Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

A form of congenital adrenal hyperplasia (CAH) characterized by simple virilizing or salt wasting forms that can manifest with abnormal genital development with variable levels of virilization in females and with adrenal insufficiency in both sexes, and that presents with dehydration and hypoglycemia (which can be lethal if left untreated) in the neonatal period, as well as hyperandrogenia.

Summary:
Epidemiology
Classic CAH due to 21-hydroxylase deficiency (21-OHD) is the most common form of CAH with a prevalence estimated at 1/14,000.
Clinical description
Classic 21-OHD CAH can be divided into 2 clinical groups: simple-virilizing or salt wasting. Clinical signs are observed prenatally or at birth. Girls present with abnormal genital development with variable levels of virilization, ranging from a nearly male appearance to minimal clitoromegaly. A normal uterus and various degrees of abnormal vaginal development are seen. The external genitalia in boys are normal. Salt wasting forms lead to symptoms of dehydration and hypotension in the first few weeks of life due to aldosterone deficiency. They can develop failure to thrive, hyponatremia, hyperkalemia, acidosis and hypoglycemia which can be life threatening if not treated immediately. Hyperandrogenia manifests with accelerated growth velocity and accelerated skeletal maturation (leading to reduced adult height), advanced bone age, premature pubarche and precocious puberty during childhood, and acne and hirsutism, menstrual problems, subfertility, obesity, and metabolic and cardiovascular disturbances during adulthood. Males with poor hormonal control may develop small testes and benign testicular adrenal rest tumors (TARTs).
Etiology
The disease is caused by a mutation in the CYP21A2 gene located on chromosome 6p21.3 which controls cortisol and aldosterone production.
Diagnostic methods
Girls are usually diagnosed at birth when virilization of external genitalia is present. Signs of adrenal insufficiency present during the second week of life in both sexes. Newborn screening programs in most European countries diagnose cases of CAH at birth through 17-hydroxy-progesterone (17-OHP) analysis.
Differential diagnosis
Differential diagnoses include other forms of CAH, polycystic ovary syndrome (mainly for non-classical CAH) or any diseases with androgen excess.
Antenatal diagnosis
Prenatal diagnosis can be achieved by measuring 17-OHP levels in amniotic fluid during the second trimester of gestation or by genotyping through chorionic villus sampling to obtain fetal DNA as early as gestational week 10-12 in families with known CYP21A2 pathogenic genotypes. Methods involving invasive sampling should only be performed if the results will lead to changes in approach or treatment.
Genetic counseling
As classic 21-OHD CAH follows an autosomal recessive pattern of inheritance, genetic counseling is possible.
Management and treatment
Prenatal treatment with dexamethasone can be administered to female fetuses at risk of developing classic CAH, but this procedure is still controversial due to potential side effects. When administered before the 9th week of gestation, it prevents the excessive androgen production responsible for genital virilization in females. If diagnosed after birth, vaginoplasty surgery is usually performed on girls but the timing of the surgery is still debated. Lifelong hormone replacement therapy is needed to treat adrenal insufficiency and to decrease elevated androgen hormone levels in order to allow for normal health, growth and puberty. Hydrocortisone is usually given to children as glucocorticoid (GC) replacement therapy (10-15mg/m2/day divided into 2 or 3 doses) and 9alpha-fludrocortisone for mineralocorticoid (MC) replacement. Dosage is monitored and should be increased during times of stress or intercurrent disease. There is a risk of developing acute adrenal insufficiency and other complications due to chronic hyperandrogenemia in case of poorly controlled disease. Excessive treatment with GC causes cushingoid features, metabolic and cardiovascular disturbances. Excess MC causes hypertension. Regular follow-up by a multidisciplinary team, including pediatric endocrinologists, surgeons, gynecologists, psychologists, is important.
Prognosis
Life expectancy may be reduced as patients with CAH have a risk of acute adrenal insufficiency and higher metabolic and cardiovascular risk. Poor disease control may increase the risk of these conditions, as well as of TARTs, menstrual irregularity and subfertility.

                            Last update:
                            February 2022

                            - Expert reviewer(s):
                            Pr Juliane LEGER | Endo-ERN*

                                * European Reference Network


A life-threatening metabolic disease with onset in the neonatal period. Infants usually develop feeding difficulties, lethargy, and severe liver disease.

Summary:
Epidemiology
Global prevalence is unknown but estimated annual incidence has been reported to be between 1/40,000 and 1/60,000 in Western countries. The disorder appears to be more common in the Caucasian population than in other ethnic groups but figures in other populations may be underestimated. Males and females are equally affected.
Clinical description
When ingesting breast milk or lactose-containing formula, infants develop feeding problems, failure to thrive, and signs of liver damage (jaundice, bleeding tendency, hypoglycemia). In the absence of appropriate treatment (galactose restriction), sepsis (E-coli) and neonatal death may occur. Despite adequate treatment, long-term complications appear including cognitive impairments, motor deficits, ovarian dysfunction with reduced fertility in women and diminished bone density. Male fertility has not yet been thoroughly studied.
Etiology
Classic galactosemia is caused by mutations in the GALT (9p13) gene encoding the galactose-1-phosphate uridyltransferase enzyme. Mutations that severely impair enzyme activity result in the classic galactosemia phenotype. The so-called variants are mutations associated with higher residual enzyme activity resulting in milder or no features of galactosemia such as the Duarte variant (GALT gene mutation).
Diagnostic methods
In many countries, infants are routinely screened for galactosemia at birth. When neonatal screening is not performed, diagnosis is based on the clinical picture. Diagnosis can be confirmed by assay of the relevant metabolites, enzyme activity and GALT gene mutational analysis.
Differential diagnosis
Differential diagnoses include galactose epimerase deficiency and other diseases causing acute liver disease in the neonate.
Antenatal diagnosis
Prenatal testing is usually performed via gene mutation analysis by chorionic villus sampling. In at-risk relatives, testing is also possible to search for the mutation when already identified in a family.
Genetic counseling
Galactosemia follows an autosomal recessive pattern of inheritance. Parents of an affected child have a 25% risk of having affected children in subsequent pregnancies.
Management and treatment
Treatment is based primarily on galactose restriction in the diet. Infants should be fed with soy formula or other lactose-free formula. Patients are advised to follow a lifelong diet. To prevent a diminished bone mass, calcium, vitamin D and vitamin K supplements are recommended if dietary intake does not meet the recommended daily allowance. Monitoring of cognitive and motor development, gonadal function and bone mass is mandatory. Eye examinations are recommended in case of neonatal cataracts or in case of poor dietary compliance. Despite dietary treatment long-term complications occur.
Prognosis
Prognosis is dependent on age of diagnosis, disease severity and compliance with dietary restrictions, which affects the onset and course of secondary complications.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Pr M.E. [Estela] RUBIO-GOZALBO  - Dr I. [Inge] TIMMERS


Classic glucose transporter type 1 deficiency syndrome

A rare inborn error of metabolism characterized by encephalopathy due to impaired glucose transport into neural cells. The most frequent clinical manifestations are epilepsy, intellectual disability and movement disorder.

Summary:
Epidemiology
In retrospective cohorts, the prevalence of GLUT1-DS is estimated between 1/25.000 and 1/80.000. However, it might be underestimated since many patients present a minimal symptom phenotype.
Clinical description
New-borns usually have normal head size at birth, but acquired microcephaly may become evident in childhood. A frequent initial sign is paroxysmal eye-head movement, characterized by episodes of multidirectional saccadic movements of the eyes and head, without loss of consciousness. Psychomotor developmental delay is usually observed, evolving into intellectual disability, ranging from mild to severe. Most patients have some degree of speech impairment with dysarthria. The most common symptom in infancy/childhood is epilepsy, frequently early onset absences and/or myoclonic-atonic seizures. Movement disorder usually become more evident later in life. They may be persistent, including gait disorders with variable combinations of ataxia and spasticity, or they may also be paroxysmal. Paroxysmal exercise-induced dyskinesia often triggered by physical and emotional stressors is characteristic. Alternating hemiplegia, migraine, cyclic vomiting, stroke-like episodes, writers' cramp, intermittent ataxia, may be possible combined features.
Etiology
Glut1 protein, encoded by SLC2A1 gene, is primarily expressed in blood-brain barrier and astrocytes and facilitates glucose transport into the brain; its defect impairs glucose transport into neural cells resulting in cerebral energy deficiency causing encephalopathy.
Diagnostic methods
Diagnosis is suggested by clinical features and confirmed by lumbar puncture showing hypoglycorrhachia in a setting of normoglycemia. Mutations or deletions/duplications in SLC2A1 gene are identified in almost 90% of patients. Molecular diagnosis remains elusive in 10% of patients with typical clinical features and CSF profile.
Differential diagnosis
Neurological disorders with similar symptoms and age of onset are familial epilepsies with autosomal dominant transmission, developmental epileptic encephalopathies, paroxysmal movement disorders, opsoclonus-myoclonus syndrome or other paroxysmal neurologic dysfunctions.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Mutations are mainly de novo autosomal dominant. Familial cases and autosomal recessive inheritance have been reported. Once a parent is diagnosed with a SLC2A1 pathogenic variant, prenatal genetic testing is possible.
Management and treatment
To establish the extent of disease and needs of a GLUT1-DS patient, the following evaluations are recommended: neurological examination, EEG monitoring, consultation with a clinical geneticist, neuropsychological assessment in order to implement a personalized motor, occupational and speech therapy. Ketogenic dietary therapies (KDTs) are, to date, the gold standard treatment for the syndrome: ketone bodies can cross the blood brain barrier and act as alternative fuel for brain metabolism. KDTs are usually effective in controlling seizures; furthermore, neuropsychological impairment and movement disorders may improve. Patients should start KDT as early as possible and continue in adulthood, as symptoms may return upon discontinuation. Some patients may also receive treatment with anti-seizure medications. Certain molecules, such as methylxanthines, phenobarbital, and valproic acid, should be avoided as they have the potential to inhibit Glut1 transport. Therapies currently under investigation are alpha-lipoic acid, ketone esters, triheptanoin and gene therapy.
Prognosis
Epileptic manifestations tend to improve or disappear later in life; however, the movement disorder becomes more prominent. Neuropsychological impairment and language disorder do not worsen, but they could be more evident affecting social functioning in adulthood.

