Gait disturbance and postural instability are common, whereas dystonia and aphasia (speech apraxia, dysfluency and agraphia) are less commonly reported. Additionally, eye movement abnormalities and behavioral manifestations can also be present. Many patients have dementia in later stages of the disease.
Etiology
Around 25% of CBS cases are shown to be due to corticobasal degeneration syndrome (CBD). CBD is a distinct tauopathy with selective aggregation of 4 repeat tau proteins with characteristic antigenic and ultrastructural characteristics. The cause is unknown and there is usually no evidence of inheritance (there has been a suggestion of genetic propensity, but this is currently poorly understood). Other causes of CBS include progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD) due to tau or TAR DNA-binding protein 43 (TDP-43), and Alzheimer disease (AD).
Diagnostic methods
The diagnosis of CBS is a clinical one, based on the recognition of characteristic clinical features. Several diagnostic criteria have been proposed, but none have gained universal acceptance. The pathological diagnosis of CBD is only possible at autopsy and is defined by nerve cell loss, gliosis and atrophy of cortical and subcortical structures such as the posterior frontal and/or parietal lobes and the substantia nigra, as well as widespread deposition of hyperphosphorylated 4-repeat tau in neurons and glia. Furthermore, many cases may have co-pathologies which must be taken into consideration.
Differential diagnosis
The main differential diagnoses include progressive non-fluent aphasia and, to a lesser extent, behavioral variant of frontotemporal dementia, progressive supranuclear palsy, multiple system atrophy, posterior cortical atrophy, AD (the typical/amnestic form) and idiopathic Parkinson's disease.
Genetic counseling
Familial CBS is extremely rare. Genetic counselling can only be offered in these exceptional cases.
Management and treatment
Treatment is symptomatic and focuses on improving function as well as palliative care. Dystonia may be treated with botulinum toxin. Brief response to levodopa may occur, but sustained response to treatment should prompt a reconsideration of the diagnosis. Physical therapy and surgery are not found to offer any symptom relief. Speech therapy can be offered to those with prominent aphasia.
Prognosis
Quality of life is decreased in CBS patients as they gradually lose their ability to function independently. The prognosis is poor with the mean disease duration being 5.4-7.9 years after onset.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr James BURRELL


Corticosteroid-binding globulin deficiency is a rare, genetic, adrenal disease characterized by diminished corticosteroid-binding capacity associated with normal or low plasma corticosteroid-binding globulin concentration and reduced total plasma cortisol levels. Patients typically present chronic pain, fatigue and hypo/hypertension.


A rare syndrome with intellectual disability, characterized by failure to thrive, short stature, joint laxity, soft skin, and distinctive facial features. Cardiac and neurological involvement is common and there is an increased lifetime risk of certain tumors. Costello syndrome belongs to the RASopathies, a group of conditions resulting from germline derived point mutations affecting the RAS-mitogen activated protein kinase pathway.

Summary:
Epidemiology
Costello syndrome (CS) estimated number of patients worldwide is 300. Estimated birth prevalence has been reported to be 1/300,000 to 1/1 250 000.
Clinical description
Patients have above-average birth weight from mild hydrops and usually present with severe postnatal feeding difficulties and failure to thrive. The severe feeding difficulties typically necessitate the placement of a feeding tube. Developmental delay with short stature and mild to moderate intellectual disability are present in most cases. Features include relative macrocephaly, coarse facial features (epicanthal folds, full cheeks, low set and prominent ears, upturned nasal nasal tip, large mouth with prominent lips), curly or sparse, fine hair, loose soft skin with deep palmar and plantar creases, and papillomata (torso, extremities, perinasal and/or perianal region generally during childhood). Musculoskeletal features include joint laxity and ulnar deviation of wrists and fingers, hip dysplasia, and kyphoscoliosis in older individuals. Cardiovascular manifestations include valvular pulmonary stenosis, arrhythmia (ectopic or multifocal atrial tachycardia), hypertrophic cardiomyopathy and rarely aortic dilation. The reported neurological signs are hydrocephalus, seizures, Arnold-Chiari malformation type I, syringomyelia, and tethered spinal cord. In later childhood, patients often develop tight Achilles tendons that may require surgical correction. Puberty is often delayed or disordered. The disorder progresses with age and patients often show signs of premature ageing, osteoporosis and osteopenia. An increased risk of about 10-15% for solid malignant tumors (embryonal rhabdomyosarcoma, neuroblastoma in early childhood and transitional cell carcinoma of the bladder in adolescence) is reported.
Etiology
CS is caused by heterozygous germline mutations in the proto-oncogene HRAS (11p15.5) involved in controlling cell growth and division in multiple organ systems. The most common variant results in the p.Gly12Ser amino acid substitution, present in about 80% of patients.
Diagnostic methods
Diagnosis is based on the constellation of clinical findings, although no single feature is characteristic of the disorder. Diagnosis can be confirmed by molecular genetic testing.
Differential diagnosis
Costello syndrome shows significant clinical overlap with Noonan syndrome and cardiofaciocutaneous syndrome, which are also RASopathies. Other disorders to consider include Beckwith-Wiedemann, Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome) and Simpson-Golabi-Behmel syndromes.
Antenatal diagnosis
Prenatal diagnosis is possible if the disease-causing mutation has been identified in an affected family member, or if the diagnosis of CS is suspected prenatally and HRAS sequence analysis is performed.
Genetic counseling
An autosomal dominant pattern of inheritance may be found, typically due to de novo dominant mutations. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Failure to thrive and cardiac manifestations should be treated with standard measures. Specific educational and intervention strategies may be required for intellectual development and developmental delay. Facial papillomata may require removal with cryotherapy or electrocoagulation. Abdominal and pelvic ultrasound examinations can be considered to screen for embryonal rhabdomyosarcoma and neuroblastoma until 8-10 years of age. Neoplastic complications are treated with standard approaches. Tethered cord may be screened by imaging. Hip dysplasia should be evaluated by an orthopedist.
Prognosis
The risk of neoplasia and severe hypertrophic cardiomyopathy negatively affects the prognosis. The prognosis varies by the specific missense mutations, with neonatal lethal phenotypes and attenuated phenotypes reported.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Karen GRIPP


A genodermatosis characterized by the presence of multiple hamartomas in various tissues and an increased risk for malignancies of the breast, thyroid, endometrium, kidney and colorectum. When CS is accompanied by germline PTEN mutations, it belongs to the PTEN hamartoma tumor syndrome (PHTS) group.