                            Last update:
                            September 2023

                            - Expert reviewer(s):
                            Dr Alessandra CAMERINI  - Dr Valentina DE GIORGIS | EpiCARE* - Pr Roser PONS

                                * European Reference Network


A rare, slowly progressive, chronic leukemia characterized by presence of abnormal B-lymphocytes (medium sized with abundant irregular pale cytoplasm, hair-like cytoplasmic projections/ruffled cytoplasmic border, a round or bean-shaped nucleus and absent nucleoli) in the blood or bone marrow, spleen and peripheral blood pancytopenia, notable monocytopenia, and marked susceptibility to infection. The characteristic immunophenotype is CD11c+, CD25+, CD103+ and CD123+ with a BRAF mutation in most cases.

Summary:
Epidemiology
Classic hairy cell leukemia (HCLc) accounts for 2% of all leukemia cases. Estimates of the annual incidence range between 1/213,000-2,860,000 worldwide. HCLc is observed more commonly in caucasians. Men are predominantly affected with a male:female ratio of 4:1.
Clinical description
Disease onset is typically in middle-age or older adults with an average age of 55 years. Symptoms of HCLc are related to the disruption of normal blood cell production. Low red cell production leads to anemia, low white cell production to increased infections, and low platelet counts to bleeding or easy bruising. Abdominal discomfort is a common symptom, resulting from hepatosplenomegaly. Splenomegaly is present in most cases, and was originally classed as massive in more than 80% of cases. In recent years, massive splenomegaly is less frequent perhaps related to earlier diagnosis. Hepatomegaly with mild liver dysfunction is found in 20% of cases and lymphadenopathy is found in 10% of cases. Complications include recurrent infections, bleeding, bruising, anemia and abdominal discomfort from splenomegaly. Splenic rupture may occur. Patients with HCLc often have monocytopenia. The patients may have opportunistic infections as a result of being immunocompromised due to intrinsic disease-related immune deficiency as well as immunosuppressive treatment.
Etiology
Etiology is unknown. Family history of blood cancers, Ashkenazi Jewish heritage, occupational or environmental exposure to chemicals (e.g. insecticides) are considered as possible risk factors. BRAFV600E mutation, which causes constitutive activation of the MAP kinase pathway, is also found in most patients with HCLc.
Diagnostic methods
Diagnosis is based on the results of the physical examination, blood tests, and bone marrow biopsy. Abdominal computer tomography may also identify lymphadenopathy. Immunophenotypic evaluations of peripheral blood or bone marrow are essential for establishing the diagnosis. Characteristic immunophenotypic markers include CD11c, CD25, CD103, CD123 positive. BRAF-V600E mutation is also found in most patients.
Differential diagnosis
Differential diagnoses includes hairy cell leukemia variant, splenic marginal zone lymphoma, and splenic diffuse red pulp B-cell lymphoma.
Management and treatment
HCLc can be treated with chemotherapy (cladribine or pentostatin) or biological therapy (interferon alpha, rituximab). The purine nucleoside analogs, either cladribine (indication authorized in Europe and the USA) or pentostatin, have a higher rate of complete remission compared to biological therapies. Complete or partial remission with chemotherapy is achieved in about 80 to 90% of patients. In patients with active infection, it is important to attempt to control infection before using cladribine because of potential profound and prolonged myelosuppression. Treating patients with uncontrolled infection is challenging. Vermurafenib has been used as a bridge to effective therapy in some patients with life-threatening, uncontrolled infection and proven BRAF-positive mutation. These patients have had anecdotal improvement in hematologic parameters with control of infection; however, more evidence is required. Off-label usage of vemurafenib has been reported to be effective in hairy cell leukemia, in particular it has helped achieve remission in patients with relapsed or resistant disease. Currently, studies are in progress to examine the use of this agent in combination chemoimmunotherapy. For patients with hairy cell leukemia who have a relapse following a prolonged period of initial remission, they may be successfully re-treated with a purine analog or a combination of the purine analog and an anti-CD20 monoclonal antibody (rituximab). For those patients who have had multiple relapses or disease refractory to standard therapy, the anti-CD22 immunotoxin conjugate, moxetumomab (approved in the USA), may also be considered. Where the disease is mild and slow growing, a small number of patients may not require any immediate treatment and remain stable for many years. However, close follow-up of the hematologic parameters is required to avoid the development of serious pancytopenia.
Prognosis
Most patients live 10 years or longer with the disease.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Michael GREVER


Classical Hodgkin lymphoma (CHL) is a B-cell lymphoma characterized histologically by the presence of large mononuclear Hodgkin cells and multinucleated Reed-Sternberg (HRS) cells.

Summary:
Epidemiology
The annual incidence of CHL in developed countries is approximately 1/40,000. It accounts for 95% of HL cases.
Clinical description
Onset most commonly occurs in young adults aged 15-30, followed by adults over the age of 55. In the early stages of the disease many patients are asymptomatic. The most common sign of CHL is the painless enlargement or swelling of upper body lymph nodes (most frequently in the neck, axillae or mediastinum). Itchy skin, fatigue and decreased appetite can also be presenting symptoms. Cellular immune deficiency seen in CHL patients increases susceptibility to bacterial, fungal and viral infections. When lymph nodes inside the chest are affected patients can have trouble breathing or a cough. A group of symptoms known as B-symptoms are sometimes present and include: fever, drenching night sweats and unexplained weight loss. Other organs can be affected such as the liver, lung, spleen, bones or bone marrow.
Etiology
The exact cause of CHL is unknown. Epstein-Barr virus (EBV) may have a role in the pathogenesis of CHL as EBV-encoded RNA is present in HRS cells in 40% of cases. A genetic predisposition could also be involved in CHL pathogenesis as polymorphisms seen in the human leukocyte antigen (HLA) genes are often associated with cases of sporadic and familial CHL. They are potentially responsible for an impaired immune response which is usually found in CHL patients. HIV patients have a 5 to 15 fold increased risk of developing CHL, further suggesting the link between immune deficiency and CHL.
Diagnostic methods
A biopsy (usually of a lymph node) is performed in order to diagnose CHL and determine one of the 4 histological subtypes of CHL: nodular sclerosis (most common subtype), mixed cellularity, lymphocyte-rich and lymphocyte-depleted. Staging based on the Cotswold staging system is performed in order to determine the severity and spread of CHL and decide on the best course of therapy. Postero-anterior and lateral radiograph and computed tomography (CT) of the chest, neck, abdomen and pelvis are taken. Bone marrow biopsy should be performed unless peripheral blood counts are normal and B symptoms absent. Positron emission tomography (PET) scans can identify sites of disease more accurately than other imaging techniques. Predominant prognostic factors are age and stage.
Differential diagnosis
Influenza, infectious mononucleosis, other lymphomas (non-Hodgkin lymphoma), systemic lupus erythematosus (see these terms) and HIV infections should be dismissed.
Management and treatment
Radiotherapy and combination chemotherapy are the methods used to treat CHL. Involved field radiotherapy (IFRT) is much preferred over extended-field radiation therapy (EFRT) which has long-term side effects but is sometimes needed in advanced cases. Two cycles of combination chemotherapy followed by IFRT (20Gy) or chemotherapy alone are acceptable standard treatments for adults with limited stage CHL. Care is taken to minimize the gonadotoxic effects of alkylating agents on male children. When standard treatment does not work (or if CHL recurs) high-dose chemotherapy and hematopoietic stem cell transplant may be a final option. Surgery is not recommended. A new targeted agent, the antibody-drug conjugate brentuximab vedotin, has shown substantial effectiveness against recurrent CHL and is being tested in combination with standard agents.
Prognosis
The prognosis of those with HL has greatly improved, with a 5 year survival rate of 80%-85%. The elderly usually have a poorer prognosis as they have a reduced tolerance for chemotherapy and treatment-related deaths can occur. The cure rates are 90% for early-stage CHL and 70% for advanced stage CHL.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Joseph CONNORS


Classic maple syrup urine disease (classic MSUD) is the most severe and probably common form of MSUD (see this term) characterized by a maple syrup odor in the cerumen at birth, poor feeding, lethargy and focal dystonia, followed by progressive encephalopathy and central respiratory failure if untreated.

Summary:
Epidemiology
Birth prevalence of MSUD is estimated at around 1/150,000. Classic MSUD may account for 50-75% of cases.
Clinical description
Onset of classic MSUD occurs in the neonatal period (usually 12 hours after birth) with the presence of a maple syrup odor in the cerumen and later in urine, poor feeding and drowsiness. Progressive encephalopathy with lethargy, intermittent apnea, stereotyped movements (described as "fencing" and bicycling") and opisthotonus occur in the first few days of life. Without treatment, coma and central respiratory failure occur by days 7 to 10. Later, catabolic stress, infection or injury may cause acute, potentially fatal, leucine intoxication with vomiting, altered consciousness, ataxia and acute dystonia in toddlers and hallucinations, hyperactivity, focal dystonia, ataxia and choreoathetosis in children and adults.
Etiology
MSUD is due to mutations in genes encoding 3 of the 4 subunits of the branched chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a, BCKDHB (6q14.1), encoding E1b, and DBT (1p31), encoding E2 respectively. Mutations lead to accumulation of branched-chain amino acids (especially leucine) and branched-chain alpha-ketoacids. In classic MSUD, mutations in BCKDHA predominate.
Diagnostic methods
Classical MSUD is readily diagnosed by tandem mass-spectrometry population newborn screening. Otherwise, isolated ketosis and encephalopathy or maple syrup odor are suggestive. Plasma leucine is greatly elevated, with a ratio of leucine/valine/isoleucine of approximately 4/2/1. Plasma allo-isolucine >5umol/L is diagnostic. Urine branched chain 2-ketoacids (BCKAs) are elevated on gas chromatopgraphy-mass spectrometry. Molecular genetic testing can identify causal mutations, and perhaps suggest a sub-type.
Differential diagnosis
Differential diagnoses include other inborn errors of metabolism associated with predominant neurological deterioration such as urea cycle defects, organic acidemias (i.e. propionic or isovaleric acidemias, methylmalonic academia with homocystinuria, multiple carboxylase deficiency), and beta-ketothiolase deficiency (see these terms). In infants, ketosis, with the absence of significant metabolic acidosis, hyperammonaemia and hypoglycaemia, rules out many inborn errors of metabolism. In older children with diabetic ketoacidosis, plasma valine is higher than leucine.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
Genetic counseling
Inheritance is autosomal recessive and genetic counseling is possible.
Management and treatment
Classic MSUD in neonates is a medical emergency. Acute management requires aggressive enhancement of protein anabolism using glucose plus insulin, intravenous lipids, plasma amino acid monitoring, and isoleucine and valine supplements. Hemodialysis is often required. Stabilized infants need high calorie BCAA-free formulas, dietary leucine restriction and close outpatient monitoring at a metabolic clinic. Patients require a strict life-long diet and special monitoring during pregnancy. Orthotopic liver transplantation is also an effective treatment.
Prognosis
Prognosis is good for those who are diagnosed early, treated promptly and who follow a strict lifelong diet.