Summary:
Epidemiology
The prevalence of Cowden syndrome is unknown but is estimated at 1/200,000.
Clinical description
Disease manifestations usually occur between the second and third decades of life but can appear at any age. The most commonly, but not uniformly, reported manifestations are macrocephaly (specifically, megalencephaly), mucocutaneous lesions, thyroid abnormalities, fibrocystic disease and carcinoma of the breast, gastrointestinal hamartomas, multiple early onset uterine leiomyomas, and developmental delay. Macrocephaly and rarely dysmorphic facies, if present, are evident at birth. Malignancies such as breast cancer (with an 85% lifetime risk), epithelial thyroid cancer, renal cancer and endometrial carcinoma often appear later in life. Clinicians should consider other red flags of a CS diagnosis which includes Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma which is pathognomonic of CS), mucocutaneous stigmata such as trichilemmomas and papillomatous papules (believed to exist in 100% of CS patients by age 30), ganglioneuromatous gastrointestinal polyps, glycogenic acanthosis, pediatric differentiated (non-medullary) thyroid cancer and endometrial cancer diagnosed relatively early.
Etiology
It is now believed that 25% of CS and CS-like cases are caused by germline mutations in PTEN (10q23), which encodes a dual-specificity phosphatase. Patients with CS/CS-like phenotypes that do not have PTEN involvement have been found to have germline promoter methylation of KLLN (up to 30%), germline variations in SDHB-D (10%), or germline mutations in AKT1 and PIK3CA (10%). More recently, germline SEC23B and USF3 were identified in PTEN wildtype CS/CS-like patients with differentiated thyroid cancer as a predominant phenotype.
Diagnostic methods
The International Cowden Consortium for CS lists the pathognomonic (mucocutaneous lesions, LDD), major (breast cancer, macrocephaly, thyroid cancer and endometrial cancer), and minor criteria used to diagnose this disease. An operational diagnosis is given if a patient displays the pathognomonic skin lesions, two or more major, one major and 3 or more minor, or 4 or more minor criteria. A quantitative scoring system for adults and a separate pediatric criteria system have now been created to aid clinicians at the point of care. Finding germline mutations in PTEN or other causal genes confirms diagnosis.
Differential diagnosis
Juvenile-polyposis syndrome, Peutz-Jeghers syndrome, Birt-Hogg-Dubé syndrome, Gorlin syndrome and neurofibromatosis type 1.
Antenatal diagnosis
Antenatal diagnosis is possible for at-risk pregnancies if the disease-causing mutation is discovered in an affected family member.
Genetic counseling
CS is inherited autosomal dominantly. Genetic counseling can be offered to patients with germline PTEN mutations and asymptomatic family members should also be tested so that those with a mutation can be monitored before symptom onset.
Management and treatment
Management and treatment are multidisciplinary and based on genotype. Once a PTEN germline mutation is identified, surveillance guidelines should be followed. Thyroid ultrasound should begin once a mutation is identified, starting at the age of 7. A colonoscopy and biennial renal imaging should begin between the ages of 35-40, unless symptomatic. Women should perform monthly breast self-examinations and yearly breast screenings as well as transvaginal ultrasounds (postmenopausal) or endometrial biopsies beginning at the age of 35.
Prognosis
The pinpointing of the diagnosis (especially by gene) and instituting organ-specific surveillance at the right time results in a good prognosis. When advanced cancers occur before diagnosis is made, a poor outcome is common.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Charis ENG


A rare primary bone defect, described only in a mother and her three daughters to date, characterized by short stature, hip dislocation, minor vertebral and pelvic changes, and microtia with hearing loss. There have been no further descriptions in the literature since 1981.


Small patella syndrome (SPS) is a very rare benign bone dysplasia affecting skeletal structures of the lower limb and the pelvis.

Summary:
Epidemiology
Less that 50 patients have been reported worldwide.
Clinical description
The main clinical features include patellar aplasia or hypoplasia, associated with absent, delayed or irregular ossification of the ischiopubic junctions and/or the infra-acetabular axe-cut notches. Additional features found in the majority of reported patients include femur and foot anomalies (a wide gap between the first and second toes, short fourth and fifth rays of the feet, and pes planus). Craniofacial anomalies (micrognathia, cleft palate, flattened nose and prominent forehead) have been reported occasionally. Intrafamilial variability of the patellar, pelvic and foot anomalies has been described. Signs and symptoms vary from pain resulting from gonarthrosis in elderly subjects to recurrent luxations from infancy, knee pain, and inability to run and ride a bicycle. However, some cases are asymptomatic.
Etiology
SPS is caused by mutations in the human TBX4 gene (chromosome 17q22). TBX4 mutations account for familial cases with a distinctive facial appearance and those without facial features. At present, there is no evidence for a genotype-phenotype correlation.
Diagnostic methods
Diagnosis is clinical and radiographical.
Differential diagnosis
SPS should be recognized and differentiated from disorders with aplastic or hypoplastic patellae, such as isolated familial patella aplasia-hypoplasia (PTLAH) syndrome and the more severe nail-patella syndrome (NPS).
Genetic counseling
SPS is inherited in an autosomal dominant manner.
Management and treatment
Early surgical treatment, pain relief therapy and supportive measures should be offered.

                            Last update:
                            November 2006

                            - Expert reviewer(s):
                            Pr Didier LACOMBE


A rare genetic neurological disorder characterized by adult onset of peripheral nerve hyperexcitability causing painful muscle cramps and fasciculations in the limbs, hyperreflexia, stiffness, and muscle pain. Other hypersensitivity-hyperexcitability symptoms are asthma, gastroesophageal reflux, migraine, tremor, cold hyperalgesia, and cardiac conduction defects. Autonomic signs and symptoms, neuropathic pain, cognitive deficits, and anxiety are also observed.


Crandall syndrome is characterized by progressive sensorineural deafness, alopecia and hypogonadism with LH and GH deficiencies. It has been described in three brothers. It resembles Björnstad's syndrome (see this term) that combines irregular pili torti and deafness. It is probably inherited as and autosomal recessive disorder.


Crane-Heise syndrome is a very rare syndrome characterized by poorly mineralized calvarium, facial dysmorphism, vertebral abnormalities and absent clavicles.

Summary:
Epidemiology
Nine cases have been reported in the literature so far.
Clinical description
Dysmorphic features include micrognathia, cleft palate, hypertelorism and upturned nares. Clavicular aplasia is constant and agenesis of cervical vertebral bodies is frequent. Intra uterine growth retardation is constant.
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 and vertebral malformations.
Prognosis
Prognosis is poor; the syndrome is almost always lethal soon after birth.

                            Last update:
                            January 2010


A rare central nervous system malformation characterized by herniation of meninges through a permanent defect in the skull. It is lined by arachnoid and contains cerebrospinal fluid, but no brain tissue. Signs and symptoms depend on the location of the lesion and are related to mass effect, skull deformities, or leaking of cerebrospinal fluid.


Cranio-cervical dystonia with laryngeal and upper-limb involvement is a rare genetic, isolated dystonia characterized by a variable combination of cervical dystonia with tremor, blepharospasm, oromandibular and laryngeal dystonia. Dystonia progresses slowly and might spread to become segmental. Arm tremor and myoclonic jerks in the arms or neck have also been reported.


Cranio-osteoarthropathy (COA) is a form of primary hypertrophic osteoarthropathy (see this term) characterized by delayed closure of the cranial sutures and fontanels, digital clubbing, arthropathy, and periostosis.

Summary:
Epidemiology
Prevalence is unknown. To date, about 30 cases have been reported.
Clinical description
COA presents in childhood with features of primary hypertrophic osteoarthropathy including digital clubbing and clinodactyly of the fingers, eczematous skin eruption, arthropathy and periosteal new bone formation as well as poor neurocranium ossification with delayed closure of the cranial sutures and fontanels, resulting in wide fontanels, and an increased number of wormian bones. COA may also be associated with congenital heart disease.
Etiology
It is caused by mutations in the HPGD gene (4q33-q34) and is inherited as an autosomal recessive trait; however, heterozygous carriers can have a mild phenotype.

                            Last update:
                            December 2010

                            - Expert reviewer(s):
                            Pr Hermann GIRSCHICK


Craniodiaphyseal dysplasia is a rare sclerotic bone disorder with a variable phenotypic expression with massive generalized hyperostosis and sclerosis, particularly of the skull and facial bones, that may lead to severe deformity.


Craniodigital syndrome - intellectual deficit is characterised by syndactyly of the fingers and toes, characteristic facies (`startled' facial expression with a small pointed nose, micrognathia, long dark eyelashes and prominent eyebrows) and intellectual deficit.

Summary:
Epidemiology
Less than 10 cases have been described in the literature so far.
Clinical description
Abnormal dermatoglyphic patterns, growth retardation and brachycephaly have also been reported.
Genetic counseling
Transmission appears to be autosomal or X-linked recessive.

                            Last update:
                            April 2008


Cranioectodermal dysplasia (CED) is a rare developmental disorder characterized by congenital skeletal and ectodermal defects associated with dysmorphic features, nephronophthisis, hepatic fibrosis and ocular anomalies (mainly retinitis pigmentosa).

Summary:
Epidemiology
To date, 20 cases have been reported in the literature.
Clinical description
CED is primarily characterized by an abnormal development of bones (i.e. craniosynostosis/dolichocephaly, narrow thorax, pectus excavatum, rhizomelic micromelia, brachydactyly, syndactyly, clinodactyly, hyperextensible joints), and ectodermal defects such as dental anomalies (reduced enamel thickness, hypodontia, microdontia, taurodontism, malformations of the cusps), sparse hair, and abnormal finger and toe nails. Dysmorphic features are observed such as epicanthic folds, hypotelorism, anteverted nares, and everted lower lip. Patients frequently develop chronic renal failure due to nephronophthisis, usually between the ages of 2 and 6. Liver involvement (hepatic fibrosis) can also be observed. Recurrent lung infections, heart defects and ocular anomalies (nystagmus, myopia, retinal dystrophy, and particularly retinitis pigmentosa) are also possible in the course of the disease.
Etiology
CED is a heterogenous condition belonging to the ciliopathy group of diseases and is due to mutations in the IFT122, IFT43, WDR19 and WDR35 genes involved in intraflagellar transport (IFT). This genetic background explains the pleiotropic phenotype of CED that includes manifestations of several ciliopathies.
Diagnostic methods
Diagnosis is based on clinical examination. Imagery (ultrasonography), laboratory findings (urine analysis, serum electrolytes, and lipid profile), histological examination and liver and renal function tests allow detection of potential renal and liver anomalies. Ocular anomalies can be detected by eye fundus and electroretinography.
Differential diagnosis
Differential diagnosis of CED includes Jeune syndrome (see this term) from which it can be distinguished by the presence of craniosynostosis, and skin and dental dysplasia. CED also overlaps with Ellis van Creveld syndrome (see this term) which also shows ectodermal defects and narrow thorax.
Genetic counseling
In most cases, transmission is autosomal recessive.
Management and treatment
In many cases, renal function rapidly deteriorates, requiring treatment of metabolic acidosis, oral sodium chloride supplementation, then dialysis or renal transplantation in case of end-stage renal failure.
Prognosis
Prognosis depends on renal, heart and lung defects which can be life threatening.

                            Last update:
                            June 2012

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


Craniofacial conodysplasia is characterised by craniofacial dysplasia, cone-shaped physes of the hands and feet, and neurological manifestations resembling cerebral palsy. It has been described in one family. The syndrome appeared to be transmitted as a dominant trait.


Craniofacial dysostosis-diaphyseal hyperplasia syndrome

Stanescu type dysostosis is a rare form of osteosclerosis.

Summary:
Epidemiology
So far it has been described in around 30 patients from three families.
Clinical description
It is characterized by craniofacial dysostosis with a small cranium and thin skull bone, depressions over the frontoparietal and occipitoparietal sutures, marked hypoplasia of mandible, exophthalmos, cortical sclerosis of the long bones and normal intelligence. The long bones are short and bent, and thickening of bone cortex occurs during the pubertal and post-pubertal periods and increases with age.
Genetic counseling
The syndrome is inherited in an autosomal dominant manner.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM


Craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism (including an abnormal skull shape, hypertelorism, downslanting palpebral fissures, epicanthal folds, low-set ears, depressed nasal bridge, micrognathia), short stature, ectodermal anomalies (such as sparse eyebrows, eyelashes, and scalp hair, hypolastic toenails), developmental delay, and intellectual disability. Additional features may include cerebral/cerebellar malformations and mild renal involvement.


A rare multiple congenital anomalies syndrome characterized by facial dysmorphism (including flat facial profile normal calvarium, hypertelorism, small downslanting palpebral fissures with an antimongoloid slant, hypoplastic nose with button tip and slitlike nares, and small, pursed mouth), profound sensorineural hearing loss/deafness and hand anomalies such as ulnar deviations and contractures of the hand.


Craniofaciofrontodigital syndrome is a rare multiple congenital anomalies syndrome characterized by mild intellectual disability, short stature, cardiac anomalies, mild dysmorphic features (macrocephaly, prominent forehead, hypertelorism, exophthalmos), cutis laxa, joint hyperlaxity, wrinkled palms and soles and skeletal anomalies (sella turcica, wide ribs and small vertebral bodies).


Craniofrontonasal dysplasia-Poland anomaly syndrome

A polymalformative syndrome characterized by craniosynostosis, Poland anomaly, cranio-fronto-nasal dysplasia, and genital and breast anomalies.


A rare X-linked malformation syndrome characterized by craniofacial abnormalities such as uni- or bicoronal synostosis, hypertelorism and a bifid nose, grooved or split nails, frizzy hair, abnormalities of the shoulder girdle, hands and feet.