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Dr Bridget WILCKEN


Classic medulloblastoma is a histological variant of medulloblastoma (see this term) ,an embryonic malignancy, having a midline location, occurring most often in children and manifesting with variable symptoms such as headaches, nausea, vomiting and ataxia.


Classical mycosis fungoides is the most common type of mycosis fungoides (MF; see this term), a form of cutaneous T-cell lymphoma, and is characterized by slow progression from patches to more infiltrated plaques and eventually to tumors.

Summary:
Epidemiology
The annual incidence of MF and its variants is estimated at between 1/350,000 and 1/110,000, with classical MF accounting for about 80-90% of MF cases. The male to female ratio is 2:1. Classical MF predominantly affects adults and the elderly (median age at diagnosis: 55-60 years).
Clinical description
The disease first manifests by skin lesions consisting of flat patches, preferentially located asymmetrically on the buttocks and other sun-protected areas (lower trunk and thighs, and the breasts in women). Usually, patches are hypo- or hyperpigmented in dark-skinned individuals. Pruritus may be observed. In the later stages of the disease, infiltrated plaques and red-violet, dome-shaped tumors or generalized erythroderma may develop. Lymph nodes are the most frequent site of extracutaneous involvement. Visceral involvement (liver, lung, and bone marrow) may also occur.
Etiology
The etiology remains unknown.
Diagnostic methods
The diagnosis is based on clinical presentation and should be confirmed by a skin biopsy. Histological findings reveal a predominance of small pleomorphic (cerebriform) cells with epidermotropism. In most cases, immunohistology shows a memory T-helper phenotype (CD3+, CD4+, CD45Ro+, CD8- and CD45Ra-). CD30 and/or cytotoxic markers (i.e. TIA-1) may be positive in late stages, particularly in tumors with large cell morphology. In rare cases, cytotoxic markers may also be positive in early lesions. Molecular analyses reveal a clonal rearrangement of the T-cell receptor genes (this finding may be absent in early lesions). Staging investigations, including a computer tomography scan and/or positron emission tomography, should be performed in cases of advanced MF.
Differential diagnosis
Differential diagnoses include inflammatory dermatoses (i.e. atopic dermatitis) in theearly stages of MF, and other large cell non-Hodgkin lymphomas (see this term) in later stages.
Management and treatment
Treatment strategies during the early phases include mainly PUVA (photochemotherapy), interferon alfa-2a, retinoids (alone or in combination, and including new retinoids such as bexarotene), topical chemotherapy, topical steroids, and narrow-band UV-B (311 nm). Advanced disease can be treated by systemic chemotherapy, extracorporeal photopheresis, and/or radiotherapy (including total body electron beam irradiation). Other treatment modalities include new chemotherapeutic drugs (i.e. gemcitabine, fludarabine and pegylated doxorubicin), denileukin diftitox, alemtuzumab, and allogeneic stem cell transplantation. Many other treatment options have been proposed but have only been used in a limited number of patients.
Prognosis
The disease is slowly progressive (it may evolve over 10 to 30 years after the initial presentation). The prognosis depends on the stage at diagnosis.

                            Last update:
                            June 2009

                            - Expert reviewer(s):
                            Pr Lorenzo CERRONI


Classic neuroendocrine tumor of appendix

A rare endocrine tumor of the appendix, seen twice as frequently in females than in males, and usually presenting before the fifth decade of life. It is usually asymptomatic when located in the tip of the appendix (without obstruction), but acute appendicitis is often associated.


A severe form of phenylketonuria (PKU) due to phenylalanine hydroxylase deficiency, an inborn error of amino acid metabolism, characterized in untreated patients by severe intellectual deficit and neuropsychiatric complications.

Summary:
Epidemiology
Exact prevalence is not known but is estimated to be about 1/15,000 births. Significant geographic variability is reported. Caucasians appear to be affected more than other ethnic groups. Males and females are affected equally.
Clinical description
Late diagnosed patients present mostly with progressive developmental delay associated with severe signs including stunted growth, microcephaly, seizures, tremors, eczema, vomiting, musty odor, and subsequently behavioral (hyperactivity) and motor disorders. Untreated patients develop profound, permanent intellectual impairment and deterioration of cognitive performance and motor skills. Demyelination and decreased dopamine, norepinephrine, and serotonin production have been found in patients who do not pursue dietary restrictions into adulthood. Complications later on include exaggerated deep tendon reflexes, tremor, and paraplegia or hemiplegia. In treated patients, clinical signs vary based on treatment and diet compliance, and may include psychiatric disorders such as attention deficit-hyperactivity disorder and depression.
Etiology
Classical PKU is related to a complete or near-complete deficiency of phenylalanine hydroxylase. The disorder is caused by variants in the PAH gene (12q22-q24.2) coding for phenylalanine (Phe) hydroxylase. The resulting deficiency in phenylalanine hydroxylase leads to toxic accumulation of Phe in the blood and brain.
Diagnostic methods
Classical PKU is usually diagnosed via neonatal screening programs with detection of hyperphenylalaninemia (HPA). Detection is standard in most industrialized countries. PKU is diagnosed at plasma or blood Phe concentrations higher than 120 micromol/L in the untreated state and elevated Phe/Tyr ratio (>2.0). In the absence of early detection through neonatal screening, suspicion is based on clinical signs and symptoms. Diagnosis is confirmed by determination of plasma or blood Phe levels.
Differential diagnosis
Differential diagnosis includes other forms of HPA such as tetrahydrobiopterin (BH4) deficiency. Neonates with increased Phe may have BH4 deficiency or PKU. An abnormal pattern of pterins in dried blood spots or urine or reduced dihydropteridine reductase activity in dried blood spots indicate BH4 deficiency. A BH4 loading test should be performed to determine whether patients are BH4-responsive or unresponsive.
Antenatal diagnosis
Prenatal testing can be performed by molecular testing of the PAH gene if the disease-causing variants have been identified in an affected family member.
Genetic counseling
Inheritance is autosomal recessive.
Management and treatment
Management involves restriction of dietary Phe, i.e. all high-protein foods, to normalize blood levels thus preventing the cognitive dysfunction, along with Phe-free medical formula to provide protein and other essential nutrients. Patients tolerate less than 250-350 mg of dietary Phe per day. Levels of Phe tolerance should be determined individually on a regular basis. Current recommendations call for lifelong maintenance of limited Phe intake. However, monitoring of levels is essential to avoid deficiencies of Phe and tyrosine. Foods containing aspartame should be avoided as aspartame releases Phe when digested. Female patients should be particularly cautious during pregnancy due to the fetotoxic effects of high maternal plasma Phe. When properly managed, the disease course is mostly favorable, but some neuropsychiatric complications may occur. Treatment and dietary compliance are the most important factors affecting outcome and prognosis.
Prognosis
The prognosis is good when diagnosis is made early and compliance is high.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Nenad BLAU


Classic progressive supranuclear palsy syndrome

A classical form of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by slowing of vertical saccadic eye movements, falls due to postural instability, axial akinetic-rigid syndrome, and cognitive impairment. Difficulties in speech and swallowing may develop.


A rare subtype of pyoderma gangrenosum disease characterized by rapidly progressive, single or multiple, painful, aseptic ulcers which present overhanging, violaceous and undermined borders, surrounding induration and erythema, and granulation tissue (occasionally necrotic tissue and/or a purulent exudate) at the base, mainly affecting the legs (but other body surfaces may also be involved), leading to chronic ulcerations and often regressing with cribriform mutilating scars. The disease presents a chronic relapsing course and systemic features (e.g. fever, malaise, arthralgia, myalgia) may be associated.


A rare inherited connective tissue disorder characterized by skin hyperextensibility, widened atrophic scars, and generalized joint hypermobility.

Summary:
Epidemiology
Worldwide prevalence is estimated at 1/20,000.
Clinical description
Skin hyperextensilibity, atrophic scarring, and generalized joint hypermobility are the hallmarks of classical Ehlers-Danlos syndrome (cEDS). However, the clinical picture variably involves multiple organ systems, and clinical presentation may occur anywhere between birth and childhood. In childhood, bruising, skin fragility, and abnormal scarring are common signs. Primary muscular hypotonia may occur and, alongside hypermobility, may delay motor development. Fatigue and muscle cramps are relatively frequent. Atrophic scarring is typically extensive, although a minority are more mildly affected. The skin is smooth and doughy. Other dermatologic features are molluscoid pseudotumors, subcutaneous spheroids, piezogenic papules, and defective wound healing. Inguinal/umbilical hernia, mitral valve prolapse, anal prolapse in childhood, cervical insufficiency, rectal and uterine prolapse are other signs of tissue fragility. Joint hypermobility may lead to joint instability, subluxation, dislocation temporomandibular joint dysfunction, joint effusions, foot deformities, osteoarthritis, and pain. In addition to scars, typical facial characteristics are blepharochalasis and epicanthal folds. Pregnancy bears risk for the newborn (prematurity and breech where the infant is affected) and for the mother (extensive episiotomy, tearing of the perineal skin, and prolapse of the uterus and/or the bladder after delivery). In patients with a COL1A1 mutation, there might be an increased at risk for vascular events (spontaneous dissection or rupture of medium-sized arteries).
Etiology
The disease is typically caused by mutations in COL5A1 or COL5A2 encoding type V collagen. In rare cases, cEDS is caused by p.(Arg312Cys) mutation in COL1A1, encoding type I collagen.
Diagnostic methods
The minimal criteria suggestive of cEDS are skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility and/or at least three of the following minor criteria: easy bruising, soft/doughy skin, skin fragility, molluscoid pseudotumors, subcutaneous spheroids, hernia, epicanthal folds, complications of joint hypermobility, family history of a first degree relative who meets clinical criteria. Definitive diagnosis is reached by genetic testing that can include single-gene testing or use of a multigene panel.
Differential diagnosis
Differential diagnosis is extensive but primarily includes other EDS types (i.e., hypermobile, cardiac-valvular, classical-like type 1, classical-like type 2, spondylodysplastic, vascular, arthrocalasia, kyphoscoliotic, dermatosparaxis EDS), Loeys-Dietz syndromes, Marfan syndrome, cutis laxa, and other inherited connective tissue disorders.
Antenatal diagnosis
Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Genetic counseling
The pattern of inheritance is autosomal dominant and genetic counseling should be offered to affected families. The risk of disease transmission to offspring from an affected parent is 50%, intrafamilial phenotypic variability is observed.
Management and treatment
Treatment and management is symptomatic and preventative. Prevention includes avoidance of undue trauma and excessive stretching. Wounds should be expertly closed via sutures and patients should be known to their local plastic surgeons. A physiotherapeutic program is important in those with hypotonia and delayed motor development. Anti-inflammatory drugs may help with joint pain. Cardiac assessment including echocardiography to look for aortic root dilation and mitral valve prolapse is recommended. Emotional support and behavioral and psychological therapy may be indicated. Surveillance during pregnancy is warranted.
Prognosis
Life expectancy can be shortened due to the possibility of vessel rupture, but is otherwise not affected. Quality of life depends on the range of severity.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Pr Marina COLOMBI


Classical-like Ehlers-Danlos syndrome type 1

A form of Ehlers-Danlos syndrome characterized by generalized joint hypermobility, skin hyperextensibility and easy bruising without atrophic scarring. Other common features include foot and hand deformities (piezogenic papules, pes planus, broad forefeet, brachydactyly, fragile and thin hand skin breaks or bruises easily), severe fatigue and neuromuscular symptoms including muscle weakness and myalgia.


Classical-like Ehlers-Danlos syndrome type 2

A rare systemic disease characterized by generalized joint hypermobility with recurrent joint dislocations, redundant and hyperextensible skin with poor wound healing and abnormal scarring, easy bruising, and osteopenia/osteoporosis. Additional manifestations include hypotonia, delayed motor development, foot deformities, prominent superficial veins in the chest region, vascular complications (like mitral valve prolapse and aortic root dilation), hernias, dental anomalies, scoliosis, and facial dysmorphisms (like high palate, micrognathia, narrow palate). Mode of inheritance is autosomal recessive.


CLCN4-related X-linked intellectual disability syndrome

A rare X-linked syndromic intellectual disability characterized by intellectual disability of variable degree, behavioral anomalies (including autism, mood disorders, obsessive-compulsive behavior, and hetero- and auto-aggression), and epilepsy. Progressive neurological symptoms like movement disorders and spasticity, as well as subtle dysmorphic features have also been reported. Heterozygous females may be as severely affected as males.


A rare, malignant, epithelilal ovarian neoplasm, composed of clear, eosinophilic and hobnail cells displaying variable degrees of tubulocystic, papillary and solid histological patterns, macroscopically appearing as a typically unilateral mass in the ovary which ranges from solid to cystic. Patients are often diagnosed in early stages and usually present with pelvic pain and pressure, an abdominal mass and/or gastrointestinal problems, such as early satiety or bloating. Association with Lynch syndrome has been reported.


Clear cell papillary renal cell carcinoma is a rare, indolent subtype of clear cell renal carcinoma, arising from epithelial cells in the renal cortex. It most frequently manifests with a well-circumscribed, well-encapsulated, unicentric, unilateral, small tumor that typically does not metastasize. Clinically it can present with flank or abdominal pain or hematuria, although most patients are usually asymptomatic at the time of diagnosis. Bilateral and/or multifocal presentation should raise the suspicion of von Hippel-Lindau syndrome.


A rare renal tumor arising from proximal tubular epithelial cells of the renal cortex, characterized histologically by malignant epithelial cells with typical clear cytoplasm in conventional staining methods due to a high glycogen and lipid content, featuring a nested growth pattern. Clinically it may present with hematuria, flank pain, anemia or, less commonly, a palpable abdominal mass.


Clear cell sarcoma of kidney is a rare, primary, genetic renal tumor usually characterized by a unilateral, unicentric, morphologically diverse tumor that arises from the renal medulla and has a tendency for vascular invasion. Clinically it presents with a palpable abdominal mass, abdominal or flank pain, hematuria, anemia and/or fatigue. Metastatic spread to lymph nodes, bones, lungs, retroperitoneum, brain and liver is common at time of diagnosis and therefore bone pain, cough or neurological compromise may be associated. Metastasis to unusual sites, such as the scalp, neck, nasopharynx, axilla, orbits and epidural space, have been reported.


Cleft lip and alveolus is a fissure type embryopathy that involves the upper lip, nasal base and alveolar ridge in variable degrees.

Summary:
Epidemiology
The annual incidence varies from 1/4,000 to 1/10,000 births with major variation among geographic regions and ethnic groups. Cleft lip/alveolus is twice as common in boys as girls and is seen more frequently on the left side.
Clinical description
The cleft is paramedian and is located at the philtrum level for the lip and nasal base and at the level of the upper lateral incisor for the alveolar ridge. It involves a cutaneous, muscular and mucosal interruption in the lip, in addition to nostril and nasal septum deformations and an interruption in the alveolar bone and dental arch. The maxillary lateral incisor, at the site of the alveolar cleft, can present with anomalies in shape, number (duplication or agenesis) and position. There is no correlation seen between temporary (primary) and permanent dentition.
Etiology
Cleft lip/alveolus is an embropathy that appears in the 5th to 7th week of pregnancy, following an error in fusion of the frontal processes (fronto-nasal process, medial and lateral nasal processes, maxillary process). Cleft lip and alveolus are isolated, non-syndromic anomalies in 70% of cases. The remaining 30% of cases are seen in about 300 syndromes where cleft lip/alveolus is just one of the featured anomalies. Non-syndromic clefts are believed to be caused by a combination of genetic and environmental factors. Factors such as the exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can influence genetic susceptibility.
Diagnostic methods
Diagnosis is clinical.
Differential diagnosis
The presence of associated malformations allows for differentiation between isolated and syndromic forms.
Antenatal diagnosis
Antenatal diagnosis is often made during prenatal ultrasound. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.
Management and treatment
Management requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary surgery followed by secondary maxilla-facial surgery along with plastic surgery. An initial treatment timeline is established during the neonatal period. Management is adapted to the child and based on morphological and functional problems that may arise during growth and development. Orthodontic management aims to correct the dental alignment problems, sometimes during the early primary teeth stage and then in the mixed and permanent stage. Treatment of the alveolar cleft requires a maxillary bone graft and a dental implant can correct permanent lateral incisor agenesis, if present after growth has stopped. The capacity to chew properly depends on the bucco-facial clinical history of the patient and any dental alignment problems. Breathing difficulties can occur due to the nostril anomaly as well as deviation of the vomer and nasal septum and turbinate hypertrophy. Secondary surgery of the nose can be performed to improve nasal appearance and function if necessary.
Prognosis
The prognosis depends on the quality of initial management and the regular follow-up by an experienced interdisciplinary team until the child is fully grown. Cleft lip/alveolus can have functional (morphological, respiratory), esthetic and psychological consequences that require management in a specialized health center.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ


Cleft lip and palate-craniofacial dysmorphism-congenital heart defect-hearing loss syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome without intellectual disability characterized by unilateral or bilateral cleft lip and palate and craniofacial dysmorphism (including frontal bossing, hypertelorism, broad flat nasal bridge, cupped ears/thickened helices, and micrognathia). Additional manifestations are variable congenital cardiac anomalies, pectus excavatum, abnormalities of the hands and feet, ocular abnormalities (myopia, cataract, staphyloma), and conductive or sensorineural hearing loss.


An exceedingly rare association characterized by cleft lip and progressive retinopathy.


Cleft lip/palate-deafness-sacral lipoma syndrome is characterised by cleft lip/palate, profound sensorineural deafness, and a sacral lipoma. It has been described in two brothers of Chinese origin born to non consanguineous parents. Additional findings included appendages on the heel and thigh, or anterior sacral meningocele and dislocated hip. The mode of inheritance is probably autosomal or X-linked recessive.


Cleft lip/palate-ectodermal dysplasia syndrome

Zlotogora-Ogur syndrome is an ectodermal dysplasia syndrome characterized by hair, skin and teeth anomalies, facial dysmophism with cleft lip and palate, cutaneous syndactyly and, in some cases, intellectual disability.