Summary:
Epidemiology
It occurs in fewer than 1/100,000 newborns. Detailed phenotypic analysis shows that females are more severely affected than males, a highly unusual characteristic for an X-linked disorder.
Clinical description
Female patients have hypertelorism, and a broad nose with a vertical groove on the top of the nose or a bifid nose, uni or bicoronal craniosynostosis. The following facial abnormalities may be seen: facial asymmetry, downslanting palpebral fissures, dry, curly and frizzy hair, widow's peak, low posterior hairline, webbed neck, highly arched palate, cleft lip and palate, a narrow and V-shaped maxilla. Ophthalmologic abnormalities, abnormal auditory ossicles, and both conductive and sensorineural deafness can be seen. Skeletal deformities may include sloping shoulders with dysplastic clavicles, broad or duplicated thumbs and halluces, short thumbs, brachydactyly, clinodactyly, gaps between the first and second toes, syndactyly, camptodactyly, scoliosis and hyperextensible joints. Longitudinal splits or grooves in the finger- and toe- nails are frequent and characteristic. Diaphragmatic hernia, pectus excavatum or carinatum, breast hypoplasia, cardiac abnormalities, bicornuate uterus, shawl scrotum, hypospadias and agenesis of the corpus callosum occur occasionally. Mild developmental delay can occur. Variable difficulties with speech and language development can be associated. Most of the male patients are mildly affected with hypertelorism only but can occasionally present with a severe female-like phenotype. The cause for this severe phenotype in males is probably mosaic pathogenic variants in EFNB1.
Etiology
The syndrome is caused by variants in the EFNB1 gene. This gene encodes ephrin-B1 and maps to Xq13.1. Random X-inactivation explains the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of ephrin-B1, generating abnormal tissue boundaries.
Diagnostic methods
In case of a low-level of mosaicism for EFNB1 variants, extensive analysis of several types of tissues might be required to detect variants. Variation in EFNB1 is detected from DNA isolated from blood, fibroblast cell lines, saliva and hair roots by a combination of PCR/Sanger sequencing, or by next-generation sequencing and multiplex ligation-dependent probe amplification (MPLA; for the detection of deletions in females).
Differential diagnosis
Isolated hypertelorism can mimic the mild presentation of craniofrontonasal syndrome. The disease needs to be distinguished from other syndromes associated with hypertelorism such as SPECC1L-related hypertelorism syndrome and Baraitser-Winter cerebrofrontofacial syndrome.
Antenatal diagnosis
In case of an established EFNB1 mutation in a parent, prenatal diagnosis is possible.
Genetic counseling
The risk that an affected female will pass the disease on her daughter or son is 50%. An affected male will pass the disease on to all of his daughters but none of his sons.
Management and treatment
Multistage surgery is the general treatment plan for craniosynostosis. The synostotic sutures of the skull are released in the first year of life. The aim of this surgery is decompression of the brain and remodeling of the skull. Correction of the facial anomalies is usually delayed until the age of 5 or later, depending on the severity of hypertelorism, orbital dystopia and shape of the maxilla. Surgical correction of strabismus can be indicated and timing should be discussed within the craniofacial team. Multidisciplinary treatment is mandatory with the input of plastic surgeons, maxillofacial surgeons, ophthalmologists, orthoptists, otolaryngotologists, speech therapists, psychologists and social workers, and orthodontists.
Prognosis
Life expectancy in general is similar to the normal population. Quality of life may be affected because of a different facial appearance and the consequences of other congenital abnormalities.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Pr Irene MATHIJSSEN | ERN CRANIO* - Pr Andrew WILKIE | ERN CRANIO*

                                * European Reference Network


Craniolenticulosutural dysplasia (CLSD), also known as Boyadjiev-Jabs syndrome, is characterized by the specific association of large and late-closing fontanels, hypertelorism, early-onset cataract and mild generalized skeletal dysplasia.

Summary:
Epidemiology
It was originally described in 21 members of a Saudi Arabian family, but six new cases from a consanguineous family and one unrelated individual have recently been reported.
Clinical description
Patients have abnormal hair, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, macrocephaly, significant hypertelorism, and a broad and prominent nose. In addition, CLSD patients have Y-shaped sutural cataracts diagnosed by 1-2 years of age. All affected individuals have proportionate short stature but intellectual development is normal. They have flat feet, joint hypermobility and abnormal dentition. Skeletal defects include scoliosis, high and narrow iliac wings and vertebral body defects. The anterior fontanel does not completely ossify in adulthood.
Etiology
CLSD maps to chromosome 14q13-q21 and causative mutations have been identified in the SEC23A gene.
Diagnostic methods
CLSD should be considered in evaluation of patients with late-closing fontanels.
Genetic counseling
Transmission is consistent with an autosomal recessive pattern of inheritance but other modes of inheritance can not be excluded.
Management and treatment
Treatment of the disorder is symptomatic.
Prognosis
The prognosis is good.

                            Last update:
                            June 2008


Craniometadiaphyseal dysplasia, wormian bone type is an extremely rare craniotubular bone dysplasia syndrome described in fewer than 10 patients to date. Clinical manifestations include macrocephaly, frontal bossing, malar hypoplasia, prominent mandible and dental hypoplasia. Other skeletal anomalies include abnormal bone modeling in tubular bones, multiple wormian bones and deformities of chest, pelvis and elbows. An increased risk of fractures is noted.


Craniometaphyseal dysplasia (CMD) is a very rare genetic bone disease characterized by progressive diffuse hyperostosis of cranial bones causing facial dysmorphism and functional repercussions, and metaphyseal widening of long bones.


A rare syndromic craniosynostosis malformation syndrome characterized by intrauterine growth retardation, underossification of the skull with large fontanels, short limbs with absent phalanges, and finger and toe syndactyly. Reported dysmorphic features include a narrow face with small palpebral fissures, small pointed nose, microstomia, micrognathia, and low-set and posteriorly rotated ears. A posterior encephalocele and other congenital malformations can also be observed.


A rare neoplastic/endocrine disease characterized by benign slow growing tumors of low-grade histological malignancy (WHO grade 1) that are located within the sellar and parasellar regions of the skull base.

Summary:
Epidemiology
The point prevalence of this tumor is approximately 1/50,000.
Clinical description
Clinical manifestations frequently occur long time before diagnosis with most patients at diagnosis having neurological (headaches, visual disturbances) and endocrine (growth delay, disturbances of pubertal development, central diabetes insipidus) dysfunction.
Etiology
Craniopharyngiomas are thought to arise from epithelial remnants of the craniopharyngeal duct or Rathke's pouch (adamantinomatous type tumors) or from metaplasia of squamous epithelial cell rests that are remnants of the part of the stomadeum that contributed to the buccal mucosa (squamous papillary type tumors).
Diagnostic methods
The neuroradiological diagnosis is mainly based on the three components of the tumor (cystic, solid and calcified) in the characteristic sellar/parasellar location. Definitive diagnosis is based on histological examination of a surgical specimen.
Differential diagnosis
The differential diagnosis includes other tumors occurring in this region (pituitary adenomas, germinoma, low-grade glioma), infectious or inflammatory processes (Langerhans cell histiocytosis), vascular malformations (aneurysms) and congenital anomalies (Rathke's cleft cysts).
Antenatal diagnosis
Due to increased sensitivity of antenatal diagnostics (ultrasound), the rate of prenatal craniopharyngioma diagnosis is rising.
Management and treatment
If there is no hypothalamic involvement, the currently favored treatment strategy is tumor resection preserving the integrity of hypothalamus and visual structures. In the presence of hypothalamic invasion, the current hypothalamus-sparing strategy involves sub-total resection with post-operative radiotherapy. Endocrine disturbances are normally permanent and need careful replacement.
Prognosis
The 5 year overall-survival rate is 80%. However, high survival rates are associated with marked morbidity (hypothalamic syndrome, including morbid severe obesity; altered neuropsychological profile) in case of tumor- and/or treatment-associated hypothalamic damage.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                            Pr Hermann MÜLLER | PaedCan-ERN*

                                * European Reference Network


Craniorachischisis is the most severe form of neural tube defect in which both the brain and spinal cord remain open to varying degrees. It is a very rare congenital malformation of the central nervous system.