Summary:
Epidemiology
The prevalence is unknown but to date, less than 50 cases have been described in the literature. The disorder is frequent on Margarita Island due to a founder effect.
Clinical description
Zlotogora-Ogur syndrome is a congenital disorder characterized by sparse and twisted hair (pili torti) and absent or sparse eyebrows, hypohidrosis, dry skin, palmoplantar keratoderma, abnormal teeth (delayed eruption, microdontia/hypodontia, and anodontia in adults), facial dysmophism (protruding and malformed ears, micrognathia, bilateral cleft lip and palate), cutaneous syndactyly (fingers and toes) and transverse crease on the palms. Onychodystrophy may be present. Additional features including intellectual disability, deafness, hypoplastic lacrimal puncta, nipple anomalies, genitourinary abnormalities (hypoplastic scrotum and presence of the testes in the inguinal canal), and lumbar lordosis may be observed. Zlotogora-Ogur syndrome and Margarita Island ectodermal dysplasia are the same entity.
Etiology
Zlotogora-Ogur syndrome is caused by mutations in the gene PVRL1 (11q23-q24) which encodes nectin-1, the principal receptor used by alpha-herpesviruses to mediate entry into human cells. Although the mechanism underlying the physiopathology of Zlotogora-Ogur syndrome is still unknown, it has been proposed that nectin-1 is a cell-cell adhesion molecule that is preferentially expressed in keratinocytes and that mutations in PVRL1 may abrogate NAP (nectin, afadin, ponsin)-dependent cell-cell adhesion.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Joel ZLOTOGORA


Cleft lip/palate-intestinal malrotation-cardiopathy syndrome

A rare multiple congenital anomaly syndrome characterized by flat face, hypertelorism, flat occiput, upward slanting palpebral fissures, cleft palate, micrognathia, short neck, and severe congenital heart defects. Malrotation of the intestine, bilateral clinodactyly, bilobed tongue, short fourth metatarsals and bifid thumbs may be additionally observed.


Cleft lip and palate is a fissure type embryopathy extending across the upper lip, nasal base, alveolar ridge and the hard and soft palate.

Summary:
Epidemiology
The annual incidence ranges from 1/2,000 to 1/5,000 births. Cleft lip and palate is seen twice as commonly in boys.
Clinical description
The malformation is the association, in varying degrees, of cleft lip/alveolus and cleft palate (see these terms). The lip and alveolus anomaly is paramedian and is located at the philtrum level for the lip and at the level of the upper lateral incisors for the alveolar ridge. It involves a cutaneous, muscular and mucosal interruption in the lip in addition to a nostril and nasal septum deformity and a gap in the alveolar bone and dental arch. Clinical forms range from a simple midline groove in the lip to a complete cleft lip and palate reaching the incisive foramen with an opening in the base of the nostril. The cleft seen in cleft palate is median. The clinical forms range from a simple bifid uvula (see this term) to a complete cleft palate reaching the incisive foramen. Cleft palate can disrupt sucking-swallowing in newborns. In addition, Eustachian tube malformation can lead to incomplete drainage of the middle ear with recurrent otitis and transmission hypoacousia. The maxillary lateral incisor, at the site of the alveolar cleft, can present with anomalies in shape, number (duplication or agenesis) and position. There is no correlation seen between temporary (primary) and permanent dentition.
Etiology
Cleft lip and palate is an embryopathy that appears, for the cleft lip, in the 5th and 7th week of pregnancy, following an error in fusion of the frontal processes, and for the cleft palate in the 7th and 12th week of pregnancy following an error in fusion of the palatine process. Cleft lip and palate is an isolated, non-syndromic anomaly in 70% of cases and the remaining 30% of cases are seen in about 300 syndromes. Non-syndromic clefts are believed to be caused by a combination of genetic and environmental factors. Factors such as exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can have an influence on genetic susceptibility.
Diagnostic methods
The diagnosis is clinical.
Differential diagnosis
The presence  of associated malformations allows for differentiation between isolated and syndromic forms.
Antenatal diagnosis
Antenatal diagnosis is often made during prenatal ultrasound. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.
Management and treatment
Management requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary followed by secondary surgery (maxilla-facial and plastic). Speech therapy management involves guidance and rehabilitation from an early age as well as a pharyngoplasty before entering primary school, if necessary. In the presence of a hypomaxilly, due to an error in maxillary growth, an intermediate bone and/or orthognatic surgery on the maxillae is necessary. Treatment of an alveolar cleft most often requires a maxillary bone graft and, in the presence of permanent lateral incisor agenesis, a dental implant at the end of growth. ENT management involves the monitoring of sero-mucosal pathologies (otitis), hearing, phonation and breathing. Breathing difficulties can occur due to malformation of the nostril as well as deviation of the vomer and nasal septum and turbinate hypertrophy.
Prognosis
The prognosis depends on the quality of initial management and regular follow-up. Cleft palate can have functional, esthetic and psychological consequences that require management in a specialized health center.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ


A rare, congenital, non-syndromic heart malformation characterized by a slit-like hole or defect in one of the mitral valve leaflets, which is usually thickened and distorted. It usually affects the anterior leaflet, but the cleft of posterior leaflet has also been described. Cleft mitral valve can be isolated or associated with other congenital heart anomalies.


Cleft palate-congenital heart defect-intellectual disability syndrome due to 15q14 microdeletion

15q14 microdeletion syndrome is a recently described syndrome characterized by developmental delay, short stature and facial dysmorphism.

Summary:
Epidemiology
It has been described in 4 patients so far.
Clinical description
Dysmorphic features include bitemporal narrowing, smooth philtrum, pointed chin and dysmorphic ears. All reported patients had a cleft palate, whereas congenital heart defects or epilepsy are observed in patients with large deletions.
Etiology
Deletions are located within chromosome band 15q14, distal to the Prader-Willi/Angelman region. They were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size with the smallest deletion being 1.6 Mb in length.

                            Last update:
                            May 2011

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


Cleft palate-large ears-small head syndrome is a rare, genetic syndrome characterized by cleft palate, large protruding ears, microcephaly and short stature (prenatal onset). Other skeletal abnormalities (delayed bone age, distally tapering fingers, hypoplastic distal phalanges, proximally placed thumbs, fifth finger clinodactyly), Pierre Robin sequence, cystic renal dysplasia, proximal renal tubular acidosis, hypospadias, cerebral anomalies on imaging (enlargement of lateral ventricles, mild cortical atrophy), seizures, hypotonia and developmental delay are also observed.


Cleft palate-lateral synechia syndrome (CPLS) is a congenital malformation syndrome characterized by the association of cleft palate and intra-oral lateral synechiae connecting the free borders of the palate and the floor of the mouth. CPLS is presumed to be inherited in an autosomal dominant manner.

Summary:
Epidemiology
11 cases have been reported in the worldwide literature.
Clinical description
Patients present with cleft palate at birth and on examination are found to have multiple cord-like adhesions running from the free internal borders of the palate to the lateral parts of the tongue and floor of the mouth. Babies manifest symptoms of cleft palate such as disrupted sucking and swallowing, recurrent ear infections and speech impairment. Lateral synechiae may be asymptomatic or cause feeding difficulty due to restricted opening of mouth. In some cases the synechiae undergo spontaneous resolution.
Etiology
Etiology is unclear but interposition of the tongue between the palatal shelves in the embryo due to genetic, teratogenic or mechanical insults could result in a cleft palate while close contact between the floor of the mouth and the palate could predispose to the formation of intraoral synechiae. This can be either due to failed regression of buccopharyngeal membrane or formation of subglossopalatal membrane during the 7th week of embryonic life. Less than normal movement of the mandible and tongue is presumed to predispose to the formation of this subglossopalatal membrane.
Diagnostic methods
Diagnosis is clinical. When necessary, computed tomography can help to detect the presence of any bony fusion.
Differential diagnosis
Phenotypic features of CLPS can occur with other congenital anomalies, particularly the Van der Woude (VDW), orofaciodigital syndrome and popliteal pterygium syndrome (see these terms). In one reported family with CPLS, the monozygotic twin of the index case had classic phenotypic features of Fryns syndrome (see this term) suggesting that CPLS may represent a mild phenotypic expression of this syndrome.
Antenatal diagnosis
Prenatal diagnosis of cleft palate can be made by prenatal ultrasonogram.
Genetic counseling
An autosomal dominant inheritance pattern with variable expressivity has been proposed.
Management and treatment
Management includes excision of synechiae and palatal closure. Immediate excision of the synechiae may be necessary due to breathing or feeding problems; obtaining a safe airway for the release of the bands may be difficult. When immediate release of synechiae is not warranted, excision is done during palatal closure. The synechiae has been used to provide additional tissue for the surgical closure of soft palate.
Prognosis
The prognosis depends on the presence of associated anomalies (especially, congenital syngnathia (see this term)), quality of initial repair and regular follow-up.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Marie-Paule VAZQUEZ


Cleft palate-short stature-vertebral anomalies syndrome

A rare, genetic, multiple congenital anomalies syndrome characterized by the association of cleft palate, peculiar facies (asymmetrical appearance, inner epicanthal folds, short nose, anteverted nostrils, low and back-oriented ears, thin upper lip and micrognathism), short stature, short neck , vertebral anomalies and intellectual disability. There have been no further descriptions in the literature since 1993.


Cleft palate-stapes fixation-oligodontia syndrome

A rare congenital malformation syndrome characterized by cleft soft palate, severe oligodontia of the deciduous teeth, absence of the permanent dentition, bilateral conductive deafness due to fixation of the footplate of the stapes, short halluces with a wide space between the first and second toes, and fusion of carpal and tarsal bones. There have been no further descriptions in the literature since 1971.


A fissure type embryopathy that affects the soft and hard palate to varying degrees.

Summary:
Epidemiology
The annual incidence varies from 1/3,300 to 1/ 10,000 births. Cleft palate is more frequent in girls.
Clinical description
The cleft is median and connects the buccal cavity to the two nasal fossa and the naso-pharynx. The clinical forms range from a cleft velum (see this term) with a notch in the back of the hard palate to a complete cleft palate that extends to the incisive foramen. Submucous cleft palate is a specific form with muscle and bone dehiscence covered by oral and nasal mucosa. In these cases, diagnosis is more difficult but milk reflux occurs from birth and speech problems can occur. Cleft palate can disrupt sucking-swallowing in newborns to varying degrees. In the non-syndromic forms, normal feeding is possible. In the syndromic forms, there is a risk of food aspiration. Cleft velum disrupts the physiology of the Eustachian tube which can induce incomplete drainage of the middle ear with recurrent otitis and transmission hypoacousia. Dental alignment problems are due to an error in maxillary growth.
Etiology
This embryopathy appears in the 7th to 12th week of pregnancy following an error in fusion of the palatine process. Non-syndromic clefts are believed to be caused by a combination of genetic and environmental factors. Factors such as exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can influence genetic susceptibility.
Diagnostic methods
Diagnosis is clinical.
Differential diagnosis
The presence of associated malformations allows for differentiation between isolated and syndromic forms. Differential diagnoses include hereditary syndromic forms (in 20% of cases), such as Pierre-Robin, Stickler, van der Woude and velocardiofacial syndromes (see these terms).
Antenatal diagnosis
Antenatal diagnosis with an ultrasound is possible from the 2nd trimester onwards by looking for a mandibular retrognathism, an anomaly associated with abnormal amniotic fluid flow. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.
Management and treatment
Management requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary surgery sometimes followed by secondary surgery (maxillo-facial and plastic). An initial treatment timeline is established during the neonatal period. Secondary management is adapted to the child and based on morphological and functional problems that may arise during growth and development. Speech therapy management involves guidance and rehabilitation from an early age as well as a pharyngoplasty before entering primary school, if necessary. Orthodontic treatment manages dental alignment problems. In the presence of hypomaxilly caused by an error in maxillary growth, intermediate bone and/or orthognatic surgery on the maxillae is necessary. ENT management monitors seromucous (otitis), auditory and phonetic manifestations.
Prognosis
The prognosis depends on the quality of initial management and regular follow-up. Cleft palate can have functional consequences (morphological, phonetic, orthodontic, masticatory and auditory) that require management in a specialized health center. The syndromic forms, in particular a 22q11 deletion, have a poorer prognosis with more serious speech problems requiring complementary surgical treatment.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ


Cleft velum is a fissure type embryopathy that affects in varying degrees the soft palate.