Summary:
Epidemiology
The prevalence is not known.
Clinical description
Craniorachischisis totalis, the most complete form of craniorachischisis, presents anencephaly and total spina bifida together and is lethal.
Etiology
As with other neural tube defects, craniorachischisis is thought to be of multifactorial origin.
Antenatal diagnosis
Antenatal diagnosis is possible by ultrasonographic monitoring.

                            Last update:
                            January 2010


A rare frontonasal dysplasia malformation syndrome characterized by an oxycephalic skull with craniosynostosis, wide nose with anteverted nostrils, hirsutism at base of nose, agenesis of the nasolacrimal ducts, and bilateral, symmetrical nasolabial cysts on upper lip. Additional features may include hypertelorism. There have been no further descriptions in the literature since 1991.


Craniosynostosis, Boston type is a form of syndromic craniosynostosis, characterized by a highly variable craniosynostosis with frontal bossing, turribrachycephaly and cloverleaf skull anomaly. Hypoplasia of the supraorbital ridges, cleft palate, extra teeth and limb anomalies (triphalangeal thumb, 3-4 syndactyly of the hands, a short first metatarsal, middle phalangeal agenesis in the feet) have also been described. Associated problems include headache, poor vision, and seizures. Intelligence is normal.


Craniosynostosis, Herrmann-Opitz type is a rare bone development disorder characterized by intellectual disability, short stature, turribrachycephaly, facial dysmorphism (i.e. severe hypertelorism, hypoplasia of supraorbital ridges, abnormal ears, and micrognathia), bony defects of the occiput, and digital anomalies (incl. syndactyly, oligodactyly, and/or brachydactyly). Urethral atresia has also been reported. There have been no further descriptions in the literature since 1987.


Craniosynostosis, Philadelphia type is a form of syndromic craniosynostosis, characterized by sagittal/dolichocephalic head shape with a relatively normal facial appearance and complete soft tissue syndactyly of hand and foot. Transmission is autosomal dominant with variable expression of the hand findings, and incomplete penetrance of the sagittal craniosynostosis. Craniosynostosis, Philadelphia type has been suggested to share the same etiology as syndactyly type 1A.


Craniosynostosis - anal anomalies - porokeratosis, or CDAGS, is a very rare condition characterized by craniosynostosis and clavicular hypoplasia, (C), delayed closure of the fontanel (D), anal anomalies (A), genitourinary malformations (G) and skin eruption (S).

Summary:
Epidemiology
It has been described in seven patients from four unrelated families.
Clinical description
Cranial abnormalities include a coronal synostosis with wide-open anterior and posterior fontanels and large parietal foramina. In some patients the skin eruption has been classified as porokeratosis (a disorder of keratinization). Sensorineural hearing loss and mild to severe developmental delay are common.
Genetic counseling
The condition is transmitted as an autosomal recessive trait.

                            Last update:
                            October 2010


A rare malformation disorder characterized by sagittal craniosynostosis, Dandy-Walker malformation, hydrocephalus, craniofacial dysmorphism (including dolichocephaly, hypertelorism, micrognathia, positional ear deformity) and variable developmental delay.


A rare syndromic craniosynostosis characterized by premature fusion of multiple or all calvarial sutures (resulting in variable abnormal shape of the head), midface hypoplasia, delayed and ectopic tooth eruption and supernumerary teeth. Associated facial dysmorphism includes proptosis, hypertelorism, beaked nose, and relative prognathism. Variable digital anomalies (e.g. finger and/or toe syndactyly, clinodactyly), short stature, cognitive and/or motor delay, high palate, ear deformity and conductive hearing loss have also been reported.


Craniosynostosis-hydrocephalus-Arnold-Chiari malformation type I-radioulnar synostosis syndrome

A rare syndromic craniosynostosis characterized by sagittal craniosynostosis, hydrocephalus, Chiari I malformation and radioulnar synostosis. Other clinical findings include blepharophimosis, small low-set ears, hypoplastic philtrum, kidney malformation, and hypogenitalism.


Craniosynostosis-intracranial calcifications syndrome is a form of syndromic craniosynostosis characterized by pancraniosynostosis, head circumference below the mid-parental head circumference, mild facial dysmorphism (prominent supraorbital ridges, mild proptosis and maxillary hypoplasia) and calcification of the basal ganglia. The disease is associated with a favorable neurological outcome, normal intelligence and is inherited in an autosomal recessive manner.


Craniosynostosis-microretrognathia-severe intellectual disability syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, moderate to severe intellectual disability, dysmorphic features including craniosynostosis, micro-/retrognathia, cleft palate, and brachydactyly, and short stature. Seizures, skeletal anomalies (such as arthrogryposis, gracile bones, and pathological fractures), and renal abnormalities have also been described. Cerebral MRI may show periventricular white matter changes and ventriculomegaly.


Craniosynostosis is defined as the premature fusion of one or more cranial sutures leading to secondary distortion of skull shape resulting in skull deformities with a variable presentation. Craniosynostosis may occur in an isolated setting or as part of a syndrome.


Craniotelencephalic dysplasia is an extremely rare, genetic developmental defect during embryogenesis syndrome characterized by craniosynostosis with frontal encephalocele and various additional brain anomalies (severe hydrocephalus, agenesis of the corpus callosum, lissencephaly and polymicrogyria, parenchymal cysts, septo-optic dysplasia) resulting in marked cerebral dysfunction, seizures and very severe psychomotor delay. There have been no further descriptions in the literature since 1983.


Creatine deficiency syndrome (CDS) comprises a group of inborn errors of creatine metabolism, characterized by a global developmental delay, intellectual disability and associated neurological (seizures, movement disorders, myopathy) and behavioral manifestions. CDS includes two creatine biosynthesis disorders; guanidinoacetate methyltransferase deficiency and L- Arginine: glycine amidinotransferase deficiency, as well as X-linked creatine transporter deficiency.