Summary:
Epidemiology
The annual incidence varies from 1/3,300 to 1/10,000 births, depending on the geographic origin and ethnic group. It is more frequent in girls.
Clinical description
Cleft velum joins the buccal cavity and the nasopharynx or cavum. The clinical forms range from a partial cleft velum to a complete cleft velum extending to the posterior edge of the hard palate. A submucous cleft palate is a specific form with muscular and bony defects covered by the oral and nasal mucosa. In these cases, diagnosis is more difficult but milk reflux occurs from birth and speech problems can occur. Cleft velum can disrupt sucking-swallowing in newborns to varying degrees. In the non-syndromic forms, normal breastfeeding is possible. In syndromic forms, there is a risk of food aspiration (isolated or syndromic Pierre Robin sequence). Cleft velum can disrupt Eustachian tube physiology that can lead to incomplete drainage of the middle ear with recurrent infections (otitis) and transmission hypoacousia.
Etiology
This embryopathy appears between the 7th and 12th week of pregnancy following an error in fusion of the palatine process. Implicated causes include both genetic and environmental factors. Factors such as exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can have an influence on genetic susceptibility.
Diagnostic methods
Diagnosis is clinical.
Differential diagnosis
The presence of associated malformations allows for differentiation between isolated and syndromic forms. Differential diagnoses include syndromic hereditary forms of cleft velum (Pierre-Robin, Stickler, van der Woude and velocardiofacial syndromes;see these terms).
Antenatal diagnosis
Starting from the 2nd trimester, antenatal diagnosis with ultrasounds is possible by looking for a mandibular retrognathism, an anomaly associated with abnormal amniotic fluid flow. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.
Management and treatment
Management requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary surgery sometimes followed by secondary surgery (maxillo-facial and plastic). An initial treatment timeline is established during the neonatal period. Secondary management is adapted to the child and based on morphological and functional problems that may arise during growth and development. Speech therapy management involves guidance and rehabilitation from an early age as well as a pharyngoplasty before entering primary school, if necessary. ENT management monitors any seromucous (otitis), auditory or phonological manifestations.
Prognosis
The prognosis depends on the quality of initial management and the regular follow-up by an experienced multidisciplinary team. Cleft velum can have functional consequences (morphological, phonetic, and auditory) that require management in a specialized health center.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ


Cleidocranial dysplasia (CCD) is a rare genetic developmental abnormality of bone characterized by hypoplastic or aplastic clavicles, persistence of wide-open fontanels and sutures and multiple dental abnormalities.

Summary:
Epidemiology
The prevalence of CCD is 1/1,000,000, with higher rates in groups with a founder effect. The disorder is found in many ethnic groups and no sex predilection has been reported. It may be underdiagnosed because of the number of relatively mild cases.
Clinical description
There is an extremely wide range of clinical manifestations (even within the same family) from isolated dental anomalies to severe malformations with functional repercussions. The main clinical signs are hypoplasia or aplasia of the clavicles with narrow, sloping shoulders that can be approximated anteriorly, delayed fusion of cranial sutures with large, wide-open fontanels at birth that may persist throughout life, and a wide spectrum of dental anomalies including abnormal dentition, uniform or chaotic supernumerary teeth (hyperdontia) in the primary and secondary dentition resulting in crowding and malocclusion, retention of deciduous teeth, delayed eruption of secondary dentition and failure to shed the primary teeth. The dental manifestations may affect articulation and mastication. Other signs include broad flat forehead, hypertelorism, midface hypoplasia, and a pointed jaw giving a characteristic facial appearance as well as brachydactyly, tapering fingers and short, broad thumbs. Associated skeletal abnormalities include short stature, scoliosis, genu valgum, pes planus, a wide pubic symphysis, dysplastic scapulae, and coxa vara, generally with little clinical significance. Secondary complications include recurrent infections of the upper respiratory tract, sleep apnea, mild motor delay and variable degrees of hearing loss. Cognitive and intellectual functions are normal. The proportion of women with CCD requiring cesarean section is higher than in the general population due to cephalopelvic disproportion.
Etiology
CCD is caused by mutations in the RUNX2 gene (6p21) involved in differentiation of osteoblasts and bone formation. A wide range of mutations have been identified, with high penetrance and significant variability. No clear phenotype-genotype correlations have been established.
Diagnostic methods
Diagnosis is based on clinical signs and on characteristic radiographic findings (wide-open sutures, patent fontanels, cone-shaped thorax with narrow upper thoracic diameter, hand deformities, abnormal dentition). Molecular genetic testing can be used to confirm the diagnosis in patients with atypical clinical and radiological diagnostic features.
Differential diagnosis
Differential diagnoses include mandibuloacral dysplasia, Crane-Heise syndrome, Yunis-Varon syndrome, pycnodysostosis, CDAGS syndrome, and hypophosphatasia.
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is possible and requires identification of the disease-causing genetic mutation in the family.
Genetic counseling
Cleidocranial dysplasia follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to affected families. The number of cases related to de novo mutations appears to be high.
Management and treatment
Management of dental anomalies is very important with the aim of achieving optimal function and esthetics. Options include removal of retained deciduous, supernumerary and abnormal permanent teeth. Dental surgery should be considered for unerupted teeth and orthodontics for malocclusion. Speech therapy may be required. Antibiotics are recommended for recurrent infections. Because of the role of RUNX2 in bone maintenance and ossification, bone mineral density should be monitored and preventive treatment for osteoporosis considered.
Prognosis
The malformations and complications of CCD rarely cause significant disability. The prognosis is generally good.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Roberto MENDOZA-LONDONO


Cleidorhizomelic syndrome is a rhizo-mesomelic dysplasia characterized by rhizomelic short stature/dwarfism in combination with lateral clavicular defects. Additional manifestations include brachydactyly with bilateral clinodactyly and hypoplastic middle phalanx of the fifth digit. X-ray demonstrated an apparent Y-shaped or bifid distal clavicle. Cleidorhizomelic syndrome has been reported in one family (mother and son) and is suspected to be transmitted in an autosomal dominant manner. There have been no further descriptions in the literature since 1988.


A rare superficial corneal dystrophy characterized by progressive opacity of the most anterior corneal layers. Slit-lamp examination reveals typical confluent translucent subepithelial deposits, extending in size and growing into clusters of golden droplets covering the cornea with disease progression. Patients present variably compromised visual acuity, depending on the stage of the disease. In advanced stages, decreased corneal sensation may lead to corneal trophic changes, perforation, and permanent visual loss.


CLIPPERS is a rare neuroinflammatory disorder characterized by brainstem-predominant encephalomyelitis which typically presents with cerebellar and cranial nerve manifestations (gait ataxia, dysarthria, visual disorders, parasthesias), as well as brainstem, myelopathy and cognitive findings, that respond to steroid treatment. Punctate curvilinear post-gadolinium contrast enhancement predominantly in the pons and cerebellum is observed on brain MRI and prominent, perivascular, CD3+ T-cell predominantly lymphocytic inflammation in neuropathology.


A rare neuronal ceroid lipofiscinosis disorder characterized by juvenile-onset of progressive spinocerebellar ataxia, bulbar syndrome (manifesting with dysarthria, dysphagia and dysphonia), pyramidal and extrapyramidal involvement (including myoclonus, amyotrophy, unsteady gait, akinesia, rigidity, dysarthric speech) and intellectual deterioration. Muscle biopsy displays autofluorescent bodies and lipofuscin deposits in brain and, occasionally the retina, upon post mortem.


A major birth defect representing the severe end of the spectrum of the exstrophy-epispadias complex (EEC) characterized by omphalocele, exstrophy, imperforate anus and spinal defects (also referred to as the OEIS complex), often associated with other malformations.