A rare cutaneous myiasis characterized by infestation of humans by the larvae of horse or cattle bot flies. After penetration of the skin, horse bot fly larvae form tunnels in the lower layers of the epidermis, where they can migrate for up to several months, causing serpentine, erythematous lesions with intense pruritus. Cattle bot fly larvae penetrate deeper into the subcutaneous tissue, producing more painful, erythematous lesions, which usually resolve after several hours or days, when the larvae move on to infest another area.


A form of Crigler Najjar syndrome (CNS), a hereditary disorder of hepatic bilirubin conjugation, characterized by severe neonatal unconjugated hyperbilirubinemia due to a complete absence of hepatic UDP-glucuronosyltransferase 1A1. The disorder clinically manifests with neonatal, isolated, severe and permanent jaundice with a permanent risk of bilirubin encephalopathy.

Summary:
Epidemiology
The prevalence of Crigler-Najjar syndrome type 1 (CNS1) is unknown.
Clinical description
Infants present with persistent jaundice at or soon after birth. Bilirubin encephalopathy (kernicterus manifesting as hypertonia, deafness, oculomotor palsy and lethargy) due to hyperbilirubinemia is a permanent risk. Neurologic defects (injury to basal ganglia, cerebellar and likely hippocampal structures) can occur, generally associated with intellectual and motor impairment.
Etiology
Numerous variants in the gene UGT1A1 gene (2q37), encoding the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), have been linked to CNS1. In the liver, UGT1A1 conjugates bilirubin with glucuronic acid, thereby increasing bilirubin water solubility and thus facilitating its excretion. The UGT1A1 variants result in absent UGT1A1 activity with marked impairment of bilirubin conjugation.
Diagnostic methods
Diagnosis is based on findings of total serum bilirubin between 20 and 45 mg/dL and presence of traces of bilirubin glucuronides in bile. Diagnosis is confirmed by genomic DNA analysis (ruling out the need for liver biopsy). When liver biopsy was performed, it showed a total deficiency of hepatic UGT1A1 activity.
Differential diagnosis
Differential diagnosis includes disorders of excessive bilirubin production (hemolysis, infections). CNS type 2 (CNS2) can be excluded by the lack of response to phenobarbital treatment and by DNA analysis.
Antenatal diagnosis
Prenatal diagnosis is possible provided both disease-causing mutations have been identified in the proband.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment relies on phototherapy for 10-12 hours a day (to maintain levels of unconjugated hyperbilirubinemia below the neurotoxic threshold and the bilirubilbumin molar ratio <0.7). Orthotopic liver transplantation may be considered and is more effective when performed before onset of neurologic damage. Bilirubin chelators (calcium salts, cholestyramine) may be used. Treatment with heme oxygenase inhibitors (tin-mesoporphyrin) can decrease plasma bilirubin concentrations but are not advised in the long term, because of their side effects (photosensitization). They may be useful for treating acute and severe hyperbilirubinemia but are not available for daily clinical practice. Gene therapy trials are ongoing. Prompt treatment of neurologic manifestations is required to avoid potentially devastating neurologic sequelae (intensive phototherapy, albumin infusions, and plasma exchanges). Unlike CNS2, patients with CNS1 do not respond to phenobarbital.
Prognosis
Without treatment, CNS1 is lethal as a result of kernicterus. With treatment and management children have a good prognosis and may follow normal schooling, even though the treatment is very restrictive. Adult patients who have not undergone liver transplantation still require phototherapy but may have ''near normal'' social and familial lives. A few adult women have given birth to normal children, provided their pregnancies have been carefully followed up.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Philippe LABRUNE | MetabERN*

                                * European Reference Network


A form of Crigler Najjar syndrome (CNS), a rare hereditary disorder of bilirubin metabolism, characterized by unconjugated hyperbilirubinemia due to reduced and inducible activity of hepatic UDP-glucuronosyltransferase 1A1. The disorder clinically manifests with neonatal, isolated jaundice with a risk of developing bilirubin encephalopathy later in life due to triggers such as stress or infection.

Summary:
Epidemiology
The prevalence of Crigler Najjar syndrome type 2 (CNS2) is unknown.
Clinical description
First clinical manifestations usually appear soon after birth. CNS2 patients are less severely jaundiced than CNS type 1 (CNS1) patients, have pigmented bile that contains bilirubin glucuronides, and generally do not present neurologic or intellectual impairment. Bilirubin encephalopathy may develop in later life when patients experience a superimposed infection or stress.
Etiology
Numerous variants in the UGT1A1 gene (2q37), encoding the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), have been linked to CNS2. In the liver, UGT1A1 conjugates bilirubin with glucuronic acid, thereby increasing bilirubin water solubility and thus facilitating its excretion. The UGT1A1 variants result in reduced, but inducible bilirubin UGT1A1 activity, with marked impairment of bilirubin conjugation.
Diagnostic methods
Diagnosis is based on biochemical findings with total serum bilirubin ranging from 6 to 20 mg/dL and presence of bilirubin glucuronides in bile. Diagnosis is confirmed by genomic DNA analysis (ruling out the need for liver biopsy). It may also help in differentiating between the two types of CNS. Liver biopsy, when it was performed, revealed residual enzymatic activity.
Differential diagnosis
Differential diagnosis includes disorders of excessive bilirubin production (hemolysis). CNS2 can be differentiated from CNS1 by the response to phenobarbital treatment and from mild hepatic deficiency of UGT1A1 (Gilbert syndrome).
Antenatal diagnosis
Prenatal diagnosis is possible provided both disease-causing mutations have been identified in the proband.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment relies on daily phenobarbital administration that can induce the expression of UGT1A1 resulting in a decrease in the serum bilirubin level by approximately 60-70%. Patients and their families must be educated to be very careful during infectious episodes and/or fasting periods that are likely to increase bilirubin production and thus increase hyperbilirubinemia. Should this occur, patients must be examined by their physician and serum bilirubin concentration must be measured.
Prognosis
Prognosis is good: this form does not cause cognitive or motor impairment during childhood. Adult patients remain jaundiced and must continue phenobarbital treatment throughout their life. However, all patients have to be educated and informed regarding at-risk-for-increase of bilirubin production (infection, stress and prolonged fasting).

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Philippe LABRUNE | MetabERN*

                                * European Reference Network


A rare hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to a either a complete (type 1) or partial and inducible (type 2) hepatic deficit of UDP-glucuronosyltransferase 1A1 activity. The disorder manifests with neonatal jaundice with a risk of developing bilirubin encephalopathy.