Summary:
Epidemiology
Prevalence at birth for EEC is reported at 1/10,000. Epispadias (E), classic bladder exstrophy (CEB) and EC are recognized clinical variants of the same spectrum, so accurate epidemiological data on E/EC/CEB are no longer available. The male-to-female ratio varies between studies; male or female predominance and a sex ratio close to unity have been described.
Clinical description
Patients present at birth with two exstrophied hemibladders separated by a foreshortened hindgut (often blind-ending resulting in an imperforate anus) or cecum. Omphalocele is found in 88-100% of patients and gastrointestinal (GI) malrotation/duplication and short bowel syndrome (see this term) are present in 46%, with absorptive dysfunction in some cases. The symphysis pubis is widely separated and the pelvis is often asymmetrically shaped. The genitalia, e.g. the penile or clitoral halves, can be located separately on either side of the bladder plates with the adjacent scrotal or labial part. Duplication of the vagina and uterus, as well as vaginal agenesis, has also been reported. Various urological malformations (ureteropelvic junction obstruction, ectopic pelvic kidney, horseshoe kidney, renal hypo- or agenesis, megaureter, ureteral ectopy and ureterocele) may also be present. Spinal abnormalities ranging from hemivertebra to myelomeningocele occur in all patients and may be accompanied by skeletal and limb anomalies (clubfoot deformities, absence of feet, tibial/fibular deformities, and hip dislocation).
Etiology
EC results from an anomaly during early embryologic development associated with rupture of the cloacal membrane before fusion with the urorectal septum. The underlying cause remains unknown: genetic and environmental factors are likely to play a role.
Diagnostic methods
Diagnosis is evident at birth but spinal ultrasound and radiographs, MRI and urogenital ultrasound are recommended to determine the nature and extent of the malformations, with laboratory tests to detect electrolyte losses from the terminal ileum.
Antenatal diagnosis
Prenatal diagnosis is possible from ultrasound findings (non-visualization of the bladder, anterior wall defects, omphalocele and myelomeningocele are major criteria). Prenatal diagnosis should lead to parental counseling to provide information on the nature of the malformation and the extent of surgical reconstruction required. However, termination of pregnancy should not be automatically indicated.
Management and treatment
Patients require immediate postnatal multidisciplinary care followed by surgical management, usually beginning in the newborn period with immediate closure of the meningocele and omphalocele as well as adaptation of bladder halves. Later, a multistage approach for bladder and bowel reconstruction is used, including a mandatory osteotomy due to severe pelvic asymmetry and the large ventral defect. The main aims of management are secure abdominal wall closure, prevention of short bowel syndrome, urinary and fecal continence, preserved renal function, and adequate cosmetic and functional genital reconstruction. Multiple associated anomalies have to be considered to achieve successful reconstruction.
Prognosis
Surgical advances and improved neonatal care have led to a dramatic increase in survival rates and improvements in continence rates and therefore quality of life. However, patients require life-long follow up, including psychosocial and psychosexual aspects, from a multidisciplinary team of experts.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Pr Anne-Karoline EBERT  - Dr Michaël LUDWIG  - Pr Heiko REUTTER  - Pr Wolfgang RÖSCH


Cloverleaf skull-asphyxiating thoracic dysplasia syndrome

A rare syndromic craniosynostosis characterized by prenatal presentation with cloverleaf skull, micromelia and asphyxiating thoracic dysplasia. Radiologic features include short ribs, horizontal roof of the acetabulum with a rounded median prominence and lateral spurs, deformed long bones with broad metaphyses, and absent ossification of the terminal phalanges. There have been no further descriptions in the literature since 1987.


Cloverleaf skull-multiple congenital anomalies syndrome

This newly described syndrome is characterized by cloverleaf skull, limb anomalies, facial dysmorphism and multiple congenital anomalies.

Summary:
Epidemiology
It has been described in three sibs from one family.
Clinical description
Dysmorphic features include protruding forehead, hypertelorism, broad nasal bridge, wide anterior fontanel, short philtrum, downturning mouth, micrognathia and low-set ears. The limbs show rhizomelic shortening. Additional malformations are not constant: omphalocele, bilateral microphthalmia, cataract, narrow chest, ambiguous genitalia, cardiac ventricular septal defect and agenesis of the corpus callosum
Antenatal diagnosis
Antenatal diagnosis is possible by ultrasonographic monitoring.
Genetic counseling
The condition seems to be inherited as an autosomal recessive trait.
Prognosis
Prognosis is poor.

                            Last update:
                            November 2010


A rare developmental defect during embryogenesis characterized by congenital lipomatous overgrowth, complex and progressive combined vascular malformations affecting the trunk, and epidermal nevi.

Summary:
Epidemiology
The prevalence of CLOVES syndrome is unknown and there is no sex predominance. CLOVES syndrome is the most common overgrowth syndrome associated with a PIK3CA variant, also known as PROS (for PIK3CA-related overgrowth spectrum), affecting over 500 patients in France.
Clinical description
CLOVES syndrome is defined by its acronym (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies). In most cases, hypertrophy, often asymmetrical, is present at birth. The postnatal progression of lesions is usually moderate, but some patients may present hypertrophy with a more severe course. Hypertrophies can affect different parts of the body, more or less extensive, and involve fatty, muscular, nervous and/or skeletal tissues. Associated vascular anomalies (capillary, venous and/or lymphatic) are present in almost half of patients, and epidermal hamartomas are less frequent. Extremity anomalies (syndactyly, polydactyly) are sometimes observed.
Etiology
The syndrome is due to a heterozygous mosaic variation - also known as postzygotic - in the PIK3CA gene, occurring in early embryogenesis. The PIK3CA gene encodes the catalytic alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase protein.
Diagnostic methods
Diagnosis must be confirmed by identification of a mosaic PIK3CA variation on affected tissue without culture, using high-depth high-throughput sequencing. Samples are usually taken by skin biopsy.
Differential diagnosis
The differential diagnosis includes: 1) other PROS syndromes (Klippel-Trenaunay syndrome, megalencephaly-capillary malformation-polymicrogyria syndrome), 2) Proteus syndrome, which is due to a mosaic variation in the AKT1 gene, and is characterized by the absence of congenital manifestations, the onset of a pathognomonic cerebriform hamartoma, and a rapidly progressive natural course, 3) PTEN-related overgrowth disorders.
Antenatal diagnosis
The diagnosis may be suspected during pregnancy in the presence of segmental tissue hypertrophy, possibly associated with abnormalities of the extremities. A negative amniocentesis does not exclude the diagnosis.
Genetic counseling
The risk for siblings of a proband with a PIK3CA mosaic variant is the same as in the general population if the parents are not variant carriers. Therefore, prenatal diagnosis is not particularly recommended.
Management and treatment
Because of the multisystemic involvement, patient management requires multi-disciplinary care by expert teams, with at least one annual physical examination, and further investigations may be needed based on clinical presentation. Screening for Wilms tumor (nephroblastoma) is not needed when the risk is less than 5 %. Therapeutic management of CLOVES syndrome consists of preventing and treating complications: medical management of inflammatory or painful inflammatory flare-ups, thrombo-embolic complications, superficial or non-disabling vascular malformations, correction of lower limb length discrepancy, and of a possibly associated scoliosis. Alpelisb, a specific inhibitor of the PI3K-mTOR pathway, is proposed in therapeutic trials or on a compassionate basis, according to a therapeutic protocol. This treatment improves quality of life, reduces hypertrophy and vascular symptoms, and avoids the need for surgery.
Prognosis
The clinical presentation of the disease can be extremely variable, depending on the type of tissue affected by the variation and its extent. Treatment with alpelisib changes the prognosis of the disease for most of the patients.

                            Last update:
                            January 2024

                            - Expert reviewer(s):
                            Pr Laurent GUIBAUD | ERN CRANIO* - Pr Laurence OLIVIER-FAIVRE | ITHACA*

                                * European Reference Network


A rare, genetic, syndromic neurodevelopmental disorder characterized by moderate to mostly severe intellectual disability, speech impairment with normal or mildly delayed motor development and early-onset seizures often accompanied by developmental regression. Autistic behavior and stereotypic movements are common.

Summary:
Epidemiology
CNTNAP2-related developmental and epileptic encephalopathy is a very rare disease and to date, 28 affected individuals from 15 families are reported in literature worldwide.
Clinical description
In all affected individuals, moderate to usually severe intellectual disability with speech impairment and seizures is present. Initial motor and cognitive development may be unaffected or only mildly delayed in few cases. Onset of seizures is usually during infancy or early childhood, typically within the first 3.5 years of life. With seizure onset, developmental regression with loss of verbal skills frequently occurs. Subsequently, speech is absent or very limited with only few words in most of the affected individuals. Ataxic gait, muscular hypo- or hypertonia or hyporeflexia can occur. Moreover, behavioral abnormalities such as stereotypic hand movements, teeth grinding, reduced eye contact, self-harm or aggressivity and autistic features are common. Further clinical aspects may include paroxysmal hyperventilation or breathing abnormalities or, rarely, a large head circumference. Focal cortical dysplasia, cerebellar hypoplasia or vermian atrophy may be detected in cerebral magnetic resonance imaging (MRI), but cerebral MRI might also be normal. Minor, but non-specific facial dysmorphism might be noted in few of the affected individuals.
Etiology
The disorder is caused by bi-allelic intragenic deletions (rarely duplications) or truncating variants in the CNTNAP2 gene (7q35-q36.1). It encodes contactin-associated protein 2 (CASPR2), a transmembrane protein from the neurexin superfamily, which is involved in neural-glia interactions and clustering of potassium channels in myelinated axons.
Diagnostic methods
Diagnosis might be achieved by targeted testing upon clinical suspicion, but in most cases, it is made by untargeted approaches such as chromosomal microarray analysis and/or multigene panel or exome sequencing.
Differential diagnosis
The differential diagnosis includes other developmental and epileptic encephalopathies, such as MEF2C-related neurodevelopmental disorder (5q14.3 microdeletion syndrome), Pitt Hopkins syndrome, Angelman syndrome, Rett syndrome or NRXN1-associated autosomal recessive neurodevelopmental disorder.
Antenatal diagnosis
Prenatal diagnosis and preimplantation-diagnostics are possible where the pathogenic variant(s) has/have been identified in a family member and/or where carrier status in the parents has been confirmed.
Genetic counseling
Inheritance is autosomal recessive. For parents who are both carriers of the variant there is a 25% recurrence risk for each pregnancy. Heterozygous carriers of deletions/variants in CNTNAP2 may have an increased risk for variable neuropsychiatric abnormalities.
Management and treatment
Management of seizures is required. Ongoing developmental assessments are recommended to tailor educational services to individual needs, e.g. physical, occupational, speech therapies and behavioral management strategies.
Prognosis
There are affected individuals living in their fourth decade. Moderate to severe cognitive impairment is present with dependence on others for help in daily living.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Dr Katalin HETZELT | ITHACA* - Pr André REIS | ITHACA* - Pr Christiane ZWEIER

                                * European Reference Network


COASY protein-associated neurodegeneration (CoPAN) is a very rare, slowly progressive form of neurodegeneration with brain iron accumulation (NBIA) characterized by classic NBIA features. The clinical manifestations include early-onset spastic-dystonic paraparesis, oromandibular dystonia, dysarthria, parkinsonism, axonal neuropathy, progressive cognitive impairment, complex motor tics, and obsessive-compulsive disorder.