Summary:
Epidemiology
Whilst data on prevalence is very limited, Crigler Najjar syndrome (CNS) is estimated to affect less than 1/100,000 people in Europe. Both sexes are equally affected.
Clinical description
First clinical manifestations usually appear soon after birth, presenting with isolated jaundice that is more severe in CNS type 1 (CNS1) than in CNS type 2 (CNS2). In CNS1, it may evolve to bilirubin encephalopathy (kernicterus) with hypertonia, deafness, oculomotor palsy and lethargy when the treatment is delayed or inadequate. In CNS2, the risk of kernicterus is much lower but does exist.
Etiology
Numerous variants in the gene UGT1A1 (2q37), encoding the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), have been linked to CNS. In the liver, UGT1A1 conjugates bilirubin with glucuronic acid, thereby increasing bilirubin water solubility and thus facilitating its excretion. The UGT1A1 variants result in absent (CNS1) or reduced (CNS2) UGT1A1 activity, with marked impairment of bilirubin conjugation.
Diagnostic methods
The physical examination shows isolated jaundice and biological analyses detect only severe unconjugated hyperbilirubinemia with normal liver function tests. Abdominal imaging studies (CT scans or ultrasonograms) are normal. Currently, definitive diagnosis relies on genomic DNA analysis (ruling out the need for liver biopsy). In the past, definitive diagnosis was based on demonstration of the enzymatic deficiency in the liver (hepatic biopsy performed after three months of age); however, liver biopsy is no longer performed.
Differential diagnosis
Differential diagnosis varies depending of the type of CNS and includes disorders of excessive bilirubin production (hemolysis) and mild hepatic deficiency of hepatic UGT1A1 (Gilbert syndrome).
Antenatal diagnosis
Prenatal diagnosis is possible provided both disease-causing mutations have been identified in the proband.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment of CNS1 relies on phototherapy (initially at hospital and then at home) for 10-12 hours per day. Bilirubin chelators and ursodeoxycholic acid may also be prescribed in these patients. To date, the only effective treatment for CNS1 is liver transplantation. Treatment of CNS2 consists of daily phenobarbital.
Prognosis
Children with CNS1 may develop neurological complications as a consequence of the neurotoxicity of unconjugated bilirubin whereas prognosis is generally good for patients with CNS2.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Philippe LABRUNE | MetabERN*

                                * European Reference Network


Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne zoonotic disease caused by CCHF virus and characterized by initial fever, headache, and malaise followed by gastrointestinal symptoms and, in severe cases, bleeding, shock, and multi-organ system failure.

Summary:
Epidemiology
CCHF is endemic throughout Africa, the Balkans, the Middle East, and western Asia. Cases are usually sporadic, although small nosocomial outbreaks sometimes occur when proper infection control practices are not maintained. Around 500 cases are reported per year worldwide, although systematic surveillance is lacking.
Clinical description
The incubation period is typically 3-7 days from animal exposure and 1-3 days from a tick bite. Patients generally present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain, and myalgia/arthralgia followed rapidly by gastrointestinal symptoms (diarrhea, nausea, vomiting) and, in some cases, rash. Severe cases develop bleeding (ecchymoses, sub-conjunctival and gastrointestinal hemorrhage), neurologic involvement (disorientation, convulsions, coma), shock, and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often noted at presentation and disseminated intravascular coagulation (DIC) commonly develops, best indicated by the presence of D-dimers.
Etiology
Over 25 different viruses cause viral hemorrhagic fever. CCHF virus is a member of the virus family Bunyaviridae, genus Nairovirus. The virus is maintained in nature in a cycle between small mammals and ticks, primarily of the Hyalomma species. Ticks also spread CCHF virus to domestic livestock, who are transiently and asymptomatically viremic. Humans are infected either by tick bites or exposure to contaminated blood or excreta of the reservoir or transiently viremic domestic animals. Farmers, abattoir workers, and veterinarians are at risk. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons.
Diagnostic methods
Common diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA) and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically only performed in a few specialized laboratories.
Differential diagnosis
CCHF is difficult to distinguish from a host of other febrile illnesses, at least early in the course of disease. Malaria, typhoid fever, leptospirosis, rickettsial infection, other viral hemorrhagic fevers (see these terms) and meningococcemia need to be excluded.
Management and treatment
Patients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns, and aprons) should be used to prevent nosocomial transmission. Although there are few controlled data, the nucleoside analogue drug ribavirin appears to be efficacious for CCHF. Otherwise, treatment generally follows the guidelines for severe septicemia. Anti-malarials and broad spectrum antibiotics should be considered until the diagnosis of CCHF can be confirmed. Persons who have unprotected contact with someone with CCHF should be monitored and post-exposure treatment with oral ribavirin considered.
Prognosis
The case-fatality rate is 15-30%. Shock, bleeding, neurological manifestations, high viremia, aspartate aminotransferase (AST) > 150 IU/L, and pregnancy confer a poor prognosis. Although convalescence may last up to a year, survivors usually have no lasting sequelae.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Daniel BAUSCH  -  Andrew BENNETT


Crisponi syndrome (CS) is a severe disorder characterized by muscular contractions at birth, intermittent hyperthermia, facial abnormalities and camptodactyly.

Summary:
Epidemiology
Since the first description of the disease in 1996, it has been described in less than 30 patients from 13 Italian (mainly Sardinian) families.
Clinical description
Extensive paroxysmal muscular contractions in the face (resembling neonatal tetanus) develop after minimal stimuli. Frequent contractions of the oropharyngeal muscles associated with absence of the swallowing reflex lead to major feeding and respiratory difficulties. All patients described to date displayed facial anomalies, including a large face, chubby cheeks, a broad nose with anteverted nostrils and long philtrum, and bilateral camptodactyly. Hypertonia is frequent. Early in the neonatal period, CS patients develop continuous hyperthermia (unrelated to infectious agents), dyspnea, spells of apnea, and cyanosis during crying. Abnormal central control of respiration may be present at birth, increasing the risk of sudden death. Febrile episodes disappear after the first year of life, whereas feeding difficulties persist. Paradoxal sweating after exposure to low ambient temperatures has been observed in some adolescents.
Etiology
Mutations in the CRLF1 gene are causative.
Differential diagnosis
CS belongs to a group of conditions with overlapping features, including cold-induced sweating syndromes and Stüve-Wiedemann syndrome (see these terms).
Genetic counseling
The disease is transmitted as an autosomal recessive trait.
Management and treatment
Surviving patients usually develop severe progressive kyphoscoliosis that requires corset therapy or corrective surgery. Marked feeding difficulties require nasogastric tube feeding.
Prognosis
Characteristic hyperthermic crises frequently lead to death within the first months of life.

                            Last update:
                            June 2008

                            - Expert reviewer(s):
                            Pr Didier LACOMBE


Criss cross heart (CCH) is a cardiac malformation where the inflow streams of the two ventricles cross due to twisting of the heart about its major axis. The clinical features depend on the particular cardiac defects associated, like simple or corrected transposition of the great arteries and ventricular septal defects.