Coats disease (CD) is an idiopathic disorder characterized by retinal telangiectasia with deposition of intraretinal or subretinal exudates, potentially leading to retinal detachment and unilateral blindness. CD is classically an isolated and unilateral condition affecting otherwise healthy young children.

Summary:
Epidemiology
Annual incidence is <1/1,000,000 in the UK, approximately 80% of cases occur in males.
Clinical description
CD onset predominantly occurs in male children between 6 and 8 years old. Early stages of the disease are generally asymptomatic and evolution is variable. As children with unilateral vision loss usually do not complain of symptoms, the diagnosis is often based on an abnormal appearance of the pupillary reflex that can best be seen in photos or on red reflex testing. Other common presentations include the onset of strabismus or failure of a school vision screening examination. Ophthalmoscopy reveals unilateral retinal telangiectasia and aneurysms of the retinal vasculature. This is followed by exudation of fluids producing yellow subretinal deposits. The most advanced stages of CD include total retinal detachment, leukocoria and painful glaucoma secondary to angle closure.
Etiology
An abnormal permeability of capillary endothelial cells in the retina, along with abnormal pericytes, causes the retinal vascular leakage that is the hallmark of CD. CD is not heritable, however, somatic mutations in the Norrie Disease Pseudoglioma, NDP, gene have been hypothesized to play a role in the pathogenesis of CD.
Diagnostic methods
Diagnostic methods include indirect ophthalmoscopy, fluorescein angiography, ultrasonography, computerized tomography scanning and magnetic resonance imaging.
Differential diagnosis
Retinoblastoma (see this term) is the most important differential diagnosis. B-scan ultrasound and MRI with gadolinium contrast aid in distinguishing between late stage CD and solid tumors. Others include familial exudative vitreoretinopathy, Von Hippel-Lindau disease, intermediate uveitis and incontinentia pigmenti which are more often bilateral, as well as the more typically unilateral conditions such as ocular toxocariasis and persistent hyperplastic primary vitreous (see these terms).
Management and treatment
Treatment depends on severity of disease. Mild peripheral vascular abnormalities may be followed with serial fundus photography. When exudation is present, ablation of incompetent vessels and avascular retina should be performed using laser or less often, cryotherapy. More advanced cases can require surgical intervention for retinal reattachment, such as scleral buckling, or laser photocoagulation combined with pars plana vitrectomy and removal of the vitreous membrane. Intravitreal corticosteroid as well as anti-VEGF agents have been used as adjuvant therapies.
Prognosis
The majority of cases stabilize with proper therapy, although exudation and macular scarring commonly compromise vision. A retrospective study showed that 16% of patients had a final visual acuity of 20/50 or better and 47% had hand motions to no light perception in the affected eye. Approximately 20% of eyes may require enucleation.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Dr Baker HUBBARD  - Dr Philip LAIRD


Coats plus syndrome is a pleiotropic multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is transmitted as an autosomal recessive disease.


Cobblestone lissencephaly without muscular or ocular involvement

A rare, genetic, cobblestone lissencephaly disease characterized by the presence of a constellation of brain malformations, including cortical gyral and sulcus anomalies, white matter signal abnormalities, cerebellar dysplasia and brainstem hypoplasia, existing alone or in conjunction with minimal muscular and ocular abnormalities, typically manifesting with severe developmental delay, increased head circumference, hydrocephalus and seizures.


A rare central nervous system malformation which includes a group of diseases that are characterized by a bumpy (or pebbled) appearance of the cerebral cortex, associated with a thickened cortex, reduction in normal sulcation, ventriculomegaly and reduced, abnormal white matter, as well as brainstem and cerebellum hypoplasia and corpus callosum agenesis. Patients generally present variable degrees of developmental delay, hypotonia and ocular abnomalities, however muscular and ocular involvement may be absent.


Cocaine embryofetopathy is a group of clinical signs observed in newborns exposed in utero to cocaine, a short-acting central nervous system stimulant used as a recreational drug through inhalation of the powder or intravenous injection. Cocaine use during pregnancy is associated with intrauterine growth restriction, low birth weight, seizures, respiratory distress (decreased apnea density and periodic breathing), feeding difficulties, irritability and lability of state, decreased behavioral and autonomic regulation, poor alertness and orientation and cognitive impairment (impaired auditory information processing , visual-spatial delay and subtle language delay) in the offspring.


A rare disorder due to poisoning characterized by variable combination and dose-dependent severity of clinical manifestations, affecting behavior, central nervous and cardiovascular system. Patients present with euphoria, irritability, agitation, psychosis, hallucinations, paranoia, seizures, decreased responsiveness, mydriasis, tachyarrhythmia, chest pain, and cardiovascular collapse. Sometimes also dyspnea, hypertension, hyperthermia, hypothermia, lack of sleep and serotonin syndrome are present. Severe intoxication may lead to coma and death.


Coccidioidomycosis is a fungal infection caused by Coccidioides immitis and C. posadasii, which is endemic to the Southwestern United States, Central America, South America and Mexico, and is acquired by inhalation of the infective arthroconidia, often found in soil. In most cases it is a benign, self-limiting febrile illness, but in a minority of cases it can become a potentially lethal infection of the lungs and, extremely rarely, spread to other organs (through hematogenous dissemination) with manifestations including meningitis, osteomyelitis, and skin and soft-tissue involvement.


A rare otorhinolaryngological malformation characterized by a hypoplastic or absent cochlear nerve, resulting in variable hearing loss or total deafness, depending on the quantity of nerve fibers present. The condition can be unilateral or bilateral, occur as an isolated malformation or in the context of a complex syndrome, and may be associated with a hypoplastic internal auditory or cochlear nerve canal.


Cochleosaccular degeneration-cataract syndrome is characterised by progressive sensorineural hearing loss due to severe cochleosaccular degeneration and cataract. So far, it has been reported in two families. Transmission is autosomal dominant.


Cockayne syndrome (CS) is a multisystem condition characterized by short stature, a characteristic facial appearance, premature aging, photosensitivity, progressive neurological dysfunction, and intellectual deficit.

Summary:
Epidemiology
The annual incidence of CS is close to 1/200,000 in European countries.
Clinical description
Disease severity and the age of onset are variable. In classical type I CS, the first symptoms usually appear during the first year of life. Early-onset cases with more severe symptoms (type II) and late-onset cases with milder symptoms (type III) have also been described. Common signs of the disease include progressive growth failure, intellectual deficit, cerebellar ataxia, spasticity, peripheral demyelinating neuropathy, pigmentary retinopathy, sensorineural hearing loss and dental anomalies (presence of caries). The typical facial appearance includes microcephaly, large ears, a thin nose, and enophthalmia. Cataracts and cutaneous photosensitivity are observed in some patients. Subcutaneous lipoatrophy is present and can lead to signs of premature aging of the skin. COFS syndrome (see this term) is the extreme prenatal form of the CS clinical spectrum characterized by congenital microphthalmia and arthrogryposis.
Etiology
CS belongs to the family of NER (nucleotide excision repair)-related disorders together with xeroderma pigmentosum and trichothiodystrophy (see these terms). CS cells show a specific defect in transcription-coupled DNA repair (TCR), a subpathway of NER involved in the removal of UV-induced DNA lesions in actively transcribed genes. Additional defects in basal transcription or in oxidative repair have also been put forward to account for the noncutaneous symptoms of CS. Mutations have been described in two major genes, ERCC6 (CSB; 10q11) and ERCC8 (CSA; 5q12.1). So far, no correlation was found between the three types of CS and the genes involved.
Diagnostic methods
Diagnosis is based on detection of the specific TCR defect that can be identified using a radioactive assay in cultured fibroblasts that measures the recovery of RNA synthesis after UV irradiation. This DNA repair test is a decisive tool for the diagnosis of CS. Brain imaging reveals diffuse hypomyelination of the cerebral white matter, calcifications in the putamen, and vermian atrophy.
Differential diagnosis
The differential diagnosis mainly includes mitochondrial diseases that may show similar clinical features to those seen in CS.
Antenatal diagnosis
Prenatal diagnosis can be performed on amniocytes or chorionic cells (using the same cellular test as that employed in fibroblasts) or by direct molecular sequencing if the causative mutations in the family have already been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management is purely supportive and includes physiotherapy, sun protection, hearing aids and often tube feeding or gastrostomy.
Prognosis
In CS type I, death occurs before the end of the second decade as a result of progressive neurologic degeneration. Patients with type II present with a more severe prognosis, whereas patients with type III live into adulthood.

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                            Pr Hélène DOLLFUS  - Pr Vincent LAUGEL


Codas syndrome is a multiple congenital anomalies syndrome characterized by Cerebral, Ocular, Dental, Auricular and Skeletal anomalies.

Summary:
Epidemiology
To date, three affected children (an unrelated Canadian girl and boy of Mennonite descent, and a girl from Brazil) have been reported.
Clinical description
Characteristic features consist of psychomotor delay, cataracts, abnormally shaped teeth (including enamel projections extending from the tips of the cusps), delayed tooth eruption, malformed ears (overfolded and crumpled ears), sensorineural hearing loss, short stature with marked epiphyseal dysplasia, and an unusual facial phenotype characterized mainly by ptosis, epicanthal folds and a grooved nose.
Etiology
Etiology remains unknown but some of the features suggest involvement of a collagen gene defect.
Diagnostic methods
X-rays show delayed ossification, delayed bone age and spine and pelvic anomalies.
Differential diagnosis
The differential diagnosis should include chondrodysplasia punctata (the rhizomelic, Conradi-Hunermann, and X-linked dominant types) and Kabuki syndrome (see these terms).
Genetic counseling
The occurrence of two affected children within the Manitoba Mennonite community (a genetic isolate) suggests autosomal recessive inheritance, but other modes of transmission could not be excluded. Familial recurrence has not been documented.
Management and treatment
Management requires a multidisciplinary approach by specialists in neurology, ophthalmology, otorhinolaryngology, odontology, orthopedics and genetics.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Pr Alain VERLOES