Summary:
Epidemiology
The birth prevalence of CCH is 1 /125, 000 live births and accounts for <0.1% of all congenital heart defects.
Clinical description
CCH is a congenital disorder which can manifest by severe dyspnea with nasal flaring, retraction of sternal notch, subcostal and intercostal indrawing, diaphoresis, cyanosis, pallor, feeding difficulty, systolic murmur at the left sternal edge and accentuated P2 heart sound, depending on the associated lesions. The most common associations are ventricular septal defect (VSD), complete or congenitally corrected transposition of the great arteries, double outlet right ventricle, pulmonary branch stenosis, straddling mitral or tricuspid valve, mitral stenosis, and subpulmonary, subaortic or supravalvular aortic stenosis (see these terms).
Etiology
CCH is caused by abnormal rotation (clockwise or counterclockwise) of the ventricular mass along its long axis during embryonic development. The developmental mechanisms and causes of CCH are still elusive but some studies in mice have linked mutations in the Gja1  gene to the pathogenesis of CCH.
Diagnostic methods
Diagnosis is confirmed by 2-dimensional and color Doppler echocardiography revealing the crossing of the atrioventricular connections, without mixing, at the level of the atrioventricular (AV) valves. Failure to obtain a characteristic 4-chamber view (4CV) is a key diagnostic feature of CCH. Biventricular function is normal but perimembranous ventricular septal defects are usually observed. MRI and angiography may be used for the diagnosis of anomalies of the coronary circulation.
Differential diagnosis
Differential diagnosis includes straddling mitral or tricuspid valve, severe forms of Ebstein malformation (the tricuspid valve opens to the infundibulum, giving the appearance of crossing the valves) (see these terms), and double atrial outlet (an outlet orifice apparently crosses the other valve).
Antenatal diagnosis
Prenatal diagnosis can be achieved with a color Doppler ultrasound, by identifying key features of CCH that include the inability to obtain a 4CV at the standard transverse plane through the fetal chest and visualization of the criss cross arrangement of the inflow tracts into the two ventricles simultaneously in the transverse plane of the fetal chest.
Management and treatment
The surgical management of CCH consists of the repair of major and limiting malformations, with ventricular rotation itself being excluded as the reason for the correction. The initial management is determined by the presence or absence of pulmonary stenosis, and its severity. Where the pulmonary flow is inadequate, early intervention with prostaglandin E1 is indicated for maintaining the patency of the patent arterial duct. When anatomic correction fails, balance in pulmonary flow can be achieved with the construction of a systemic-pulmonary shunt. The corrective surgery is determined by the potential use of both ventricles. The Fontan correction may be indicated as a palliative repair option. Jatene's surgical technique (the arterial switch operation) may be proposed to patients where CCH is associated with transposition of the great arteries, VSD, atrial septal defect and patent arterial duct (see these terms).
Prognosis
The prognosis is unfavorable without surgical treatment. However, after correction of the main defect, normal physical, psychomotor and cardiovascular development may be achieved.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Pr Vera AIELLO  - Dr Italo DE OLIVEIRA


Cronkhite-Canada syndrome (CCS) is a rare gastrointestinal (GI) polyposis syndrome characterized by the association of non-hereditary GI polyposis with the cutaneous triad of alopecia, nail changes and hyperpigmentation.

Summary:
Epidemiology
To date, there have been more than 500 cases reported worldwide. Individuals of European and Asian descent are most often affected, with most case reports emerging from Japan. A slight male predominance has been reported.
Clinical description
The mean age of onset is 59 years, but the age at presentation may vary from 31 to 85 years. Presenting symptoms include watery diarrhea with stool volumes of 4-6 L (steatorrhea and melena may also occur), dysgeusia, dry mouth, partial or total lack of appetite, weight loss (often >10 kg), constant or episodic abdominal pain, and weakness. Diarrhea is usually followed by a variable sequence of onychodystrophy (including onycholysis, thinning of the nail plate, onychoschizia and onychomadesis), alopecia (initially patchy, rapidly leading to complete hair loss), and hyperpigmentation (diffuse light-to-dark brownish macules and plaques, and patchy vitiligo) distributed on the palms and soles, upper extremities, face, and chest. More than 10% of CCS patients develop GI cancer (mostly in the sigmoid colon and rectum). Neurologic symptoms (numbness and tingling in the extremities, dysphagia and convulsions) and autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, scleroderma (see these terms), hypothyroidism and membranous glomerulopathy) have been reported in some patients. The GI lesions are usually generalized. The stomach and colon almost always contain polyps and the small bowel is affected in more than 50% of cases. The esophagus is less frequently involved. Common complications include GI bleeding, malabsorption, malnutrition, and infection.
Etiology
The pathogenesis of CCS is still elusive but an immune-mediated process has been proposed and this hypothesis is supported by the increased systemic levels of immunoglobulin G4 and antinuclear antibody found in CCS patients as well as the higher frequency of autoimmune disorders associated with CCS. The cutaneous manifestations of CCS have been attributed to malabsorption and malnutrition caused by the GI pathology. Dysgeusia and dry mouth might result from mucositis or oral infections secondary to malnutrition but other mechanisms may be involved.
Diagnostic methods
Diagnosis relies on clinico-pathological features with the correlating cutaneous, radiological, endoscopic and pathological findings. Endoscopic evaluation may reveal multiple sessile polyps in the stomach, small bowel, colon and rectum. Histopathological examination of biopsies may show different types of polyps (hyperplastic or adenomatous (with malignant potential), juvenile, hamartomatous and inflammatory) in the same patient, necessitating resection and/or surveillance. Laboratory parameters reveal normocytic, normochromic anemia, vitamin deficiency, hypoproteinemia and hypoalbuminemia.
Differential diagnosis
Differential diagnosis includes familial adenomatous polyposis, hyperplastic polyposis syndrome, cap polyposis, juvenile polyposis syndrome, Peutz-Jeghers syndrome and Cowden syndrome (see these terms), as well as lipomatous polyposis, inflammatory polyposis and lymphomatous polyposis.
Genetic counseling
CCS occurs sporadically so there is no risk of intrafamilial transmission.
Management and treatment
Current treatments, which can be used individually or in combination, include steroids, nutritional therapy (fluid, electrolyte, protein and vitamin supplementation and, if necessary, an elemental diet or parenteral nutrition), 5-aminosalicylate acid, histamine H2 receptor antagonists, anti-tumor necrosis factor alpha agents, immunomodulators, and eradication of Helicobacter pylori. Regular surveillance for GI malignancy is recommended as development of colorectal or gastric cancer has been reported in 10 to 15% of cases.
Prognosis
The clinical course of CCS is progressive with occasional spontaneous remissions and frequent relapses, and with rare progression to malignancy. The 5-year mortality rate of CCS can be as high as 50 % (mainly due to GI malignancy or portal vein thrombosis, infection and membranous glomerulonephritis), even with treatment.

                            Last update:
                            May 2016

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


A rare, hereditary, congenital limb malformation characterized by polydactyly with crossed involvement of hands and feet with no other associated malformations or anomalies. Patients present with a combination of unilateral or bilateral preaxial polydactyly of hands with postaxial polydactyly of feet or postaxial polydactyly of hands with preaxial polydactyly of feet. Additional manifestations include bilateral cutaneous syndactyly of first, second and third toes and occasionally cutaneous syndactyly of hands.